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1300

Outbreak of Diarrhoeal illness in participants in an obstacle adventure race, Alpes-Maritimes, France, June 2015

At the end of July 2006, an unusually high number of patients with acute diarrhoea were reported by the accident and emergency departments in Taranto, Apulia. Subsequently, a field investigation was conducted jointly by the Apulia Regional Epidemiological Observatory and the Regional Reference Laboratory in Bari, and the Epidemiological Department of Taranto Local Health Unit. Field investigation: The outbreak investigation carried out between July and October 2006, involving hospitals in the whole province of Taranto, included the following main elements: Case ascertainment and descriptive epidemiology. A case was defined as a patient with diarrhoea (at least three loose or liquid stools in a day) and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea [1,2]. Five out of six hospitals in the province of Taranto provided information on patients with acute gastroenteritis. Data were collected retrospectively for the period between May and July and prospectively for August and September 2006. In addition, the special medical facilities set up for tourists in the summer season (June-August) in the province of Taranto were also asked to report cases. Microbiological investigation of stool samples of hospitalised patients. Microbiological investigation of environmental samples (including tap water, sea water and shellfish) [1-4]. Case control study performed between 1 August and 15 September 2006 in order to identify the possible sources of infection. Outbreak description From 1 May to 30 September 2006, a total of 2,860 patients with gastroenteritis symptoms were either admitted to hospital or seen by the hospitals’ outpatient accident and emergency units. This significantly exceeded the number reported in the same period in 2005, when a total of 586 patients with gastroenteritis were treated by the same hospitals. The epidemic curve is shown in Figure 1. Figure 1. Number of patients with gastroenteritis seeking hospital care, by week. Taranto province, 1 May-30 September, 2005 and 2006 The first peak in incidence was observed at the end of June (26 week of the year), followed by a second peak at the end of July (weeks 29 and 30). The number of patients with gastroenteritis seeking hospital care decreased in the following weeks. By mid-September, the number of cases per week was similar to that seen in the same period of 2005. Patients mean age was 25 years; 19% of the cases were under 5 years of age, 16% were 5 to 15 years old, and 65% were above 15 years of age. Incubation time was not calculated because it was not possible to determine the exact time of exposure. Incidence by town of residence was highest in the city of Taranto (9.5 cases per 1,000 inhabitants) (Figure 2). Figure 2. Number of patients with gastroenteritis seeking hospital care, by town of residency per 1,000 inhabitants. Taranto province, 1 May-30 September 2006 Data collected by the tourist medical facilities in Taranto province showed a total of 361 cases of acute gastroenteritis, significantly more than a year before. Hence the same trend was observed as in the case of hospital data. Microbiological analysis: A total of 70 stool samples from patients affected by the outbreak were collected and analysed. Results by age group are reported in Table 1. Table 1. Stool samples collected from patients and tested by the Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 (°) Nested PCR in VP7 region (*) Nested PCR in the polymerase gene Stool samples were also examined with respect to gastrointestinal bacteria and parasites. No samples examined were positive for the entire range of pathogens tested. Further genotyping of the samples is currently being done. Environmental samples, systematically collected for microbiological analyses, were tap water from the water distribution system across the whole area affected by the outbreak, sea water and shellfish. The water samples were collected at the local waterworks, from major water pipelines and wells, and from tap water in pubs. No faecal indicator bacteria and endotoxins were detected in the environmental samples of tap water collected in Taranto city. Of 44 samples tested, four (9%) were positive for norovirus and 11 (25%) for rotavirus (Table 2). The tests were performed using molecular techniques. Table 2. Drinkable tap water samples collected and tested – Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 Molecular profiles of rotavirus and norovirus identified in some tap water samples were the same as the ones found in some patients’ stool samples. Sequence analysis showed the new norovirus strain GGII.4 2006a and rotavirus genotype G9. The laboratory investigations, however, are still ongoing and more results are expected in the future. Of 12 sea water samples tested, four (33%) were positive for norovirus and one (8,3%) for rotavirus. No shell fish samples were positive for bacteria or viruses. Case control study: A case control study was performed in order to find an association between the occurrence of gastroenteritis and the exposure to one or more risk factors. A case was defined as a patient with at least 3 loose or liquid stools in a day and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea. 166 cases were selected among patients treated at the accident and emergency departments of the hospitals in Taranto province, in the period between 1 August and 15 September 2006. The control group consisted of 146 non-hospitalised healthy individuals who during the study period were resident in the same area as the case patients. Cases and controls were age-matched. A standard questionnaire was used for the interview. Risk factors which were shown to be significantly associated with the onset of acute diarrhoea/gastroenteritis were the use of tap water (OR= 2; 95% CI: 1,23-3,36), and the use of water of uncertain origin in the 72 hours before the onset of the symptoms (OR= 3,9; 95% CI: 1,41-10,54). Conclusion and control measures: The epidemiological investigation and the laboratory tests showed that the possible source of infection was the drinkable tap water contaminated with (at least) rota- and noroviruses. An extra chlorination treatment for household water supplies was therefore performed starting from the 34th week of the year in order to stop a possible contamination of the water. Systematic technical and microbiological investigations of the pipelines and wells of the water distribution system did not reveal the source of contamination even though technical problems at the local chlorination treatment facilities could not have been excluded. To date, the outbreak of viral gastroenteritis described in this paper is probably the largest one associated with drinking tap water in Italy.

What was done to fix the problem?

1301

Outbreak of Diarrhoeal illness in participants in an obstacle adventure race, Alpes-Maritimes, France, June 2015

At the end of July 2006, an unusually high number of patients with acute diarrhoea were reported by the accident and emergency departments in Taranto, Apulia. Subsequently, a field investigation was conducted jointly by the Apulia Regional Epidemiological Observatory and the Regional Reference Laboratory in Bari, and the Epidemiological Department of Taranto Local Health Unit. Field investigation: The outbreak investigation carried out between July and October 2006, involving hospitals in the whole province of Taranto, included the following main elements: Case ascertainment and descriptive epidemiology. A case was defined as a patient with diarrhoea (at least three loose or liquid stools in a day) and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea [1,2]. Five out of six hospitals in the province of Taranto provided information on patients with acute gastroenteritis. Data were collected retrospectively for the period between May and July and prospectively for August and September 2006. In addition, the special medical facilities set up for tourists in the summer season (June-August) in the province of Taranto were also asked to report cases. Microbiological investigation of stool samples of hospitalised patients. Microbiological investigation of environmental samples (including tap water, sea water and shellfish) [1-4]. Case control study performed between 1 August and 15 September 2006 in order to identify the possible sources of infection. Outbreak description From 1 May to 30 September 2006, a total of 2,860 patients with gastroenteritis symptoms were either admitted to hospital or seen by the hospitals’ outpatient accident and emergency units. This significantly exceeded the number reported in the same period in 2005, when a total of 586 patients with gastroenteritis were treated by the same hospitals. The epidemic curve is shown in Figure 1. Figure 1. Number of patients with gastroenteritis seeking hospital care, by week. Taranto province, 1 May-30 September, 2005 and 2006 The first peak in incidence was observed at the end of June (26 week of the year), followed by a second peak at the end of July (weeks 29 and 30). The number of patients with gastroenteritis seeking hospital care decreased in the following weeks. By mid-September, the number of cases per week was similar to that seen in the same period of 2005. Patients mean age was 25 years; 19% of the cases were under 5 years of age, 16% were 5 to 15 years old, and 65% were above 15 years of age. Incubation time was not calculated because it was not possible to determine the exact time of exposure. Incidence by town of residence was highest in the city of Taranto (9.5 cases per 1,000 inhabitants) (Figure 2). Figure 2. Number of patients with gastroenteritis seeking hospital care, by town of residency per 1,000 inhabitants. Taranto province, 1 May-30 September 2006 Data collected by the tourist medical facilities in Taranto province showed a total of 361 cases of acute gastroenteritis, significantly more than a year before. Hence the same trend was observed as in the case of hospital data. Microbiological analysis: A total of 70 stool samples from patients affected by the outbreak were collected and analysed. Results by age group are reported in Table 1. Table 1. Stool samples collected from patients and tested by the Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 (°) Nested PCR in VP7 region (*) Nested PCR in the polymerase gene Stool samples were also examined with respect to gastrointestinal bacteria and parasites. No samples examined were positive for the entire range of pathogens tested. Further genotyping of the samples is currently being done. Environmental samples, systematically collected for microbiological analyses, were tap water from the water distribution system across the whole area affected by the outbreak, sea water and shellfish. The water samples were collected at the local waterworks, from major water pipelines and wells, and from tap water in pubs. No faecal indicator bacteria and endotoxins were detected in the environmental samples of tap water collected in Taranto city. Of 44 samples tested, four (9%) were positive for norovirus and 11 (25%) for rotavirus (Table 2). The tests were performed using molecular techniques. Table 2. Drinkable tap water samples collected and tested – Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 Molecular profiles of rotavirus and norovirus identified in some tap water samples were the same as the ones found in some patients’ stool samples. Sequence analysis showed the new norovirus strain GGII.4 2006a and rotavirus genotype G9. The laboratory investigations, however, are still ongoing and more results are expected in the future. Of 12 sea water samples tested, four (33%) were positive for norovirus and one (8,3%) for rotavirus. No shell fish samples were positive for bacteria or viruses. Case control study: A case control study was performed in order to find an association between the occurrence of gastroenteritis and the exposure to one or more risk factors. A case was defined as a patient with at least 3 loose or liquid stools in a day and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea. 166 cases were selected among patients treated at the accident and emergency departments of the hospitals in Taranto province, in the period between 1 August and 15 September 2006. The control group consisted of 146 non-hospitalised healthy individuals who during the study period were resident in the same area as the case patients. Cases and controls were age-matched. A standard questionnaire was used for the interview. Risk factors which were shown to be significantly associated with the onset of acute diarrhoea/gastroenteritis were the use of tap water (OR= 2; 95% CI: 1,23-3,36), and the use of water of uncertain origin in the 72 hours before the onset of the symptoms (OR= 3,9; 95% CI: 1,41-10,54). Conclusion and control measures: The epidemiological investigation and the laboratory tests showed that the possible source of infection was the drinkable tap water contaminated with (at least) rota- and noroviruses. An extra chlorination treatment for household water supplies was therefore performed starting from the 34th week of the year in order to stop a possible contamination of the water. Systematic technical and microbiological investigations of the pipelines and wells of the water distribution system did not reveal the source of contamination even though technical problems at the local chlorination treatment facilities could not have been excluded. To date, the outbreak of viral gastroenteritis described in this paper is probably the largest one associated with drinking tap water in Italy.

What could have been done to prevent the event?

1302

Outbreak of Diarrhoeal illness in participants in an obstacle adventure race, Alpes-Maritimes, France, June 2015

At the end of July 2006, an unusually high number of patients with acute diarrhoea were reported by the accident and emergency departments in Taranto, Apulia. Subsequently, a field investigation was conducted jointly by the Apulia Regional Epidemiological Observatory and the Regional Reference Laboratory in Bari, and the Epidemiological Department of Taranto Local Health Unit. Field investigation: The outbreak investigation carried out between July and October 2006, involving hospitals in the whole province of Taranto, included the following main elements: Case ascertainment and descriptive epidemiology. A case was defined as a patient with diarrhoea (at least three loose or liquid stools in a day) and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea [1,2]. Five out of six hospitals in the province of Taranto provided information on patients with acute gastroenteritis. Data were collected retrospectively for the period between May and July and prospectively for August and September 2006. In addition, the special medical facilities set up for tourists in the summer season (June-August) in the province of Taranto were also asked to report cases. Microbiological investigation of stool samples of hospitalised patients. Microbiological investigation of environmental samples (including tap water, sea water and shellfish) [1-4]. Case control study performed between 1 August and 15 September 2006 in order to identify the possible sources of infection. Outbreak description From 1 May to 30 September 2006, a total of 2,860 patients with gastroenteritis symptoms were either admitted to hospital or seen by the hospitals’ outpatient accident and emergency units. This significantly exceeded the number reported in the same period in 2005, when a total of 586 patients with gastroenteritis were treated by the same hospitals. The epidemic curve is shown in Figure 1. Figure 1. Number of patients with gastroenteritis seeking hospital care, by week. Taranto province, 1 May-30 September, 2005 and 2006 The first peak in incidence was observed at the end of June (26 week of the year), followed by a second peak at the end of July (weeks 29 and 30). The number of patients with gastroenteritis seeking hospital care decreased in the following weeks. By mid-September, the number of cases per week was similar to that seen in the same period of 2005. Patients mean age was 25 years; 19% of the cases were under 5 years of age, 16% were 5 to 15 years old, and 65% were above 15 years of age. Incubation time was not calculated because it was not possible to determine the exact time of exposure. Incidence by town of residence was highest in the city of Taranto (9.5 cases per 1,000 inhabitants) (Figure 2). Figure 2. Number of patients with gastroenteritis seeking hospital care, by town of residency per 1,000 inhabitants. Taranto province, 1 May-30 September 2006 Data collected by the tourist medical facilities in Taranto province showed a total of 361 cases of acute gastroenteritis, significantly more than a year before. Hence the same trend was observed as in the case of hospital data. Microbiological analysis: A total of 70 stool samples from patients affected by the outbreak were collected and analysed. Results by age group are reported in Table 1. Table 1. Stool samples collected from patients and tested by the Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 (°) Nested PCR in VP7 region (*) Nested PCR in the polymerase gene Stool samples were also examined with respect to gastrointestinal bacteria and parasites. No samples examined were positive for the entire range of pathogens tested. Further genotyping of the samples is currently being done. Environmental samples, systematically collected for microbiological analyses, were tap water from the water distribution system across the whole area affected by the outbreak, sea water and shellfish. The water samples were collected at the local waterworks, from major water pipelines and wells, and from tap water in pubs. No faecal indicator bacteria and endotoxins were detected in the environmental samples of tap water collected in Taranto city. Of 44 samples tested, four (9%) were positive for norovirus and 11 (25%) for rotavirus (Table 2). The tests were performed using molecular techniques. Table 2. Drinkable tap water samples collected and tested – Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 Molecular profiles of rotavirus and norovirus identified in some tap water samples were the same as the ones found in some patients’ stool samples. Sequence analysis showed the new norovirus strain GGII.4 2006a and rotavirus genotype G9. The laboratory investigations, however, are still ongoing and more results are expected in the future. Of 12 sea water samples tested, four (33%) were positive for norovirus and one (8,3%) for rotavirus. No shell fish samples were positive for bacteria or viruses. Case control study: A case control study was performed in order to find an association between the occurrence of gastroenteritis and the exposure to one or more risk factors. A case was defined as a patient with at least 3 loose or liquid stools in a day and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea. 166 cases were selected among patients treated at the accident and emergency departments of the hospitals in Taranto province, in the period between 1 August and 15 September 2006. The control group consisted of 146 non-hospitalised healthy individuals who during the study period were resident in the same area as the case patients. Cases and controls were age-matched. A standard questionnaire was used for the interview. Risk factors which were shown to be significantly associated with the onset of acute diarrhoea/gastroenteritis were the use of tap water (OR= 2; 95% CI: 1,23-3,36), and the use of water of uncertain origin in the 72 hours before the onset of the symptoms (OR= 3,9; 95% CI: 1,41-10,54). Conclusion and control measures: The epidemiological investigation and the laboratory tests showed that the possible source of infection was the drinkable tap water contaminated with (at least) rota- and noroviruses. An extra chlorination treatment for household water supplies was therefore performed starting from the 34th week of the year in order to stop a possible contamination of the water. Systematic technical and microbiological investigations of the pipelines and wells of the water distribution system did not reveal the source of contamination even though technical problems at the local chlorination treatment facilities could not have been excluded. To date, the outbreak of viral gastroenteritis described in this paper is probably the largest one associated with drinking tap water in Italy.

How to prevent this?

1303

Outbreak of Diarrhoeal illness in participants in an obstacle adventure race, Alpes-Maritimes, France, June 2015

At the end of July 2006, an unusually high number of patients with acute diarrhoea were reported by the accident and emergency departments in Taranto, Apulia. Subsequently, a field investigation was conducted jointly by the Apulia Regional Epidemiological Observatory and the Regional Reference Laboratory in Bari, and the Epidemiological Department of Taranto Local Health Unit. Field investigation: The outbreak investigation carried out between July and October 2006, involving hospitals in the whole province of Taranto, included the following main elements: Case ascertainment and descriptive epidemiology. A case was defined as a patient with diarrhoea (at least three loose or liquid stools in a day) and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea [1,2]. Five out of six hospitals in the province of Taranto provided information on patients with acute gastroenteritis. Data were collected retrospectively for the period between May and July and prospectively for August and September 2006. In addition, the special medical facilities set up for tourists in the summer season (June-August) in the province of Taranto were also asked to report cases. Microbiological investigation of stool samples of hospitalised patients. Microbiological investigation of environmental samples (including tap water, sea water and shellfish) [1-4]. Case control study performed between 1 August and 15 September 2006 in order to identify the possible sources of infection. Outbreak description From 1 May to 30 September 2006, a total of 2,860 patients with gastroenteritis symptoms were either admitted to hospital or seen by the hospitals’ outpatient accident and emergency units. This significantly exceeded the number reported in the same period in 2005, when a total of 586 patients with gastroenteritis were treated by the same hospitals. The epidemic curve is shown in Figure 1. Figure 1. Number of patients with gastroenteritis seeking hospital care, by week. Taranto province, 1 May-30 September, 2005 and 2006 The first peak in incidence was observed at the end of June (26 week of the year), followed by a second peak at the end of July (weeks 29 and 30). The number of patients with gastroenteritis seeking hospital care decreased in the following weeks. By mid-September, the number of cases per week was similar to that seen in the same period of 2005. Patients mean age was 25 years; 19% of the cases were under 5 years of age, 16% were 5 to 15 years old, and 65% were above 15 years of age. Incubation time was not calculated because it was not possible to determine the exact time of exposure. Incidence by town of residence was highest in the city of Taranto (9.5 cases per 1,000 inhabitants) (Figure 2). Figure 2. Number of patients with gastroenteritis seeking hospital care, by town of residency per 1,000 inhabitants. Taranto province, 1 May-30 September 2006 Data collected by the tourist medical facilities in Taranto province showed a total of 361 cases of acute gastroenteritis, significantly more than a year before. Hence the same trend was observed as in the case of hospital data. Microbiological analysis: A total of 70 stool samples from patients affected by the outbreak were collected and analysed. Results by age group are reported in Table 1. Table 1. Stool samples collected from patients and tested by the Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 (°) Nested PCR in VP7 region (*) Nested PCR in the polymerase gene Stool samples were also examined with respect to gastrointestinal bacteria and parasites. No samples examined were positive for the entire range of pathogens tested. Further genotyping of the samples is currently being done. Environmental samples, systematically collected for microbiological analyses, were tap water from the water distribution system across the whole area affected by the outbreak, sea water and shellfish. The water samples were collected at the local waterworks, from major water pipelines and wells, and from tap water in pubs. No faecal indicator bacteria and endotoxins were detected in the environmental samples of tap water collected in Taranto city. Of 44 samples tested, four (9%) were positive for norovirus and 11 (25%) for rotavirus (Table 2). The tests were performed using molecular techniques. Table 2. Drinkable tap water samples collected and tested – Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 Molecular profiles of rotavirus and norovirus identified in some tap water samples were the same as the ones found in some patients’ stool samples. Sequence analysis showed the new norovirus strain GGII.4 2006a and rotavirus genotype G9. The laboratory investigations, however, are still ongoing and more results are expected in the future. Of 12 sea water samples tested, four (33%) were positive for norovirus and one (8,3%) for rotavirus. No shell fish samples were positive for bacteria or viruses. Case control study: A case control study was performed in order to find an association between the occurrence of gastroenteritis and the exposure to one or more risk factors. A case was defined as a patient with at least 3 loose or liquid stools in a day and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea. 166 cases were selected among patients treated at the accident and emergency departments of the hospitals in Taranto province, in the period between 1 August and 15 September 2006. The control group consisted of 146 non-hospitalised healthy individuals who during the study period were resident in the same area as the case patients. Cases and controls were age-matched. A standard questionnaire was used for the interview. Risk factors which were shown to be significantly associated with the onset of acute diarrhoea/gastroenteritis were the use of tap water (OR= 2; 95% CI: 1,23-3,36), and the use of water of uncertain origin in the 72 hours before the onset of the symptoms (OR= 3,9; 95% CI: 1,41-10,54). Conclusion and control measures: The epidemiological investigation and the laboratory tests showed that the possible source of infection was the drinkable tap water contaminated with (at least) rota- and noroviruses. An extra chlorination treatment for household water supplies was therefore performed starting from the 34th week of the year in order to stop a possible contamination of the water. Systematic technical and microbiological investigations of the pipelines and wells of the water distribution system did not reveal the source of contamination even though technical problems at the local chlorination treatment facilities could not have been excluded. To date, the outbreak of viral gastroenteritis described in this paper is probably the largest one associated with drinking tap water in Italy.

What were the investigation steps?

1304

Outbreak of Diarrhoeal illness in participants in an obstacle adventure race, Alpes-Maritimes, France, June 2015

At the end of July 2006, an unusually high number of patients with acute diarrhoea were reported by the accident and emergency departments in Taranto, Apulia. Subsequently, a field investigation was conducted jointly by the Apulia Regional Epidemiological Observatory and the Regional Reference Laboratory in Bari, and the Epidemiological Department of Taranto Local Health Unit. Field investigation: The outbreak investigation carried out between July and October 2006, involving hospitals in the whole province of Taranto, included the following main elements: Case ascertainment and descriptive epidemiology. A case was defined as a patient with diarrhoea (at least three loose or liquid stools in a day) and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea [1,2]. Five out of six hospitals in the province of Taranto provided information on patients with acute gastroenteritis. Data were collected retrospectively for the period between May and July and prospectively for August and September 2006. In addition, the special medical facilities set up for tourists in the summer season (June-August) in the province of Taranto were also asked to report cases. Microbiological investigation of stool samples of hospitalised patients. Microbiological investigation of environmental samples (including tap water, sea water and shellfish) [1-4]. Case control study performed between 1 August and 15 September 2006 in order to identify the possible sources of infection. Outbreak description From 1 May to 30 September 2006, a total of 2,860 patients with gastroenteritis symptoms were either admitted to hospital or seen by the hospitals’ outpatient accident and emergency units. This significantly exceeded the number reported in the same period in 2005, when a total of 586 patients with gastroenteritis were treated by the same hospitals. The epidemic curve is shown in Figure 1. Figure 1. Number of patients with gastroenteritis seeking hospital care, by week. Taranto province, 1 May-30 September, 2005 and 2006 The first peak in incidence was observed at the end of June (26 week of the year), followed by a second peak at the end of July (weeks 29 and 30). The number of patients with gastroenteritis seeking hospital care decreased in the following weeks. By mid-September, the number of cases per week was similar to that seen in the same period of 2005. Patients mean age was 25 years; 19% of the cases were under 5 years of age, 16% were 5 to 15 years old, and 65% were above 15 years of age. Incubation time was not calculated because it was not possible to determine the exact time of exposure. Incidence by town of residence was highest in the city of Taranto (9.5 cases per 1,000 inhabitants) (Figure 2). Figure 2. Number of patients with gastroenteritis seeking hospital care, by town of residency per 1,000 inhabitants. Taranto province, 1 May-30 September 2006 Data collected by the tourist medical facilities in Taranto province showed a total of 361 cases of acute gastroenteritis, significantly more than a year before. Hence the same trend was observed as in the case of hospital data. Microbiological analysis: A total of 70 stool samples from patients affected by the outbreak were collected and analysed. Results by age group are reported in Table 1. Table 1. Stool samples collected from patients and tested by the Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 (°) Nested PCR in VP7 region (*) Nested PCR in the polymerase gene Stool samples were also examined with respect to gastrointestinal bacteria and parasites. No samples examined were positive for the entire range of pathogens tested. Further genotyping of the samples is currently being done. Environmental samples, systematically collected for microbiological analyses, were tap water from the water distribution system across the whole area affected by the outbreak, sea water and shellfish. The water samples were collected at the local waterworks, from major water pipelines and wells, and from tap water in pubs. No faecal indicator bacteria and endotoxins were detected in the environmental samples of tap water collected in Taranto city. Of 44 samples tested, four (9%) were positive for norovirus and 11 (25%) for rotavirus (Table 2). The tests were performed using molecular techniques. Table 2. Drinkable tap water samples collected and tested – Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 Molecular profiles of rotavirus and norovirus identified in some tap water samples were the same as the ones found in some patients’ stool samples. Sequence analysis showed the new norovirus strain GGII.4 2006a and rotavirus genotype G9. The laboratory investigations, however, are still ongoing and more results are expected in the future. Of 12 sea water samples tested, four (33%) were positive for norovirus and one (8,3%) for rotavirus. No shell fish samples were positive for bacteria or viruses. Case control study: A case control study was performed in order to find an association between the occurrence of gastroenteritis and the exposure to one or more risk factors. A case was defined as a patient with at least 3 loose or liquid stools in a day and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea. 166 cases were selected among patients treated at the accident and emergency departments of the hospitals in Taranto province, in the period between 1 August and 15 September 2006. The control group consisted of 146 non-hospitalised healthy individuals who during the study period were resident in the same area as the case patients. Cases and controls were age-matched. A standard questionnaire was used for the interview. Risk factors which were shown to be significantly associated with the onset of acute diarrhoea/gastroenteritis were the use of tap water (OR= 2; 95% CI: 1,23-3,36), and the use of water of uncertain origin in the 72 hours before the onset of the symptoms (OR= 3,9; 95% CI: 1,41-10,54). Conclusion and control measures: The epidemiological investigation and the laboratory tests showed that the possible source of infection was the drinkable tap water contaminated with (at least) rota- and noroviruses. An extra chlorination treatment for household water supplies was therefore performed starting from the 34th week of the year in order to stop a possible contamination of the water. Systematic technical and microbiological investigations of the pipelines and wells of the water distribution system did not reveal the source of contamination even though technical problems at the local chlorination treatment facilities could not have been excluded. To date, the outbreak of viral gastroenteritis described in this paper is probably the largest one associated with drinking tap water in Italy.

What did the investigation find?

1305

Outbreak of Diarrhoeal illness in participants in an obstacle adventure race, Alpes-Maritimes, France, June 2015

At the end of July 2006, an unusually high number of patients with acute diarrhoea were reported by the accident and emergency departments in Taranto, Apulia. Subsequently, a field investigation was conducted jointly by the Apulia Regional Epidemiological Observatory and the Regional Reference Laboratory in Bari, and the Epidemiological Department of Taranto Local Health Unit. Field investigation: The outbreak investigation carried out between July and October 2006, involving hospitals in the whole province of Taranto, included the following main elements: Case ascertainment and descriptive epidemiology. A case was defined as a patient with diarrhoea (at least three loose or liquid stools in a day) and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea [1,2]. Five out of six hospitals in the province of Taranto provided information on patients with acute gastroenteritis. Data were collected retrospectively for the period between May and July and prospectively for August and September 2006. In addition, the special medical facilities set up for tourists in the summer season (June-August) in the province of Taranto were also asked to report cases. Microbiological investigation of stool samples of hospitalised patients. Microbiological investigation of environmental samples (including tap water, sea water and shellfish) [1-4]. Case control study performed between 1 August and 15 September 2006 in order to identify the possible sources of infection. Outbreak description From 1 May to 30 September 2006, a total of 2,860 patients with gastroenteritis symptoms were either admitted to hospital or seen by the hospitals’ outpatient accident and emergency units. This significantly exceeded the number reported in the same period in 2005, when a total of 586 patients with gastroenteritis were treated by the same hospitals. The epidemic curve is shown in Figure 1. Figure 1. Number of patients with gastroenteritis seeking hospital care, by week. Taranto province, 1 May-30 September, 2005 and 2006 The first peak in incidence was observed at the end of June (26 week of the year), followed by a second peak at the end of July (weeks 29 and 30). The number of patients with gastroenteritis seeking hospital care decreased in the following weeks. By mid-September, the number of cases per week was similar to that seen in the same period of 2005. Patients mean age was 25 years; 19% of the cases were under 5 years of age, 16% were 5 to 15 years old, and 65% were above 15 years of age. Incubation time was not calculated because it was not possible to determine the exact time of exposure. Incidence by town of residence was highest in the city of Taranto (9.5 cases per 1,000 inhabitants) (Figure 2). Figure 2. Number of patients with gastroenteritis seeking hospital care, by town of residency per 1,000 inhabitants. Taranto province, 1 May-30 September 2006 Data collected by the tourist medical facilities in Taranto province showed a total of 361 cases of acute gastroenteritis, significantly more than a year before. Hence the same trend was observed as in the case of hospital data. Microbiological analysis: A total of 70 stool samples from patients affected by the outbreak were collected and analysed. Results by age group are reported in Table 1. Table 1. Stool samples collected from patients and tested by the Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 (°) Nested PCR in VP7 region (*) Nested PCR in the polymerase gene Stool samples were also examined with respect to gastrointestinal bacteria and parasites. No samples examined were positive for the entire range of pathogens tested. Further genotyping of the samples is currently being done. Environmental samples, systematically collected for microbiological analyses, were tap water from the water distribution system across the whole area affected by the outbreak, sea water and shellfish. The water samples were collected at the local waterworks, from major water pipelines and wells, and from tap water in pubs. No faecal indicator bacteria and endotoxins were detected in the environmental samples of tap water collected in Taranto city. Of 44 samples tested, four (9%) were positive for norovirus and 11 (25%) for rotavirus (Table 2). The tests were performed using molecular techniques. Table 2. Drinkable tap water samples collected and tested – Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 Molecular profiles of rotavirus and norovirus identified in some tap water samples were the same as the ones found in some patients’ stool samples. Sequence analysis showed the new norovirus strain GGII.4 2006a and rotavirus genotype G9. The laboratory investigations, however, are still ongoing and more results are expected in the future. Of 12 sea water samples tested, four (33%) were positive for norovirus and one (8,3%) for rotavirus. No shell fish samples were positive for bacteria or viruses. Case control study: A case control study was performed in order to find an association between the occurrence of gastroenteritis and the exposure to one or more risk factors. A case was defined as a patient with at least 3 loose or liquid stools in a day and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea. 166 cases were selected among patients treated at the accident and emergency departments of the hospitals in Taranto province, in the period between 1 August and 15 September 2006. The control group consisted of 146 non-hospitalised healthy individuals who during the study period were resident in the same area as the case patients. Cases and controls were age-matched. A standard questionnaire was used for the interview. Risk factors which were shown to be significantly associated with the onset of acute diarrhoea/gastroenteritis were the use of tap water (OR= 2; 95% CI: 1,23-3,36), and the use of water of uncertain origin in the 72 hours before the onset of the symptoms (OR= 3,9; 95% CI: 1,41-10,54). Conclusion and control measures: The epidemiological investigation and the laboratory tests showed that the possible source of infection was the drinkable tap water contaminated with (at least) rota- and noroviruses. An extra chlorination treatment for household water supplies was therefore performed starting from the 34th week of the year in order to stop a possible contamination of the water. Systematic technical and microbiological investigations of the pipelines and wells of the water distribution system did not reveal the source of contamination even though technical problems at the local chlorination treatment facilities could not have been excluded. To date, the outbreak of viral gastroenteritis described in this paper is probably the largest one associated with drinking tap water in Italy.

How was the infrastructure affected?

1306

Outbreak of Diarrhoeal illness in participants in an obstacle adventure race, Alpes-Maritimes, France, June 2015

At the end of July 2006, an unusually high number of patients with acute diarrhoea were reported by the accident and emergency departments in Taranto, Apulia. Subsequently, a field investigation was conducted jointly by the Apulia Regional Epidemiological Observatory and the Regional Reference Laboratory in Bari, and the Epidemiological Department of Taranto Local Health Unit. Field investigation: The outbreak investigation carried out between July and October 2006, involving hospitals in the whole province of Taranto, included the following main elements: Case ascertainment and descriptive epidemiology. A case was defined as a patient with diarrhoea (at least three loose or liquid stools in a day) and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea [1,2]. Five out of six hospitals in the province of Taranto provided information on patients with acute gastroenteritis. Data were collected retrospectively for the period between May and July and prospectively for August and September 2006. In addition, the special medical facilities set up for tourists in the summer season (June-August) in the province of Taranto were also asked to report cases. Microbiological investigation of stool samples of hospitalised patients. Microbiological investigation of environmental samples (including tap water, sea water and shellfish) [1-4]. Case control study performed between 1 August and 15 September 2006 in order to identify the possible sources of infection. Outbreak description From 1 May to 30 September 2006, a total of 2,860 patients with gastroenteritis symptoms were either admitted to hospital or seen by the hospitals’ outpatient accident and emergency units. This significantly exceeded the number reported in the same period in 2005, when a total of 586 patients with gastroenteritis were treated by the same hospitals. The epidemic curve is shown in Figure 1. Figure 1. Number of patients with gastroenteritis seeking hospital care, by week. Taranto province, 1 May-30 September, 2005 and 2006 The first peak in incidence was observed at the end of June (26 week of the year), followed by a second peak at the end of July (weeks 29 and 30). The number of patients with gastroenteritis seeking hospital care decreased in the following weeks. By mid-September, the number of cases per week was similar to that seen in the same period of 2005. Patients mean age was 25 years; 19% of the cases were under 5 years of age, 16% were 5 to 15 years old, and 65% were above 15 years of age. Incubation time was not calculated because it was not possible to determine the exact time of exposure. Incidence by town of residence was highest in the city of Taranto (9.5 cases per 1,000 inhabitants) (Figure 2). Figure 2. Number of patients with gastroenteritis seeking hospital care, by town of residency per 1,000 inhabitants. Taranto province, 1 May-30 September 2006 Data collected by the tourist medical facilities in Taranto province showed a total of 361 cases of acute gastroenteritis, significantly more than a year before. Hence the same trend was observed as in the case of hospital data. Microbiological analysis: A total of 70 stool samples from patients affected by the outbreak were collected and analysed. Results by age group are reported in Table 1. Table 1. Stool samples collected from patients and tested by the Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 (°) Nested PCR in VP7 region (*) Nested PCR in the polymerase gene Stool samples were also examined with respect to gastrointestinal bacteria and parasites. No samples examined were positive for the entire range of pathogens tested. Further genotyping of the samples is currently being done. Environmental samples, systematically collected for microbiological analyses, were tap water from the water distribution system across the whole area affected by the outbreak, sea water and shellfish. The water samples were collected at the local waterworks, from major water pipelines and wells, and from tap water in pubs. No faecal indicator bacteria and endotoxins were detected in the environmental samples of tap water collected in Taranto city. Of 44 samples tested, four (9%) were positive for norovirus and 11 (25%) for rotavirus (Table 2). The tests were performed using molecular techniques. Table 2. Drinkable tap water samples collected and tested – Regional Reference Laboratory (U.O.C. Igiene, Azienda Ospedaliera Policlinico), Bari, August – September 2006 Molecular profiles of rotavirus and norovirus identified in some tap water samples were the same as the ones found in some patients’ stool samples. Sequence analysis showed the new norovirus strain GGII.4 2006a and rotavirus genotype G9. The laboratory investigations, however, are still ongoing and more results are expected in the future. Of 12 sea water samples tested, four (33%) were positive for norovirus and one (8,3%) for rotavirus. No shell fish samples were positive for bacteria or viruses. Case control study: A case control study was performed in order to find an association between the occurrence of gastroenteritis and the exposure to one or more risk factors. A case was defined as a patient with at least 3 loose or liquid stools in a day and one or more of the following symptoms: fever >= 38°C, headache, vomit, abdominal pain, nausea. 166 cases were selected among patients treated at the accident and emergency departments of the hospitals in Taranto province, in the period between 1 August and 15 September 2006. The control group consisted of 146 non-hospitalised healthy individuals who during the study period were resident in the same area as the case patients. Cases and controls were age-matched. A standard questionnaire was used for the interview. Risk factors which were shown to be significantly associated with the onset of acute diarrhoea/gastroenteritis were the use of tap water (OR= 2; 95% CI: 1,23-3,36), and the use of water of uncertain origin in the 72 hours before the onset of the symptoms (OR= 3,9; 95% CI: 1,41-10,54). Conclusion and control measures: The epidemiological investigation and the laboratory tests showed that the possible source of infection was the drinkable tap water contaminated with (at least) rota- and noroviruses. An extra chlorination treatment for household water supplies was therefore performed starting from the 34th week of the year in order to stop a possible contamination of the water. Systematic technical and microbiological investigations of the pipelines and wells of the water distribution system did not reveal the source of contamination even though technical problems at the local chlorination treatment facilities could not have been excluded. To date, the outbreak of viral gastroenteritis described in this paper is probably the largest one associated with drinking tap water in Italy.

What were the infrastructure complaints?

1307

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What happened?

1308

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What was the event?

1309

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

When did this happen?

1310

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

When did this event start?

1311

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What is the date of this event?

1312

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

How long was the event?

1313

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

How long did the event last?

1314

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

In which street did this happen?

1315

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

In which city did this happen?

1316

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

In which region did this happen?

1317

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

In which country did this happen?

1318

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

Where did this happen?

1319

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What caused the event?

1320

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What was the cause of the event?

1321

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What source started the event?

1322

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

How was the event first detected?

1323

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

How many people were ill?

1324

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

How many people were hospitalized?

1325

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

How many people were dead?

1326

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

Which contaminants or viruses or bacteria were found?

1327

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

Which were the symptoms?

1328

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What did the patients have?

1329

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What were the first steps?

1330

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What did they do to control the problem?

1331

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What did the local authorities advise?

1332

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What were the control measures?

1333

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What type of samples were examined?

1334

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What did they test for in the samples?

1335

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What is the concentration of the pathogens?

1336

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What steps were taken to restore the problem?

1337

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What was done to fix the problem?

1338

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What could have been done to prevent the event?

1339

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

How to prevent this?

1340

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What were the investigation steps?

1341

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What did the investigation find?

1342

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

How was the infrastructure affected?

1343

Outbreak of Hepatitis E in Urban Bangladesh Resulting in Maternal and Perinatal Mortality

Background. Hepatitis E virus (HEV) causes outbreaks of jaundice associated with maternal mortality. Four deaths among pregnant women with jaundice occurred in an urban community near Dhaka, Bangladesh, in late 2008 and were reported to authorities in January 2009. We investigated the etiology and risk factors for jaundice and death. Methods. Field workers identified suspected cases, defined as acute onset of yellow eyes or skin, through house-to-house visits. A subset of persons with suspected HEV was tested for immunoglobulin M (IgM) antibodies to HEV to confirm infection. We used logistic regression analysis to identify risk factors for HEV disease and for death. We estimated the increased risk of perinatal mortality associated with jaundice during pregnancy. Results. We identified 4751 suspected HEV cases during August 2008–January 2009, including 17 deaths. IgM antibodies to HEV were identified in 56 of 73 (77%) case-patients tested who were neighbors of the case-patients who died. HEV disease was significantly associated with drinking municipally supplied water. Death among persons with HEV disease was significantly associated with being female and taking paracetamol (acetaminophen). Among women who were pregnant, miscarriage and perinatal mortality was 2.7 times higher (95% confidence interval, 1.2–6.1) in pregnancies complicated by jaundice. Conclusions. This outbreak of HEV was likely caused by sewage contamination of the municipal water system. Longer-term efforts to improve access to safe water and license HEV vaccines are needed. However, securing resources and support for intervention will rely on convincing data about the endemic burden of HEV disease, particularly its role in maternal and perinatal mortality. Keywords. Bangladesh; hepatitis E; outbreak; pregnancy; safe water. Outbreaks of acute infectious hepatitis have been attributed to hepatitis E virus (HEV) since the 1950s [1]. Large HEV outbreaks reported from Asia and Africa have been associated with fecally contaminated drinking water [2–20]. Although persons with HEV disease usually fully recover, clinical studies report that pregnant women who become infected with HEV, and their newborns, often die [21–26], and this has also been observed during HEV outbreaks [4, 9, 27–30]. There is no surveillance for HEV in Bangladesh, although limited studies suggest that it is the commonest cause of fulminant hepatitis [31]. In late 2008, icddr,b (International Center for Diarrheal Disease Research, Bangladesh) began a maternal health project called “Manoshi†in low-income urban areas. In January 2009, a researcher with this project noted that 4 pregnant women in an urban community called East Arichpur, approximately 15 km north of Dhaka, died following acute onset of jaundice during November and December 2008, suggesting HEV infection [32]. A collaborative team from the Institute of Epidemiology, Disease Control and Research, the Ministry of Health and Family Welfare, Government of Bangladesh, and icddr,b investigated with the goals of determining the etiology and size of the outbreak, community perceptions about the cause of the outbreak, and risk factors for illness and death (Supplementary Appendix 1). METHODS Case Finding From 12 January through 23 February 2009, we visited every household in East Arichpur and every fifth household in West Arichpur to record the number of households and residents, their demographics, and the number of suspected cases of HEV, defined as a person with new onset of illness with either yellow eyes or skin occurring during August 2008–January 2009. We used suspected HEV cases to calculate attack rates, mortality rates, and case fatality; we multiplied the number of cases identified in West Arichpur by 5 to estimate the total number of suspected cases. We inquired about all recent deaths during household surveys and investigated all deaths to determine if they had illness with jaundice. Family members were enrolled as proxy respondents for persons who died. Determining the Etiology of the Outbreak We invited suspected HEV cases living in the same housing compounds as deceased suspected HEV cases to provide a 5-mL blood specimen for testing. Blood specimens were stored on ice and transported to icddr,b where they were tested for immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis E and hepatitis A viruses (MP Bio, Singapore). Investigating Water Systems The outbreak investigation team observed water distribution systems in the area and tested the municipal water supply at the originating pump and at spigots in households of deceased suspected HEV case-patients and tested those for thermotolerant coliforms at icddr,b. Anthropologists trained in outbreak investigation conducted interviews and group discussions with families and neighbors of suspected HEV case-patients who died and asked their opinions about the cause of jaundice in their community. Case-Control Study for Risk Factors Associated With HEV Disease During May 2009, we randomly selected 160 households from the East Arichpur household listing who reported a suspected HEV case during case-finding activities. The team visited these households, and if there was no one meeting the suspected HEV case definition who was currently ill residing there, they visited the next closest household until they identified someone meeting the suspected HEV case definition who was currently ill with jaundice. The field team collected a blood sample from persons with suspected HEV and asked about their exposures and illness history using a structured questionnaire. Persons with suspected HEV who were ill during May 2009 and had IgM antibodies to HEV in serum were defined as confirmed HEV cases and included as cases in the case-control analysis. To identify controls, we randomly selected 400 households from our household list and, using a random number table, selected 1 person from each selected household for possible participation. Interviewers made at least 3 attempts to meet with the household members selected as possible controls. We first verified that the person selected had not experienced jaundice in the previous 2 years and then collected a blood sample and exposure history using a structured questionnaire. For the analysis, we defined a control as someone with no history of jaundice during the previous 2 years and no evidence of IgM or IgG antibodies to HEV in their serum. The sensitivity and specificity of HEV serological tests are suboptimal [33], and asymptomatic infections are common, even in outbreak settings [34]. Therefore, we aimed to improve the positive and negative predictive values of the tests, and thereby reduce misclassification of cases and controls, by selecting only symptomatic laboratory-confirmed cases and asymptomatic laboratory-confirmed controls for the study. Our analysis focused on HEV disease rather than all infections because of concerns about misclassification and the focus on public health burden caused primarily by disease. We compared confirmed HEV cases and controls in terms of their demographics, drinking water supply, and foods consumed using univariate logistic regression. We then built a multivariate logistic regression model to identify risk factors for HEV disease; we used backward stepwise selection and defined the best model as the one with the lowest Akaike information criterion [35]. Exposures were considered statistically significantly associated with HEV disease with a P value <.05 in the multivariate model. Investigators have suggested the possibility of intrahousehold transmission of HEV infection, presumably through fecally contaminated hands [36]. To investigate whether HEV might have been transmitted within households through fecally contaminated hands, we compared the proportion of households with a handwashing station with soap between households reporting 1 suspected HEV case and households reporting >1, as this has been shown to be a predictor of hand hygiene behavior in this setting [37]. Outcomes During Pregnancy and Risk of Mortality A second household survey was completed to estimate the increased risk of perinatal mortality associated with jaundice among women who were pregnant. During 5 March–15 April 2009, we visited every fifth household in East Arichpur and sought to identify all incident pregnancies in these households from January 2008 through February 2009, the status and outcome of those pregnancies, and whether or not pregnant women experienced jaundice during pregnancy. We compared the proportion of pregnancies ending in miscarriage, stillbirth, or neonatal death between women with and without reported jaundice during their pregnancy. To identify risk factors for death among persons with suspected HEV disease, we also compared the demographics, environmental exposures, and healthcare-seeking behaviors of persons who died with suspected HEV disease with those who survived HEV disease in East Arichpur using univariate logistic regression. Human Subjects Considerations All participants provided informed written consent prior to participation in this study, and the government of Bangladesh reviewed and approved the plans for this outbreak investigation. RESULTS Description of Arichpur Arichpur comprises an area of approximately 1.2 km2. Our census identified 29 264 households and 128 926 persons residing there—50 941 residents in East Arichpur and 77 985 in West Arichpur. People frequently lived in compounds where nuclear families shared 1 room and multiple families shared a stove, toilet, and water source. Attack Rates and Etiology Eighteen percent (2273/12 938) of households reported at least 1 suspected HEV case in East Arichpur and 11% (1920/16 326) in West Arichpur during August 2008–January 2009. The attack rate was 4% overall (4751/128 926)—5% (2756/50 941) in East Arichpur and 3% (1995/77 985) in West Arichpur. Overall, 53% of suspected case-patients were male and 56% were aged 15–34 years (Table 1). Peak incidence of suspected HEV disease occurred during November and December 2008 (Figure 1). There were 17 deaths among suspected HEV case-patients during the outbreak, and all but 1 occurred in East Arichpur. In addition to the 4 deaths among pregnant women first reported by the Manoshi project, there were 6 additional deaths in women of reproductive age whose pregnancy status was unknown, 5 deaths in adult males, and 2 deaths in neonates born to women with jaundice. The mortality rate for suspected HEV disease in East Arichpur was 3.1 per 10 000 population. The case-fatality ratio overall for suspected HEV disease was 0.4%, and 0.6% in East Arichpur. We collected illness histories for 90 case-patients—from proxies for 15 suspected HEV cases who died and from 75 surviving suspected HEV cases who were living in the same housing compounds as the case-patients who died. Two neonatal deaths were excluded because their signs and symptoms of illness were more difficult to ascertain. Among these 90 case-patients, the most commonly reported signs and symptoms were yellow eyes (100%), fever (91%), and anorexia (89%) (Table 2). Among the 75 survivors, 73 agreed to provide serum specimens, which were tested for IgM antibodies to HEV and hepatitis A virus (HAV). Fifty-six of 73 (77%) case-patients had IgM antibodies against HEV and 7 (10%) had IgM antibodies against HAV (Table 2). Community Perceptions About Jaundice and the Cause of the Outbreak Respondents did not believe that jaundice was a serious illness and preferred to seek care from traditional healers rather than allopathic practitioners. Respondents believed that the illness could have resulted from contaminated drinking water and that, in their experience, people who regularly boiled their water did not get sick. They also believed that contact between their feet and dirty water in the streets and the foul smell they inhaled from feces in open drains could also be a source of infection. Community residents described that during February 2008, 1 of the 2 municipal water pumps that supplied water to the community broke, and the remaining water pump became the water source for the entire community through June 2008. In addition, 1 of the 2 main drainage ditches for the community became clogged and remained blocked for most of 2008, which led to a marked increase in stagnant water in roadways and footpaths. Environmental Contamination Most community residents obtained drinking water from either shallow tube wells or from taps on their compound connected to the municipal water supply. The investigation team observed that connections to the main municipal water supply pipes were poorly constructed and maintained and many distribution pipes ran through open sewers to household taps. Water samples from the 2 municipality distribution pumps, an underground shallow tube well, and 7 taps located in compounds where deaths occurred were tested for thermotolerant coliforms. Although water from city distribution pumps and the underground pump contained no thermotolerant coliforms, the tapwater samples collected from households had 12–12 000 (median, 38) thermotolerant coliform-forming units/100 mL of water. Case-Control Study for Exposures Associated With Illness We enrolled 159 suspected case-patients; 61 (38%) had IgM antibodies to HEV in their serum and were used as cases in the analysis. We enrolled 352 persons with no history of jaundice in the previous 2 years as potential controls; 125 (36%) of these persons had IgM or IgG antibodies to HEV in their serum, and the remaining 227 persons were used as controls. In the univariate logistic regression, persons with confirmed HEV disease were significantly more likely than controls to be males; work outside the home; drink municipal water outside the home; and consume sugarcane juice, ice cream, and curd outside the home (Table 3). In the multivariate logistic regression model, persons with confirmed HEV disease were significantly more likely than controls to ever find dirty particles in their home drinking water (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.3) and to drink sugarcane juice (OR, 10.0; 95% CI, 4.8–20.6) (Table 3). In addition, persons with confirmed HEV disease were 4.3 (95% CI, 2.0–9.4) times more likely than controls to have drunk 1–5 glasses of municipal supply water outside the home each day, and 8.1 (95% CI, 3.1–21.5) times more likely than controls to have drunk >5 glasses (Table 3). Households with 1 reported case of jaundice were no more likely to have a handwashing station with soap than those with >1 case (57% [33/58] vs 38% [6/16]; P = .169). Outcomes During Pregnancy and Exposures Associated With Mortality We identified 270 incident pregnancies between August 2008 and February 2009, among which 21 (8%) women reported having acute onset of jaundice during the pregnancy. Of these 21 pregnancies complicated by jaundice, 8 (38%) were continuing at the time of interview, 4 (19%) had ended in miscarriage (n = 2) or stillbirth (n = 2), and 9 (43%) resulted in live births. Of the 9 live births, 2 (22%) resulted in a neonatal death. Among the 249 pregnancies uncomplicated by jaundice, 126 (51%) were continuing at the time of interview, 23 (9%) had ended in miscarriage or stillbirth, and 99 (40%) ended in live births; 3 of these neonates died (3%). Pregnancies complicated by acute onset of jaundice had a 2.7 increased odds (95% CI, 1.2–6.1) for miscarriage, stillbirth, or neonatal death compared with pregnancies without jaundice. In univariate logistic regression, case-patients who died were significantly more likely to be female, to be married, to have municipal water at home, to have visited an allopathic provider, and to have taken paracetamol (acetaminophen) during their illness (Table 4). None of the patients who died after taking paracetamol were pregnant women. Patients who died were less likely than those who survived to report a history of seeking care from an herbal healer and consuming sugarcane from a street vendor (Table 4). DISCUSSION This large outbreak of jaundice (>4000 suspected cases) in a densely populated, low-income, urban community was likely due to HEV, and evidence from this investigation suggests that it was spread through fecal contamination of the municipal water system. Although the highest risk of illness was among men who worked outside the home, most deaths occurred in women with confirmed pregnancies, their neonates, or women of reproductive age whose pregnancy status was unconfirmed; being female was associated with increased odds of death. Numerous clinical case series from India have reported increased severity of HEV disease among pregnant women [24, 25, 38], and the few studies of neonates born to women with HEV show that they frequently die and are infected [24, 26]. Verbal autopsy studies from Bangladesh have shown that approximately 19%–25% of maternal and 7%–13% of neonatal deaths are associated with acute onset of jaundice during pregnancy [39], and estimates of the maternal and neonatal mortality burden from HEV are urgently needed. Ill persons who took paracetamol, an antipyretic also known as acetaminophen and metabolized by the liver, were significantly more likely to die than those who did not take the drug. We were unable to measure the dose of the drug that patients took, so we cannot comment on how this may have affected their disease outcome. It is possible that patients who died were more seriously ill and therefore took more medicines than less ill patients, including paracetamol; this is also supported by the association between seeking allopathic care and death. However, a causal association between paracetamol use and death is plausible. Paracetamol poisoning is a leading cause of acute liver failure in the United States [40], and its use or overuse is a plausible contributor to mortality among patients with HEV infection. A study of patients with acute HAV infections in France demonstrated that patients who developed liver failure were more likely than those who did not to have taken acetaminophen during their illness (80% vs 37%), although the difference was not statistically significant, perhaps due to limited sample size [41]. The possible role of paracetamol use in increasing risk of mortality among patients with HEV deserves further study. Due to the possible added stress to the liver, patients presenting with jaundice should be offered alternative analgesics. Drinking from the municipal supply water outside the home was highly associated with HEV disease in a doseresponse manner. Drinking sugarcane juice was also associated with HEV disease, likely reflecting another route of exposure to municipal water. Sugarcane stalks are kept in buckets of water by street vendors and pressed by a machine to harvest the “juice†for each customer; sometimes it is also served with ice made with municipal water. Drinking municipal water at home was not associated with disease, but could have represented the baseline “dose†of contaminated water for cases exposed to municipal water outside the home. Although the main municipal supply water pumps showed no evidence of fecal contamination, the water taps all had thermotolerant coliform counts above those recommended by the World Health Organization (0 per 100 mL; available at: http://www.who.int/water_ sanitation_health/dwq/2edvol3a.pdf, Accesssed 8 June 2014), suggesting that drinking water becomes contaminated through poorly maintained water distribution systems. It is unlikely that this water contamination was a newly emerging problem for this community. Rather, it highlights the ongoing risk for waterborne disease. Working outside the home and drinking sugarcane juice from a street vendor were protective for death. The most likely explanation for this is that males were more likely to have these exposures, but mortality risk was higher for females. There was no evidence from our investigation that direct person-to-person transmission played a major role during this outbreak. By the time this outbreak was reported, the peak of illness onset had already passed. We were unable to collect specimens from persons who died to diagnose their cause of death; however, family members or neighbors who experienced jaundice at the same time as the deaths had IgM antibodies to HEV, providing strong evidence that the deaths were likely caused by HEV. The late reporting of the outbreak also meant that exposures associated with disease in our case-control study may have identified transmission routes related to endemic rather than epidemic transmission. HEV is preventable through provision of clean drinking water; although effective vaccines have been developed, none are currently sold internationally [42, 43]. Interventions to prevent HEV in the low-income countries where HEV is endemic will require redistribution of scarce health resources, which is unlikely to materialize unless better data on the true burden of HEV justifying intervention are assembled. Given that maternal mortality is a characteristic feature of HEV outbreaks [32], existing maternal health programs in HEV-endemic countries could be leveraged to measure the burden of HEV on maternal and child health.

What were the infrastructure complaints?

1344

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What happened?

1345

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What was the event?

1346

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

When did this happen?

1347

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

When did this event start?

1348

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What is the date of this event?

1349

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

How long was the event?

1350

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

How long did the event last?

1351

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

In which street did this happen?

1352

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

In which city did this happen?

1353

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

In which region did this happen?

1354

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

In which country did this happen?

1355

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

Where did this happen?

1356

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What caused the event?

1357

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What was the cause of the event?

1358

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What source started the event?

1359

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

How was the event first detected?

1360

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

How many people were ill?

1361

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

How many people were hospitalized?

1362

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

How many people were dead?

1363

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

Which contaminants or viruses or bacteria were found?

1364

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

Which were the symptoms?

1365

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What did the patients have?

1366

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What were the first steps?

1367

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What did they do to control the problem?

1368

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What did the local authorities advise?

1369

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What were the control measures?

1370

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What type of samples were examined?

1371

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What did they test for in the samples?

1372

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What is the concentration of the pathogens?

1373

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What steps were taken to restore the problem?

1374

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What was done to fix the problem?

1375

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What could have been done to prevent the event?

1376

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

How to prevent this?

1377

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What were the investigation steps?

1378

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What did the investigation find?

1379

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

How was the infrastructure affected?

1380

Outbreak of severe gastroenteritis with multiple aetiologies caused by contaminated drinking water in Denmark, January 2007

On Monday 15 January 2007, a municipality in Denmark received the first of several complaints from citizens who reported severe diarrhoea and vomiting over the weekend. Over the same period, the drinking water in many houses was reported to be discoloured and of unusual smell and taste. The local authorities immediately prohibited any use of the water - except for toilet flushing - in the entire area supplied with untreated drinking water from the local waterworks, which involved 5,802 citizens and a number of companies (Figure 1). The citizens in the area were warned by the police and through radio broadcasts. Figure 1. Waterborne outbreak of gastrointestinal illness in Denmark, 2007. Map of affected area. To reveal the nature and the geographical spread of the suspected water contamination, water samples for microbiological and chemical analyses were systematically collected from the water distribution system across the whole area supplied from the local waterworks. The water samples were collected at the waterworks itself, from major water pipelines and wells, and from tap water in private houses and companies. High concentrations of faecal indicator bacteria (primarily presumptive coliform counts and Escherichia coli) and endotoxins in the water samples indicated a massive faecal contamination of a part of the water distribution system, while other parts of the distribution system appeared not to be affected. On the basis of the geographical distribution of indicator bacteria, and the technical information about directions of the water flow in the different sections of the water distribution system, the area suspected to be contaminated was systematically reduced step by step during the next days. Based on the analyses of 530 water samples collected at 200 different sites, the area finally considered to be affected by the water contamination was defined on 26 January 2007 (indicated with a red line in Figure 1). This area comprised 177 households with 450 residents and several companies, among which six dealt with food. Restrictions on water use were maintained in this area, while the water was released for normal use in the area that was not considered to be contaminated. Gastrointestinal illness: A line-list of patients with gastrointestinal illness associated with the water contamination was established on the basis of notifications from general practitioners, enquiries made to the medical health officer, patients seeking advice from the emergency medical service, and patients contacting an ad hoc telephone “hotline†established by the local authorities. Additional information was collected during a house-to-house questionnaire survey conducted on 16 January among 20 households in the most severely affected street. Stool samples were examined at the Department of Bacteriology, Mycology and Parasitology, and the Department of Virology, Statens Serum Institut, Copenhagen. A case of acute gastroenteritis was defined as a person with diarrhoea, vomiting and/or abdominal pain/cramps with fever. To verify whether reported cases met the case definition, and to confirm the geographical extent of gastrointestinal illness associated with the water contamination, patients on the line-list were contacted by telephone and/or postal questionnaires. By the end of February 2007, 140 cases had been registered: 110 were residents of the area that was judged to be contaminated on the basis of the environmental investigations, 12 were shoppers or employees at the food companies in the area, and 18 affected people came from outside the contaminated area. The epidemic curve for cases among residents in the contaminated area with known date of illness onset is shown in Figure 2. No new cases in the contaminated area were registered after 24 January. Cases were largely confined to the contaminated area. A total of 24% of the residents of the contaminated area were registered with gastrointestinal illness, compared with 0.3% in the other sections of the waterworks’ supply area (relative risk 73; 95% CI 44-127). From the most severely affected street in the contaminated area, 43% of residents were reported to have fallen ill. Four patients were temporarily admitted to hospital. Figure 2. Waterborne outbreak of gastrointestinal illness in Denmark. Number of case patients living in the exposed area with known date of symptoms onset, January 2007 (n=98) Microbiological results: By the end of February 2007, stool samples from 139 patients affected by the outbreak (including 99 patients who met the case-definition criteria) had been examined with respect to gastrointestinal bacteria, viruses and parasites. Among these, 77 patients (43 cases) had one or more samples that tested positive, including 23 patients with 2-5 different pathogenic gastrointestinal organisms (Table). Not all samples were tested for the entire range of pathogens identified. Further microbiological testing and genotyping of the samples are being undertaken. Table. Waterborne outbreak of gastrointestinal illness in Denmark. Gastrointestinal microorganisms identified in stool samples from affected patients, as of end of February 2007. Technical assessment and intervention: Technical and microbiological investigations of the water indicated that the most probable cause of the contamination was the combination of a technical and a human error at a local sewage treatment facility, which allowed at least 27 m3 of partially filtered waste water to enter into the drinking water system in the period between 12 and 14 January 2007. The two pipelines were separated, and the exact circumstances of the incident that allowed the backflow of the sewage water remain to be revealed. The conclusion of the technical investigations was supported by the large variety of gastrointestinal pathogens found in the stool samples, which corroborated that the contamination was due to backflow of grossly contaminated sewage water rather than, for example, surface water or sewage from only a few households. The sewage treatment plant receives sewage from a population of approximately 40,000, as well as industrial enterprises, food production establishments and a hospital. Flushing of the area’s distribution system was initiated immediately and sustained for several weeks. As faecal indicator bacteria were still found in the drinking water after two weeks of sustained flushing, the distribution system was subsequently disinfected by chlorination on 10 and 11 February. After another two days of flushing, the drinking water was released for normal use, but recommended for drinking still only after boiling. By 12 March, the boiling restrictions were lifted for the majority of households, since by then the environmental water samples from the distribution system had fulfilled the quality criteria for untreated drinking water as defined by the Danish Ministry of Environment [3]. Commentary: The handling of the outbreak called for interdisciplinary cooperation and the epidemiological investigations supported the technical and water-microbiological analyses. Geographical information systems were used to define the contaminated area, and the 18 episodes of illness reported outside of the contaminated area (Figure 1) probably represent sporadic illness or could be associated with the outbreak in a way that was not investigated, for example by secondary transmission. Although the drinking water supply in Denmark is primarily from untreated ground water, disease cases are rarely registered in connection with incidents of contamination [1,2]. The outbreak described was unusual, partly because of the high morbidity among the exposed citizens, and partly because of the extraordinary complexity of positive microbiological findings; a recent review of disease outbreaks caused by contaminated drinking water in the United States from 2003 to 2004 reported that in only two out of 25 outbreaks with known aetiology more than one microorganism was detected [4]. The consequences were considerable for the affected families, but also for the food companies, which were not allowed to resume production until the middle of February.

What were the infrastructure complaints?

1381

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

What happened?

1382

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

What was the event?

1383

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

When did this happen?

1384

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

When did this event start?

1385

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

What is the date of this event?

1386

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

How long was the event?

1387

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

How long did the event last?

1388

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

In which street did this happen?

1389

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

In which city did this happen?

1390

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

In which region did this happen?

1391

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

In which country did this happen?

1392

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

Where did this happen?

1393

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

What caused the event?

1394

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

What caused the contamination of the wells with infected rodents or rodent excreta?

1395

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

What was the cause of the event?

1396

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

What source started the event?

1397

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

How was the event first detected?

1398

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

How many people were ill?

1399

Outbreak of tularaemia in central Norway, January to March 2011

From January to March 2011, 39 cases of tularaemia were diagnosed in three counties in central Norway: 21 cases of oropharyngeal type, 10 cases of glandular/ulceroglandular type, two of respiratory and two of typhoid type. Three cases were asymptomatic and clinical information was unavailable for one case. The mean age was 40.3 years (range 2-89 years). Thirty-four reported use of drinking water from private wells. An increased rodent (lemming) population and snow melting may have led to contamination of the wells with infected rodents or rodent excreta. Outbreak description: From 1 January to 25 March 2011, 39 confirmed cases (16 female and 23 male) of tularaemia were reported from the counties of Sør-Trøndelag (28 cases), Møre og Romsdal (5 cases) and Nord-Trøndelag (6 cases) in central Norway. A confirmed case was defined as a person who had clinical symptoms compatible with tularaemia or had used drinking water from the same source as a previous case, and in whom Francisella tularensis infection was confirmed by a laboratory test as described below. The cases were geographically scattered within each county, involving 13 different municipalities (Figure), and were not linked to one common source. In comparison, seven cases were reported in total from other parts of the country in the same period. In 2009 and 2010 four and eight cases respectively were reported from central Norway. Figure. Geographical distribution of confirmed cases of tularaemia in Norway, January to March 2011 (n=39) Tularaemia is a zoonotic disease caused by the bacterium F. tularensis. Four F. tularensis subspecies are recognised: tularensis, holarctica, mediasiatica and novicida. In Europe, the infection is due to subspecies holarctica which causes in general less severe disease than subspecies tularensis, which is common in North America. Several vectors may be involved in transmitting the disease to humans, commonly rodents and hares, but infection may also be transmitted via insect bites [1]. Several clinical forms are recognised, with oropharyngeal and ulceroglandular disease being the most common clinical presentations in Norway [2]. Oropharyngeal disease is commonly associated with contaminated food and water, while ulceroglandular forms are more often seen when there has been skin contact with infected animals or after insect bites [3]. Outbreaks of oropharyngeal tularaemia have previously been reported from several European countries [3,4]. Tularaemia is a notifiable disease in Norway and during the past 10 years, three outbreaks were reported in Norway [5-7] and all were associated with water sources in areas where dead lemmings (Lemmus lemmus) had been observed previously. From 2001 to 2010, between three and 66 cases of tularaemia were reported annually in the whole country, with an increase from 16 to 32 cases on average (data available from: www.msis.no). This increase may in part be explained by the outbreaks mentioned above. Diagnosis and clinical presentation: In the outbreak described here, the most common clinical presentation was fever and pharyngitis (oropharyngeal type, 21 cases) and cervical lymphadenopathy (glandular/ulceroglandular type, 10 cases). Among the remaining eight tularaemia cases, two were classified as respiratory and two as typhoid type, while three were asymptomatic and clinical information was unavailable for one case. The diagnosis was primarily established by serology (microagglutination and an in-house IgG/IgM Elisa) in 30 patients [8], by F. tularensis specific PCR analysis in seven patients [9] and by blood culture (BactAlert, BioMerieux) in two patients. The two bacterial isolates were verified as F. tularensis by PCR and sequencing of the 16S rDNA gene, and confirmed as non-subspecies tularensis by pdpA PCR [10]. Thirty-four of the 39 diagnosed cases had been drinking water from a private well or a stream. F. tularensis DNA was detected by PCR in filtered water from five different wells tested in Sør-Trøndelag. Seven cases in one municipality were linked to the same water source. Apart from that, only two cases have been confirmed to share a common well so far. Follow-up serology has been recommended for several of the persons exposed to some of the putative water sources. Discussion: The current outbreak involves a large number of municipalities in three counties in central Norway. The clinical presentation with oropharyngeal tularaemia and cervical lymphadenopathy linked to the use of private wells in the winter season makes contaminated water the most likely source of infection in this outbreak. Detection of F. tularensis DNA by PCR analyses in some of the wells supports this assumption for some of the cases. Use of private wells is relatively common in rural areas of Norway although exact data on such use are not available. The precise mechanism of contamination of the wells with F. tularensis is as yet unknown. However, November and December 2010 were unusually cold months, while in January 2011 temperatures increased leading to melting of snow and possible contamination of private wells by surface water contaminated with bacteria from rodent cadavers or rodent excreta. Since the incubation period for tularaemia may be up to three weeks, and time from symptoms until seroconversion might be up to six weeks, more cases may follow. Tularaemia has traditionally been called both ’lemming fever’ and ’hare plague’ and this clearly indicates rodents and hares as transmitters of disease. Years with a great increase in the rodent population are seen with intervals of about three to four years [11] and in the summer and autumn of 2010, a high density of lemmings could be observed in the southern and central parts of Norway. Simultaneously, the Norwegian Veterinary Institute observed a wide geographical distribution of fatal cases of tularaemia in the mountain hare (Lepus timidus) in these regions [12]. The mountain hare is very susceptible to this infection and normally dies from septicaemia within a few days after exposure. The use of small streams and private wells as a source of drinking water and for other purposes in rural areas of Norway is a matter of concern. In existing guidelines issued by the National Institute of Public Health the population is advised to boil drinking water and inspect the wells for dead rodents in case of suspected or confirmed cases of waterborne tularaemia. Every well owner should make the necessary effort to prevent small rodents from entering the well water by carefully covering every opening and plugging every small holes where the rodents can enter. It is also important to secure the well from contamination by surface water after snow melting. In case of proven or suspected contaminated wells, the water should be disinfected before further use. However, this may not be feasible for persons who use drinking water from a stream. The Norwegian Food Safety Authority has recently released information to the media and to the general public with similar advice and information in relation to the current outbreak. The local health authority in each municipality is responsible for instituting infection control measures including advice to the public and investigations of the putative drinking water sources.

How many people were hospitalized?