The Two Faces of Hepatitis E Virus

Transcription

1 EMERGING INFECTIONS James M. Hughes and Mary E. Wilson, Section Editors INVITED ARTICLE The Two Faces of Hepatitis E Virus Eyasu H. Teshale, Dale J. Hu, and Scott D. Holmberg Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia Hepatitis E virus (HEV) has at least 2 distinct epidemiological profiles: (1) large outbreaks and epidemics in developing countries, usually caused by HEV genotype 1, resulting in high morbidity and mortality among pregnant women and young children, and (2) very few symptomatic cases of HEV genotype 3, most cases without symptoms or clear source(s) of infection, but frequent seroreactivity in 5% 21% of asymptomatic persons in developed countries. We urge more epidemiological studies and public health interventions, including the promotion and development of existing and future vaccine candidates and the availability of US Food and Drug Administration approved serological assays for this underappreciated and poorly understood virus, a major cause of disease throughout the world. Hepatitis E virus (HEV) infection is a significant public health problem in many parts of the world, causing large outbreaks of acute hepatitis. HEV is a nonenveloped RNA virus in the genus Hepevirus, first recognized in the early 1980s [1]. The viral particles are relatively stable in the environment and have been recovered from sewage samples [2]. The virus is classified into at least 4 genotypes but can present as 2 quite different conditions: as large epidemics and sporadic cases of hepatitis E in areas of endemicity (genotype 1 [Asia and Africa], genotype 4 [Asia], or genotype 2 [Mexico and Africa]) or as isolated clinical cases occurring among a sizeable group of mostly asymptomatic seropositive residents in developed countries (genotype 3). To date, genotypes 1 and 2 have been found only in humans, whereas genotypes 3 and 4 have also been found in animals. Since the first retrospectively documented hepatitis E outbreak in India in [3], there have been many large outbreaks reported in Asia and Africa (Table 1). In contrast, while there have been sporadic cases of locally acquired hepatitis E in industrialized countries [4 6], no epidemics have been reported. Furthermore, data have shown a substantial proportion of persons with serological evidence of prior HEV exposure but no disease. The clinical features of hepatitis E are similar to those of acute viral hepatitis caused by other hepatotropic viruses. The Received 22 February 2010; accepted 27 April 2010; electronically published 23 June Reprints or correspondence: Dr Eyasu H. Teshale, Div of Viral Hepatitis, Mailstop G-37, 1600 Clifton Rd, Atlanta, GA (eht4@cdc.gov). Clinical Infectious Diseases 2010; 51(3): This article is in the public domain, and no copyright is claimed /2010/ DOI: / incubation period has a range of days, with a mean of 40 days [3]. Hepatitis E clinically manifests with icterus, malaise, anorexia, fever, hepatomegaly, and pruritus. These symptoms are accompanied by laboratory findings of elevated serum bilirubin levels, markedly elevated levels of liver enzymes, and mild increases in alkaline phosphatase activity. HEV-infected persons exhibit a wide clinical spectrum, ranging from asymptomatic infection to fulminant hepatitis. Studies of nonhuman primates have demonstrated that the clinical presentation, immunological response, severity of symptoms, and biochemical markers of liver damage increase with increasing inoculums [7]. During acute HEV infection, enzyme immunoassay shows that anti-hev immunoglobulin (Ig) M becomes detectable days before the onset of symptoms and disappears during a 4 6 month period [8]. Anti-HEV IgG appears soon after the IgM response and may persist up to 12 years after infection [9]. Although several commercial assays are available internationally, no assay is currently approved by the US Food and Drug Administration (FDA). In addition to serological assays, nucleic acid amplification methods can be used to identify HEV RNA in the blood and stool of infected individuals. In a human volunteer experiment, HEV RNA was detectable in blood at the peak of abnormal liver function tests starting from 2 weeks before to 1 week after onset of jaundice. HEV RNA appeared in stool later than in blood and disappeared from stool 2 weeks after it became undetectable in blood [10]. Chronic infection with HEV is rare, although chronic carriage may be more frequent in HIV-infected persons [11]. Chronic liver disease following acute infection has not been documented in countries where HEV is endemic. However, there are anecdotal reports and case series of chronic hepatitis 328 CID 2010:51 (1 August) EMERGING INFECTIONS

2 Table 1. Selected Large Reported Outbreaks of Hepatitis E Virus (HEV) Year(s); location Reference(s) No. of persons affected Putative mode of transmission ; India [3] 29,300 Waterborne ; Kashmir [28] 1270 Waterborne 1986; Mexico a [29] 1200 Contaminated well water ; Ethiopia [30] 1750 After monsoon rains 1991; India [31] 79,000 Contaminated river water (Ganges) 1991; China b [32, 33] 119,000 Waterborne 1994; Vietnam [34] 1300 After heavy rains 2004; Sudan b [35] Safe water insufficient 2008; Uganda b [26, 36] 110,000 Substantial person-to-person a Caused by HEV genotype 2. b Caused by HEV genotype 1. E among indigenously acquired cases of hepatitis E in developed countries, especially among transplant recipients [12 15] and other patients who were severely immunocompromised [16, 17]. Reactivation of resolved HEV infection in a patient with leukemia after allogeneic stem cell transplantation also has been reported [18]. Such cases may be best treated by a reduction in immunosuppressive therapy [19]. Another study found that 6 (13%) of 47 patients considered to have hepatitis as a result of drug-induced liver injury actually had reactivation of HEV infection [20]. HEV infection also may be associated with severe disease in persons with preexisting liver disease [21]. In HEV epidemics, disproportionately high rates of fulminant hepatitis with subsequent high mortality occur among pregnant women [22, 23]. High mortality, particularly during the third trimester of pregnancy, following fulminant hepatic failure, is a hallmark an HEV outbreak [24] and may be related to hormonal changes in pregnancy [25]. In recent studies in Central Asia and eastern Africa, high mortality rates have also been observed among children younger than 2 years of age [26, 27]. HEV infection was first described as a waterborne disease, transmitted through drinking of fecally contaminated water [3] (Table 1). However, recent investigations have not consistently found well-defined water sources of HEV, suggesting other possible modes of transmission [26, 36]. These other transmission modes may be related to the level of population immunity, sanitary conditions, living conditions, and other factors. In sporadic hepatitis E, modes of transmission are even less clear and are generally not identified. Transmission by blood transfusion has been demonstrated [37, 38], but this route of transmission is not thought to be frequent. There is growing evidence that HEV in outbreaks may be effectively transmitted person to person [36]. It is also noteworthy that, in some populations, HEV appears to be easily transmissible, with up to 76% of persons aged 120 years having serological evidence of infection but not having significant disease [39]. HEV IN DEVELOPING COUNTRIES HEV infection is a major public health problem in many developing countries (Figure 1). The first documented outbreak of hepatitis E in India resulted in 29,300 cases of jaundice [3]. Other notable large outbreaks (Table 1), resulting in significant morbidity, include outbreaks in India and China that resulted in 79,000 cases [31] and 119,000 cases [32, 33], respectively. Since genotyping of HEV strains became common in the mid- 1990s, hepatitis outbreaks in developing countries have been caused primarily by HEV genotype 1 (Table 1), with outbreaks in Mexico and western Africa caused by genotype 2 [29, 40] and sporadic cases in Asia caused by genotype 4 [41]. In countries with suboptimal sanitary conditions, HEV is the single most important cause of sporadic and epidemic hepatitis. In susceptible populations, high attack rates have been observed [26]. Case-fatality rates in epidemics range from 0.2% to 4%, but pregnant women, especially during the third trimester, may have a case-fatality rate of 10%-25% [22]. In areas of endemicity, HEV is the most common cause of hepatitis during pregnancy. In studies involving pregnant women, HEV accounted for 37% of cases of acute viral hepatitis and 81% of cases of fulminant hepatitis [43], with more than one-fourth of affected women having obstetric complications, such as premature rupture of membranes and intrauterine growth restriction [43, 44]. It is unknown why HEV causes severe disease in pregnant women. Among pregnant women who are exposed to HEV during the third trimester, death is usually due to fulminant hepatitis or obstetric complications [24]. Vertical transmission with consequent morbidity and mortality of infants is also common with third trimester hepatitis E [45]. However, in Egypt where prevalence of anti- HEV antibody in the rural population is high, compared with in other countries severe cases of hepatitis E have never been reported [46]. This suggests little understanding of the role of EMERGING INFECTIONS CID 2010:51 (1 August) 329

3 Figure 1. Worldwide distribution of hepatitis E virus in Courtesy of Dr. Chong-Gee Teo, and created for use by the Centers for Disease Control and Prevention [42]. viral-host factors in disease development following exposure to HEV. In countries where outbreaks occur, HEV genotype 1 infection has been considered a waterborne infection transmitted through drinking of fecally contaminated water [23, 30] (Table 1). However, the source of sporadic hepatitis E in those countries is not clear. In sporadic cases, virus shedding during convalescence, subclinically infected sources, and environmental contamination (water) may be culprits. For example, animal reservoirs in India including swine, sheep, goats, buffalo, and chickens have not been found to be a source of sporadic HEV genotype 1 infection [47]. Transfusion-associated hepatitis E has also been reported with HEV genotypes 1 and 3 [38, 48]. HEV can be transmitted from person to person, even though this mode of transmission was not thought to contribute significantly to morbidity in epidemics. In a recent outbreak in northern Uganda, waves of secondary cases of hepatitis E followed primary cases within households, providing, for the first time, credible evidence of person-to-person transmission [36]. 330 CID 2010:51 (1 August) EMERGING INFECTIONS Foodborne or zoonotic infection with HEV genotype 1 has not been established. Cross-species transmission of HEV genotypes 1 and 2 in developing countries has shown that the human HEV can be transmitted to nonhuman primates but not to other animals. Although zoonotic reservoirs have been demonstrated for HEV genotype 3 in Europe and the United States and for HEV genotype 4 in China and Japan [49, 50], testing of pigs and other animals near outbreaks have not supported zoonotic transfer to humans [36, 51]. Seroepidemiological evidence of HEV infection in developing countries, as determined by detection of anti-hev IgG, has consistently shown that seroprevalence increases in direct proportion with increasing age. In a seroepidemiological survey in Pune, India, HEV prevalence increased with age and peaked at 20 years of age [52]. However, unlike hepatitis A virus prevalence, which may reach close to 100% by age 5 years in countries of endemicity, the seroprevalence of HEV in any general population is usually!40%. Interestingly, studies in North Africa have shown a high prevalence of anti-hev antibody in

4 hospitalized children [53], but nonhospitalized children had an anti-hev antibody prevalence comparable to that in children of a similar age group from other countries. Persons considered at risk for HEV genotype 1 infection include those living in areas where outbreaks occur, those traveling to areas of HEV endemicity, those living in overcrowded refugee camps, those with chronic liver disease, and those handling nonhuman primates [54]. HEV prevention and control strategies typically involve improvement of hygienic conditions and provision of safe drinking water. As evidence of person-to-person transmission of HEV is increasing, it is prudent that strategies focused at reducing transmission by this route such as hand washing with soap are implemented in an effort to reduce transmission. In addition, because the success of current interventions is limited, the need to develop, test, and provide a reliable hepatitis E vaccine is imperative [55]. Although at least one hepatitis E vaccine candidate has shown promise in clinical trials, none has been approved by the FDA or by any international regulatory agency. For the major international manufacturer of the aforementioned hepatitis E vaccine candidate, with the longeststanding published data on efficacy, the start-up costs and apparent lack of market profitability remain barriers to commercial production. Trials of hepatitis E vaccine are currently underway in several countries, including one large efficacy trial in China, and perhaps these trials will encourage further vaccine candidate development and eventual implementation in susceptible populations. HEV IN DEVELOPED COUNTRIES In sharp contrast to the situation regarding HEV genotype 1 and sometimes genotype 2 or 4 in developing countries, HEV genotype 3 is considered a prevalent but rarely pathogenic agent in industrialized nations [56]. However, even this conclusion is tentative, because the true prevalence, incidence, pathogenicity, and risk of HEV in developed countries are unknown. A number of possible reasons for why this is the case have been identified. First, there are problems with the enzyme immunoassays used to detect current or previous HEV exposure. Commercial assays vary markedly in their sensitivity and specificity [8, 57]. Recently, many researchers have used in-house enzyme immunoassays to identify IgG, which is indicative of exposure to HEV sometime in the past [58, 59], but comparisons of various assays with each other show wide differences in sensitivity and specificity [60]. The question of which tests are more accurate compounds the existing difficulties in determining the rates of exposure and the epidemiology of HEV infection in developed countries. The most recent analysis of 118,000 serum samples from the Third National Health and Nutrition Examination Survey (NHANES), , showed that 21% of US residents were seropositive for anti-hev IgG [58]. Furthermore, similar to results of studies in developing countries, seropositivity increased in linear proportion with increasing age. These data and a study from Denmark [59] that also relied on the same research assay developed by the National Institutes of Health showed a relatively high seropositivity among tested populations. In contrast, recent reports from Europe and Japan that relied on other commercial assays demonstrated much lower seroprevalences ( 3% 12% of populations tested) even among putatively highly exposed persons, such as sewage workers or hemodialysis patients [61, 62]. These findings raise questions about whether the research assays yield many false-positive results from cross-reactivity with unknown antigens, or, conversely, whether certain assays are not using appropriate or sufficient antigen(s), such that they yield many false-negative results. More thorough study is needed to validate the performance of these assays for different genotypes in countries where HEV is endemic and countries where it is not. In the absence of FDA-approved assays for HEV in the United States, many potential cases of hepatitis E will remain undiagnosed and uninvestigated. The problem is not limited to ascertaining what is the true HEV seroprevalence in industrialized countries, because data on HEV incidence also are lacking. In the United States, the Centers for Disease Control and Prevention (CDC) Division of Viral Hepatitis Laboratory typically receives specimens per year for confirmation of initial HEV positive test results from US hospital and commercial laboratories using various kits. Many of these positive results cannot be replicated at the CDC laboratory. Among 82 samples from suspected cases tested by the CDC from 2002 to late 2009, only 9 cases (11%), acquired domestically (6 cases) or through travel (3 cases), have been confirmed by reverse-transcriptase polymerase chain reaction (J. Drobeniuc, personal communication). Notably, there have been only 5 cases of acute hepatitis E thought to be acquired domestically and reported in the United States in [6, 63 66]. These HEV infections were all genotype 3, all occurred in persons aged 40 years, and no clear source of infection was found despite intensive investigation. Understanding the pathogenicity of hepatitis E genotype 3 is also problematic. Clearly, if 21% of Americans have been infected [58] or even a fraction of that number but no outbreaks of hepatitis E have been observed, this suggests that the great majority of infections are not symptomatic or only very mildly symptomatic. Yet, here again, the data belie clear conclusions. Chronic and clinically severe HEV infections have been observed in organ transplant recipients and other persons [15]. In contrast to the disease in developing countries, sporadic cases in industrialized countries have been associated with wild or domestic swine consumption, especially of raw organ meat (offal). In addition, seropositivity for HEV has been associated EMERGING INFECTIONS CID 2010:51 (1 August) 331

5 with consumption of raw or undercooked pig livers in Japan [67, 68]; with being a swine worker [59, 69, 70]; and with wild boar consumption in Germany [71]. Indeed, HEV genotype 3 is a zoonotic infection of wild pigs worldwide, and these feral pigs may contaminate a wide range of agricultural products. Furthermore, HEV has been detected in 14 (11%) of 127 packaged commercial pig livers in US groceries [72]. Before attributing the high seropositivity to HEV in developed countries to pork consumption, there are several inconsistencies that have to be addressed. First, despite some indications that the practice is increasing in Japan [73] or Germany [71], wild or domestic swine offal consumption is rare in the United States and is uncommon in most European countries; thus, this exposure alone cannot account for the high seroprevalence observed in many developed countries. Second, data from NHANES in the United States did not find large or statistically significant differences between persons who consumed bacon, sausage, or other pork products in the previous year and persons who had not, such as vegetarians, orthodox Jews, and Muslims [58]. Although findings from NHANES found that HEV seropositivity was significantly associated with several miscellaneous exposures, none of the (adjusted) odds ratios was Remarkably, this serological study indicated that HEV infection, unlike almost any other infectious disease, relatively spares the rural poor living in the South, including African Americans and those drinking untreated well water, all of whom who had comparatively lower HEV seropositivity rates. If, as discussed above, the research assays used by the National Institutes of Health and the CDC are accurate, a common exposure regardless of age may be accounting for the high HEV seropositivity observed. For example, if HEV genotype 3 infected wild boars are contaminating agricultural food products, the high HEV seroprevalence may be explained by the wide distribution of these food products. However, it would be very difficult to identify these common foodstuffs as the source of HEV infection or exposure. Some occasional person-to-person transmission or infections acquired from travel to developing countries may further muddy any clear epidemiological connection with either pork or contaminated vegetables and fruits. Also, unlike for the other hepatitis viruses, anti-hev antibody is not especially prevalent in injection drug users, who would be expected to have been exposed parenterally or from a close contact [74]. Furthermore, as seen recently on a cruise ship, HEV genotype 3 might be acquired from consuming raw or undercooked shellfish [75], an association not thoroughly explored. Clearly, more epidemiologic investigations are needed. Although there is no US surveillance system to report hepatitis E (imported or indigenous), proper investigation of cases to confirm diagnosis and to verify the HEV genotype that caused the illness is crucial to identify possible cases of locally acquired infection that could be missed by a concomitant history of travel. Two of the patients with locally acquired hepatitis E documented in the United States had a history of travel to Mexico or Thailand during the incubation period [65, 66]. Clinicians should be vigilant and should consider hepatitis E in the differential diagnosis of unexplained jaundice, particularly among elderly persons, men, solid-organ transplant recipients, and those with compromised immune systems. Clinical indications, such as the lack of evidence for other causes of abnormal liver enzymes, including noninfectious causes of hepatitis and liver failure, should increase the threshold for testing for HEV infection [76]. Because the window for HEV diagnosis may be narrow, prompt collection of samples for such testing should be considered. In conclusion, HEV infection behaves in remarkable contrast between developed and developing countries. Although HEV has only 1 serotype, the different genotypes and subtypes may have different modes of transmission, pathogenicity, nonhuman reservoirs, and capacity for interspecies transmission. As a disease entity whose causative agent is relatively recently described, much remains to be understood about HEV. Given the large global burden of epidemic and sporadic hepatitis E, the high mortality among pregnant women and very young children, and the potential threat caused by the widespread prevalence of HEV in human and swine populations, we believe that epidemiological and intervention studies, as well as clinical trials of hepatitis E vaccine, should be expanded. Finally, the availability of accurate and well-validated diagnostic tests for HEV will enhance the care of patients with acute hepatitis of undetermined etiology and will help to understand the true incidence of this infection around the world. Acknowledgments We thank Dr. Deborah Holtzman, Division of Viral Hepatitis, Centers for Disease Control and Prevention, for her many helpful editorial suggestions. Potential conflicts of interest. E.H.T., D.J.H., and S.D.H.: no conflicts. References 1. Balayan MS, Andjaparidze AG, Savinskaya SS, et al. Evidence for a virus in non-a non-b hepatitis transmitted via fecal-oral route. Intervirology 1983; 20: Clemente-Caseres P, Pina S, Buti M, et al. Hepatitis E virus epidemiology in industrialized countries. Emerg Infect Dis 2003; 9: Viswanathan R. Infectious hepatitis in Delhi ( ). A critical study: epidemiology. Indian J Med Res 1957; 45: Lewis HC, Boisson S, Ijaz S, et al. Hepatitis E in England and Wales. 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