MAJOR ARTICLE

High Mortality Associated with an Outbreak

of Hepatitis E among Displaced Persons
in Darfur, Sudan
Delia Boccia,1,2 Jean-Paul Guthmann,3 Hilde Klovstad,6,7 Nuha Hamid,8 Mercedes Tatay,4 Iza Ciglenecki,4
Jacques-Yves Nizou,5 Elisabeth Nicand,5 and Philippe Jean Guerin3
1
European Programme for Intervention Epidemiology Training, Stockholm, Sweden; 2Health Protection Agency–Centre for Infection, London, United
Kingdom; 3Epicentre, 4Médecins Sans Frontières, and 5National Reference Centre of Enterically Transmitted Hepatitis (Hepatitis E Virus), Teaching
Military Hospital Val de Grâce, Paris, France; 6Norwegian Institute of Public Health, and 7Norwegian Field Epidemiology Training Programme,
Oslo, Norway; and 8World Health Organization, Khartoum, Sudan

(See the article by Guthmann et al. on pages 1685–91)

Background. Hepatitis E virus (HEV) causes acute onset of jaundice and a high case-fatality ratio in pregnant
women. We provide a clinical description of hospitalized case patients and assess the specific impact on pregnant
women during a large epidemic of HEV infection in a displaced population in Mornay camp (78,800 inhabitants),
western Darfur, Sudan.
Methods. We reviewed hospital records. A sample of 20 clinical cases underwent laboratory confirmation.
These patients were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody to HEV (serum)
and for amplification of the HEV genome (serum and stool). We performed a cross-sectional survey in the
community to determine the attack rate and case-fatality ratio in pregnant women.
Results. Over 6 months, 253 HEV cases were recorded at the hospital, of which 61 (24.1%) were in pregnant
women. A total of 72 cases (39.1% of those for whom clinical records were available) had a diagnosis of hepatic
encephalopathy. Of the 45 who died (case-fatality ratio, 17.8%), 19 were pregnant women (specific case-fatality
ratio, 31.1%). Acute hepatitis E was confirmed in 95% (19/20) of cases sampled; 18 case-patients were positive
for IgG (optical density ratio ⭓3), for IgM (optical density ratio 12 ), or for both, whereas 1 was negative for
IgG and IgM but positive for HEV RNA in serum. The survey identified 220 jaundiced women among the 1133
pregnant women recorded over 3 months (attack rate, 19.4%). A total of 18 deaths were recorded among these
jaundiced pregnant women (specific case-fatality ratio, 8.2%).
Conclusions. This large epidemic of HEV infection illustrates the dramatic impact of this disease on pregnant
women. Timely interventions and a vaccine are urgently needed to prevent mortality in this special group.

Hepatitis E virus (HEV), a nonenveloped, positive- similar. They are clinically characterized by an icteric
sense, single-stranded RNA virus, is recognized as the phase, with discoloration of sclerae, jaundice, and oc-
principal cause of enterically transmitted non-A, non- casionally dark urine. They are both self-limited, with
B hepatitis, which occurs worldwide although rarely in a low mortality rate in the general population [3, 4].
industrialized countries [1]. Evidence for the existence However, probably the most striking difference between
of a new epidemiologically distinct virus has been avail- the infections is the high mortality seen among preg-
able since the early 1980s, but the virus has only recently nant women with HEV infection, especially those in
been identified [2]. the third trimester. Case-fatality ratios range from 10%
Infections due to hepatitis A virus and HEV are very to 42% [5–9].
HEV is transmitted via the fecal-oral route and rarely
through person-to-person transmission. HEV is rec-
Received 14 October 2005; accepted 18 February 2006; electronically published ognized as a common source of waterborne outbreaks,
12 May 2006.
Reprints or correspondence: Dr. Jean-Paul Guthmann, 8 rue Saint-Sabin, 75011 involving fecally contaminated water [3]. The first doc-
Paris, France ([email protected]). umented hepatitis E outbreak occurred in Delhi, India,
Clinical Infectious Diseases 2006; 42:1679–84
 2006 by the Infectious Diseases Society of America. All rights reserved.
in 1955–1956 [1]. Additional outbreaks have been re-
1058-4838/2006/4212-0004$15.00 ported among civilians [10–15] and military popula-

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 tions [16–20]. To our knowledge, only 2 episodes have been ulation consisted of all women resident or displaced in Mornay
reported among refugees [4, 21]. Camp and pregnant between 1 July and 30 September 2004.
In June 2004, a large hepatitis E outbreak occurred in western This included women pregnant at the time of the survey and
Darfur, Sudan. A total of 2621 cases were reported between 26 women who had given birth in the past 3 months. The study
June and 31 December 2004 in Mornay Internally Displaced population also included pregnant women who had died during
Persons Camp (78,800 inhabitants). The medical nongovern- the study period. The survey was done by 13 teams of 2 in-
mental organization Médecins Sans Frontières was the main terviewers, 1 team per camp administrative district (limits de-
health care provider in the camp, with a hospital and 2 out- fined by the camp authorities). Each team was trained to rec-
patient departments. The epidemiological investigation sug- ognize jaundiced persons, and a pilot phase was conducted to
gested an increased risk of HEV infection with drinking water ensure compliance with standard procedures and definitions.
from chlorinated sources [22]. Data were gathered directly from women or from the nearest
The rationale of this investigation was to collect clinical in- relative in case of absence or death of the woman. Information
formation on cases of hepatitis E during an outbreak in a large collected included pregnancy status, based on answers given by
camp, which has rarely been reported. Specifically, we aimed to the interviewee; presence of acute jaundice, defined as yellow
have a more accurate picture of its impact on pregnant women coloration of the sclera, either observed by the interviewer or
to provide recommendations for interventions in the future. as reported by the interviewee in the study period; and occur-
rence of death reported by relatives. All pregnant women en-
METHODS countered during the survey were encouraged to seek medical
Description of hospitalized case patients. A clinical case def- attention even if only mild symptoms had occurred. Attack
inition was made after the first cases of acute hepatitis E were rates by districts were calculated.
confirmed on serum specimens at the Naval Medical Research
Unit in Cairo, Egypt. Surveillance data in Darfur did not report RESULTS
other diagnoses as important causes of acute jaundice. There-
Hospital investigation. The first 2 cases were diagnosed on 7
fore, a case of hepatitis E was defined as occurring in a person
and 8 July 2004. Both were in pregnant women, who had been
resident or displaced in Mornay who developed an acute onset
admitted to the hospital in coma, who died within 48 h. After
of jaundice since 1 July 2004 (defined as a yellow coloration
this, the number of admitted patients increased each week, peak-
of the sclera). Patients with a positive result of malaria rapid
ing during weeks 33–34 and decreasing afterwards (figure 1).
diagnostic test were excluded. Hepatic encephalopathy was clas-
A total of 253 case patients with hepatitis E were admitted
sified as either mild (presence of confusion or agitation in
to the hospital until December 31. These admissions accounted
addition to jaundice) or severe (presence of coma or convul-
sions in addition to jaundice). Diagnosis was made by the for 15.3% of all hospital admissions during this period and
medical doctor responsible on the ward of admission on the ranged between 8% of admissions in July (21 of 248) and 27%
basis of the clinical presentation of patients. in August and November (93 of 343 and 26 of 94, respectively).
During the presence of the investigation team in the field, a Twenty serum and 13 stool samples were collected from 20
sample of inpatients underwent laboratory confirmation with hospitalized case patients. The diagnosis of acute hepatitis E
serological analysis and detection of HEV RNA in serum sam- was confirmed in 19 (95%). Among these 19 with confirmed
ples and stool specimens [22]. Acute HEV infection was defined cases, 18 were positive for IgG (OD ratio, ⭓3), IgM (OD ratio,
as an optical density (OD) ratio of ⭓3 for HEV IgG, an OD 12 ), or both, and 1 was negative for IgG and IgM but had
ratio of 12 for HEV IgM, and/or presence of HEV RNA in HEV RNA detected in serum. Among the 18 who tested positive
stool or serum [22]. for IgG and IgM, 4 also had HEV RNA present in stool samples,
Demographic and clinical information was extracted from and 3 had HEV RNA present in serum and stool samples.
medical records of hospitalized case patients with hepatitis from Demographic and clinical characteristics were obtained from
1 July until 31 October 2004. Data were recorded on a standard 184 case patients (73%). The majority were adult women (129
form; entered into EpiData software, version 3.0 (EpiData As- [70.1%]), and 143 (77.7%) were aged 15–44 years. Hepatic
sociation); and analyzed on EpiInfo software, version 6.04 encephalopathy was recorded in 72 cases (39.1%); it was mild
(Centers for Disease Control and Prevention). The case-fatality in 35 cases and severe in 37. The median delay before admission
ratio among inpatients was calculated using the total number was 5 days (range, 1–25 days) (data available for 154 case
of jaundiced patients admitted at the hospital during the study patients). Duration of hospitalization was available for 180 case
period as the denominator. patients, accounting for a median duration of stay of 4 days
Cross-sectional survey of pregnant women. The study pop- (range, 1–16 days) (table 1). The most frequent symptoms at

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 Figure 1. Number of case patients who were hospitalized (n p 253 ) because of jaundice and number who died (n p 45 ), by week of admission
to Médecins Sans Frontières Hospital, Mornay Camp, western Darfur, Sudan, July–December 2004.

presentation were jaundice (98%), fever (65%), vomiting (59%), from Shamal 2 district. During the study period, 169 (77%)
abdominal pain (50%), and anorexia (42%). pregnant women with jaundice had attended a health facility
Between July and December, 45 case patients with hepatitis for a medical consultation.
E died (case-fatality ratio, 17.8%). Demographic and clinical
information were available for 31 of those patients who died: DISCUSSION
26 (83.9%) were aged 15–44 years, and 22 (71%) were female.
All 31 patients presented with mild or severe hepatic enceph- To our knowledge, this is the largest outbreak of hepatitis E
alopathy. The median duration of symptoms before admission documented in the literature among internal displaced persons
was 3 days (range, 2–19 days), and the median duration of or refugees, illustrating the dramatic impact of this disease on
hospitalization was 2 days (range, 1–7 days) (data available for pregnant women at the community level. Between July and
26 and 31 cases, respectively) (table 1). Of the 45 case patients December 2004, 2621 cases of hepatitis E were recorded in
who died, 19 (42.2%) were pregnant women, yielding a specific Mornay camp, accounting for 3% of the camp population [22].
case-fatality ratio in this group of 31.1% (19 of 61 women). The burden represented by this outbreak is reflected by the
The monthly case-fatality ratio for the 6-month period is re- proportional morbidity from hepatitis E at the hospital: case
ported in table 2. patients with hepatitis E occupied, on average, 1 in 7 beds
Cross-sectional survey. Overall, 1133 pregnant women between July and December 2004 and 1 in 4 beds in August
were identified during the 2-day survey, representing 1.4% of at the peak of the outbreak. During that month, on average, 1
the Mornay population. Among them, 220 episodes of acute patient was admitted each day to the intensive care unit with
jaundice were recorded during the study period (attack rate, a diagnosis of hepatic encephalopathy. These figures show the
19.4%). The attack rate among pregnant women ranged be- impact of this disease at the hospital level; personnel were over-
tween 10.5% (n p 4) in Salam 0 district and 33.6% (n p 41) whelmed with the number of hepatitis E cases and were unable
in Salam 2 district (table 3). Of 220 pregnant case patients, 18 to attend to other patients.
(8.2%) died (table 3). One-half of the deaths were reported Women represented a large proportion of hospitalized pa-

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 Table 1. Demographic and clinical characteristics of patients patients particularly difficult and not as effective as it could have
hospitalized with jaundice and case patients who died, Mornay been in a more stable setting. All of these aspects may have
Camp, western Darfur, Sudan, July–October 2004. increased the vulnerability of the population to the severe form
of this disease or even worsened the clinical presentation and
All hospitalized Case patients
Characteristic case patients who died outcome of patients admitted to hospital.
Age, years
Almost one-quarter of the patients with hepatitis E admitted
!5 3 (1.6) 0 (0) to the hospital were pregnant women, and among these, one-
5–14 21 (11.4) 2 (6.5) third died. In Mornay, the case-fatality ratio among pregnant
15–44 143 (77.7) 26 (83.9) women admitted to the hospital was almost twice that of other
145 14 (7.6) 2 (6.5) hospitalized patients with HEV infection (42% vs. 18%). This
Unknown 3 (1.6) 1 (3.2) high case-fatality ratio among pregnant women, although still
Total 184 (100.0) 31 (100.0) unexplained, is well documented in other studies and was ex-
Sex
pected in our case series [1, 3, 23, 25].
Male 54 (29.3) 8 (25.8)
The cross-sectional survey of pregnant women showed not
Female 129 (70.1) 22 (71.0)
only a higher case-fatality ratio among pregnant women than
Unknown 1 (0.5) 1 (3.2)
Total 184 (100.0) 31 (100.0)
among others (31% vs. 18%) but also a higher attack rate than
Delay before admission, median in the camp population (19.4% vs. 3.3%) [22]. However, com-
days (range) 5 (1–25) 3 (2–19) parisons must be interpreted with caution, because data were
Duration of hospital admission, not collected by the same means [22]. In addition, it was not
median days (range) 4 (1–16) 2 (1–7)
possible to confirm the information gathered, and quality of
Final diagnosis
data is entirely dependent on the respondents’ reliability. We
Simple hepatitis 112 (60.9) 0 (0.0)
Mild hepatic encephalopathy 35 (19.0) 9 (29.0)
could not identify particular risk factors explaining higher at-
Severe hepatic encephalopathy 37 (20.1) 22 (71.0) tack rates in certain districts than in others. Water supplies in
Total 184 (100.0) 31 (100.0) all districts were a mixture of deep-drilled water supply, mod-
Outcome erately deep water supply, chlorinated water, and water taken
Died 31 (16.8) 31 (100.0) directly from the river.
Discharged 149 (81.0) … Whether the higher attack rate and case-fatality ratio among
Unknown 4 (2.2) … pregnant women are the result of a higher risk of developing
Total 184 (100) 31 (100.0)
symptomatic disease or of an actual increased susceptibility to
NOTE. Data are no. (%) of patients, unless otherwise indicated. the infection remains unclear [26, 27]. Some authors suggest
that pregnant women are at higher a risk for developing severe
tients, although among patients with hepatitis E, male patients acute hepatitis and even fulminant hepatic failure than are the
traditionally predominate over female patients at a ratio of 1.5– general population, implying that even mild infection during
3.5:1 [23]. Sex distribution might be attributed to a more severe pregnancy might contribute to a rapid progression of infection
clinical presentation in women, especially those who are preg-
nant, and/or could reflect the unbalanced sex distribution of the
population of Darfur, caused by the violent events occurring since Table 2. Monthly case-fatality ratio among overall hospitalized pa-
tients (n p 253) and pregnant women admitted to hospital (n p 61),
December 2003 and well documented by several surveys [24].
Mornay Camp, western Darfur, Sudan, July–December 2004.
Another unexpected feature of this outbreak was the observed
case fatality. Clinical symptoms reported were those typical of Proportion of deaths Proportion of deaths
hepatitis E, whereas case fatality observed in the hospitalized among hospitalized among pregnant
patients (18%) is higher than reported elsewhere (0%–5.7%) [12, case patients per women admitted to
a
Month month (%) the hospital (%)
14, 15, 19, 21]. This result might be explained by the fact that
the outbreak at Mornay affected people with impaired health July 5/21 (23.8) 4/6 (66.7)
August 15/93 (16.1) 6/15 (40.0)
status because of poor living conditions, extremely unsafe san-
September 7/47 (14.9) 2/12 (16.7)
itary conditions, and poor access to food. Security concerns and
October 9/50 (18.0) 1/11 (9.1)
lack of confidence in Western medicine might also have delayed
November 8/26 (30.8) 5/10 (50.0)
seeking access to the healthcare facility. In addition, the extremely December 1/16 (6.3) 1/7 (14.3)
difficult working conditions (e.g., lack of proper health care in- a
These deaths represented, respectively, 5 (14%) of 36, 15 (43%) of 35,
frastructure and insufficient staff members to ensure an adequate 7 (23%) of 30, 9 (38%) of 24, 8 (42%) of 19, and 1 (20%) of 5 total monthly
turnover in the hospital), made the treatment and care of these hospital deaths between July and December 2004.

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 Table 3. Geographic distribution of cases of acute jaundice per camp district, num-
ber of deaths, and case-fatality ratio among pregnant women, Mornay Camp, western
Darfur, Sudan, July–September 2004.

No. of No. of
pregnant patients with No. of Attack Case-fatality
District Population women jaundice deaths rate, % rate, %
Salam 0 7383 38 4 1 10.5 25.0
Salam 1 5803 107 16 3 15.0 18.8
Salam 2 7966 122 41 0 33.6 0.0
Salam 3 2558 56 7 0 12.5 0.0
Jebel 1 6822 124 34 1 27.4 2.9
Jebel 2 2886 55 9 0 16.4 0.0
Wadi B 9792 121 14 1 11.6 7.1
Wadi A1 7972 126 18 0 14.3 0.0
Wadi A2 4061 64 18 0 28.1 0.0
Sherig 1 4618 58 7 0 12.1 0.0
Sherig 2 8232 72 13 0 18.1 0.0
Shamal 1 2512 25 3 3 12.0 100.0
Shamal 2 8226 165 36 9 21.8 25.0
Total 78,831 1133 220 18 19.4 8.2

and a higher rate of spontaneous abortion and intrauterine pregnant women, would have dramatically decreased the num-
death [10, 28]. ber of deaths. More research into the development of an ef-
Although it was impossible to follow-up these complications fective vaccine is therefore needed. Specific interventions tar-
associated with HEV infection in hospitalized pregnant women, geting pregnant women concerning water supply, hygiene, and
data in the literature suggest that they may have been severe. education should also be evaluated. Today, hepatitis E is con-
In a recent prospective study of 62 pregnant women who had sidered an emerging disease of global importance, but much
jaundice in the third trimester, HEV accounted for 37% of of our understanding of this disease is still based on outbreak
cases of acute viral hepatitis and 81% of cases of fulminant investigations and clinical observations. Aside from the devel-
hepatic failure [29]. More than one-quarter of women with opment of a protective vaccine, there is also an urgent need
HEV infection had obstetric complications, including prema- for population-based studies aimed at addressing major epi-
ture rupture of membrane, intrauterine growth restriction, pla- demiological issues, such as the apparent increased morbidity
centa previa, and retained placenta. Approximately two-thirds and mortality in pregnant women, the higher clinical attack
of women with HEV infection had preterm deliveries [29], and rate among adults in outbreaks, the predominance of male
in an outbreak in Pakistan, 4 of 8 fatalities occurred among patients among clinical case patients, and the importance of
infants born to HEV-infected mothers [10]. animals as a reservoir for HEV. We hope that these studies will
Another indirect effect of this outbreak that we did not assess prompt detailed investigations of future episodes and possibly
is the number of orphans the outbreak may have caused. Even their prevention.
without quantitative estimates, we can expect this number to
be significant because of the high number of children per Acknowledgments
woman in this setting [24] and the observed high mortality We thank the Médecins Sans Frontières team in Sudan for providing
observed among women of childbearing age. Consequences of logistic support and figures after our departure from the field, Dr. Hammam
orphanhood are always severe but can be even more dramatic El Sakka (World Health Organization [WHO], Khartoum, Sudan) for his
support at all levels of this work, Drs. William Perea and Daniel Lavanchy
in an unsafe and unstable context such as western Darfur. (WHO, Geneva, Switzerland) for advice and support, Dr. Vincent Enouf
The impact of this outbreak points to the importance of an and Mélanie Caron (Service de Biologie Médicale, Val de Grâce Hospital,
HEV vaccine as a potential preventive measure. At present, no Paris, France) for performing laboratory testing of samples and interpre-
tation of data, Dr. Vincent Brown and Francesco Checchi (Epicentre, Paris)
vaccine is available, although a recombinant vaccine has just
for helpful advice during and after our trip to the field, and Rebecca
undergone clinical trials in Nepal [30]. Some authors have Freeman Grais (Epicentre) for useful suggestions.
questioned the public health impact of this vaccine compared Financial support. This study was funded by Médecins sans Frontières,
with improvements in water sanitation and water supply in and laboratory analyses were performed and funded by the National Ref-
erence Centre of Enterically Transmitted Hepatitis (Hepatitis E Virus; Hôpi-
countries of endemicity [31]. We believe that the prompt use tal Val de Grâce, Paris).
of a vaccine in a context such as Mornay, especially targeting Potential conflicts of interest. All authors: no conflicts.

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