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Hepatitis E (HE) during pregnancy can be fatal; there are no prospective risk estimates for HE and its complications during pregnancy. We followed 2,404 pregnant women for HE and pregnancy outcomes from 1996 to 1998. Subjects from Nepal were enrolled at an antenatal clinic with pregnancy of ≤ 24 weeks. Most women (65.1%) were anti-HE virus negative. There were 16 cases of HE (6.7 per 1,000); three mothers died (18.8%) having had intrauterine fetal death (IUFD). Thirteen mothers survived: five preterm and seven full-term deliveries, one IUFD. HE among seronegative women was the sole cause of maternal death and increased the risk of IUFD (relative risk [RR]: 10.6; 95% confidence interval [CI]: 4.29-26.3) and preterm delivery (RR: 17.1, 95% CI 7.56-38.5). HE vaccination of females in at-risk regions before or as they attain reproductive age would reduce their risk for preterm delivery, IUFD, and maternal death.

A cohort of 62 Nepalese adults with acute hepatitis E was identified and total Ig as well as IgM levels to hepatitis E virus (HEV) capsid protein were determined using the Walter Reed Army Institute of Research (WRAIR) immunoassay. An antibody profile was constructed from serial serum specimens collected up to 14 months following the onset of illness. The decline in total Ig was rapid for the first 3 months. There followed a slow, sustained decline, but antibodies remained above the seropositive level of 20 WRAIR units. The decline of IgM was steeper than total Ig for the first 3 months, but IgM remained detectable after 14 months in 25% of cases. Study data contribute to an understanding of the pathophysiology of human hepatitis E and set an antibody response pattern to be targeted as a part of HEV vaccine development.

Hepatitis E virus (HEV) is an important cause of enterically transmitted hepatitis in developing countries. Sporadic autochthonous cases of hepatitis E have been reported recently in the United States and other industrialized countries. The source of HEV infection in these cases is unknown; zoonotic transmission has been suggested. Antibodies to HEV have been detected in many animals in areas where HEV is endemic and in domestic swine and rats in the United States. There is evidence supporting HEV transmission between swine and humans. Nevertheless, HEV has not been detected in wild rodents. We tested murid rodents and house shrews trapped in Nepal's Kathmandu Valley, where hepatitis E is hyperendemic, for HEV infection. The most commonly trapped species was Rattus rattus brunneusculus. Serum samples from 675 animals were tested for immunoglobulin G against HEV by enzyme-linked immunosorbent assay; 78 (12%) were positive, indicating acute or past infection. Antibody prevalence was higher among R. rattus brunneusculus and Bandicota bengalensis than in Suncus murinus. Forty-four specimens from 78 antibody-positive animals had sufficient residual volume for detection of HEV RNA (viremia) by reverse transcription-PCR. PCR amplification detected four animals (9%; three were R. rattus brunneusculus and one was B. bengalensis) with viremia. Phylogenetic analysis of the four genome sequences (405 bp in the capsid gene) recovered showed that they were identical, most closely related to two human isolates from Nepal (95 and 96% nucleotide homology, respectively), and distinct from HEV sequences isolated elsewhere. These data prove that certain peridomestic rodents acquire HEV in the wild and suggest that cross-species transmission occurs, with rodents serving as a virus reservoir for humans.

Hepatitis E disease is responsible for substantial morbidity in Nepal. A socioeconomic analysis was performed to describe the costs and the effects of hepatitis E disease (HE) on health status in a Nepalese population living in the Kathmandu Valley. A modified health status index was used to quantify healthy days lost associated with HE. One hundred thirty-four individuals recently recovered from HE were interviewed in June 1998. The median age was 22 years and 60% were female. Study participants were sick and bedridden for a median of 22 and 10 days, respectively. The median healthy days lost per individual was 35 (768,000 total per region). The median cost of illness per individual, including direct and indirect, was $37 ($1,238,676 total per region). The percentage of yearly income lost for wage earners totaled 19.4%. Hepatitis E disease is associated with significant costs and loss of healthy days in Nepal. Further research is warranted to understand and limit this common disease.

From 29 January 1995 to 15 March 1995, an outbreak of hepatitis occurred among 692 soldiers at an isolated training camp 25 km east of Kathmandu. Thirty-two cases occurred approximately 8 weeks after arrival of soldiers at the camp. To determine the etiology of the outbreak, patient sera were examined for evidence of infection with hepatitis A, B, C, and E viruses using commercially available enzyme-linked immunosorbent assay (ELISA) kits. The polymerase chain reaction (PCR) was used to detect hepatitis E virus (HEV) RNA. Evidence of recent infection (IgM to HEV and/or HEV RNA) was found in all but two patients, whereas none had evidence of recent infection with hepatitis A, B, or C viruses. Therefore, the outbreak was attributed to HEV. Fecally contaminated drinking water was suspected as the source of the outbreak. To determine the extent of HEV infections among those without clinical hepatitis, sera from the remaining soldiers were examined for markers of HEV infection. Evidence of past infection (IgG to HEV in the absence of IgM or HEV RNA) was found among 204 soldiers (prevalence = 30%), leaving 488 individuals susceptible to infection at the onset of the outbreak. Evidence of recent infection was found among another 83 individuals. We conclude that most exposed, susceptible soldiers sustained HEV infection without experiencing overt hepatitis. If the levels of virus inoculum and prior immunity in this population were typical, inapparent infection may be the usual adult response to virus exposure in an endemic area.

Hepatitis E has been the predominant type of acute hepatitis in Nepal both in adults and children, in sporadic and epidemic forms. We examined six hepatitis E virus (HEV) isolates obtained during an 8-year period, from 1987 to 1995, in the Kathmandu valley of Nepal. Analysis of portions of the putative helicase, polymerase and capsid genes demonstrated close genetic relatedness among themselves (> 96.4% identity) and with the Burmese (> 95.5%) and Indian (> 95.3%) isolates, and less so with the African (> 94.4%) and the Chinese (> 91%) isolates within the Asian genotype. Phylogenetic analysis placed the Nepali isolates in the Burma-India evolutionary branch and showed that the oldest isolate, TK78/87 was more similar to the Burmese isolates whereas the most recent isolates were closer to the Indian ones. Assuming no frameshifts, the Nepali isolates showed high amino acid conservation, but also unique changes when compared to other HEV isolates. Amino acid residue 614 of the capsid protein was identified as a possible marker to distinguish the Burma-Nepal-India from the China-Central Asian Republics subgenotype, and the Mexico genotype.

To determine hepatitis E virus (HEV) infection and disease rates in the Kathmandu Valley of Nepal, serum was collected from 757 healthy Nepalese (ages 12-48 years) during March and September 1992 and September 1993. At each visit, reports of interval illness were obtained. Sera were examined for IgG to HEV, using a commercially available kit. Seroconversion was used as a marker for HEV infection, and an episode of hepatitis E was defined as a history of jaundice with seroconversion. Seroprevalence ranged from 16% to 31% and increased with age, whereas both infection and disease rates decreased with age. Infection and disease rates were as high as 99/1000 and 45/1000 person-years, respectively. These results highlight the importance of sporadic hepatitis E as a public health problem among adolescents and young adults in this region.

We report the first proven outbreak of Japanese encephalitis (JE) occurring in the Kathmandu Valley of Nepal. During September and October 1995, we treated 15 patients with meningo-encephalitis. All of the patients were Nepalese, all but one lived in the Kathmandu Valley, and their overall mortality was 53%. Anti-JE virus (JEV) IgM in the cerebrospinal fluid was found in the two cases for whom it was tested. The two tested patients were similar to the other patients in clinical presentation and in home location. We recommend immunization against JEV for those traveling to Kathmandu during the months of August to October.

The prevalence of hepatitis E virus (HEV) infections among 55 domestic swine living in the Kathmandu Valley of Nepal was investigated. Sera and stool specimens were collected from 47 free-roaming swine and examined for the presence of HEV genomic sequences by the reverse transcription-polymerase chain reaction. Sera from these animals, as well as sera from eight other swine, were also examined for the presence of HEV-specific antibodies by an enzyme-linked immunosorbent assay and by a fluorescent antibody blocking assay. Hepatitis E virus RNA was detected in the sera and/or stool of three of 47 swine, while HEV-specific antibodies were detected in 18 of 55 swine. These results indicate that HEV is a zoonotic virus, and that swine are among its natural hosts.

Sera from two groups of patients in Nepal with acute hepatitis were examined for the presence of antibodies to the hepatitis A, B, C, and E viruses to determine the etiology of viral hepatitis. The first group consisted of 43 consecutive acute hepatitis patients presenting at a clinic for tourists and foreign residents in Kathmandu from January 1987 to June 1988. The other group consisted of 95 consecutive acute hepatitis patients admitted during the same period at a hospital used predominantly by adult Nepalese residents of Kathmandu. Hepatitis A was diagnosed in 39 (91%) of the foreign patients and in one of the 95 Nepalese patients, whereas hepatitis E was diagnosed in four of the 43 foreign patients and in 90 (95%) of the Nepalese patients. No cases of hepatitis B or C were identified in either group, nor were any cases of dual infection with the hepatitis A virus (HAV) and hepatitis E virus (HEV) identified. These results suggest that in the Kathmandu Valley, hepatitis A is the predominant form of hepatitis among foreigners, hepatitis E is the predominant form of hepatitis among adult Nepalese, and both HAV and HEV are endemic to the Kathmandu Valley.