Uuggh - yet another vaccine.. Hepatitis E: A potential vaccine-preventable disease needs global concern

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Hepatitis E: A potential vaccine-preventable disease needs global concernTai-Nin ChauSee articles in J. Gastroenterol. Hepatol. 2008; 23: 879–882 and883–887.Hepatitis E is the commonest cause of acute viral hepatitis worldwide,and predominantly occurs in India, China and other developingcountries where sanitation is suboptimal. It accounts for most ofthe large-scale epidemics of viral hepatitis and more than half of allacute sporadic hepatitis in areas where it is endemic. Many outbreaksof epidemic hepatitis previously ascribed to hepatitisAvirus(HAV) were in fact caused by hepatitis E virus (HEV).1 Like HAV,HEV is mainly transmitted by the fecal-oral route and is associatedwith fecal contamination of water supplies, but person-to-persontransmission appears less common, and the attack rate in adults ishigher than in children.With the widespread use of hepatitisAandB vaccines and routine screening of hepatitis C virus (HCV) ofdonated bloodworldwide, the incidences of hepatitisA, B and C aredecreasing globally. On the contrary, hepatitis E epidemics involvinghundreds of people are frequently reported.Emerging evidence has suggested that HEV infection is alsoautochthonously acquired in many industrialized countries, andthe related disease burden is probably underestimated becauseof the lack of testing.2,3 In Western countries, the clinicoepidemiologicalexpression of hepatitis E is different comparedwith its counterpart in endemic areas. The seroprevalence of anti-HEV in normal individuals in the USAand Europe ranges between1% and 6%, which is unexpectedly high in comparison with thelow rate of clinically evident disease.4 Seroepidemiological studieshave also found that the prevalence is much higher among populationswith occupational exposure to pigs or wild animals,5 suggestingthat HEV might be zoonotically transmitted from animalsto humans. The notion of zoonotic transmission of HEV in nonendemicregions is further supported by the fact that HEV isenzootic in a broad range of animals, but swine (pigs) stand out tohave the highest rate of anti-HEV seropositivity.6 The geneticsequence of human strains of HEV in these regions is genotype 3,which is closely related to those strains detected in the respectivenational pig herds, and different from human strains of HEV indeveloping countries.7 Animal studies have shown that genotype 3strains of HEV appear more attenuated for primates as comparedwith genotype 1 or 2 strains.8 Hence, it is speculative that subclinicalinfection with this strain of HEV might explain the high seroprevalenceof anti-HEV in developed countries. Furthermore,minor outbreaks of hepatitis E have occurred in Japan after eatingraw boar and deer meat, pork and pig liver. Molecular studies haveshown that the meat was contaminated by HEV whose nucleotidesequence was identical to those from the patients.9 This providesdirect evidence that HEV can be transmitted directly from animalsto humans through food ingestion.Hepatitis E is usually considered a self-limited acute hepatitisthat does not progress to chronic disease. However, this virus has apropensity to cause severe and protracted illness, especially amongimmunocompromised patients. We have previously reported thathepatitis E tends to occur in older people and leads to worse liverfunction compared with hepatitis A, thereby resulting in a highermortality rate (up to 4%).10 In line with our findings, in this issue ofthe Journal, Jeyamani et al.11 also reported a series of 12 patientswith acute hepatitis E complicated by subacute hepatic failure,which is extremely rare in hepatitis A infection. The authors consideredthat the mortality rate of 25% in their series was low whencompared with patients with subacute hepatic failure due to alternativecauses, such as drugs or autoimmune hepatitis. However,such high mortality should be regarded as a serious complication inthe clinical scenario of acute viral hepatitis, where the illness istypically expected to be self-limited and the overall fatality rate isusually less than 1%. It is noteworthy that none of the patientsreported by Jeyamani et al. were pregnant women.Further studies are needed to determine the prevalence of subacuteliver failure in hepatitis E. Indeed, HEV is the most frequentlyidentifiable agent for fulminant hepatitis in many endemicareas, like India,12 which not only reflects the endemicity of HEVbut also the virulence of this virus. There is now a substantial bodyof evidence indicating that HEV superinfection is an importantprecipitating factor for hepatic decompensation and death inpatients with chronic liver disease. This is of great concern in bothHEV endemic and non-endemic areas. Retrospective and prospectivestudies from India have suggested that HEV infection is associatedwith rapid hepatic decompensation and death in 44–50% ofcirrhotic patients.13–14 It echoes with the observation that approximately30% of fatal liver failure during the course of chronichepatitis B in southeast China is due to HEV superinfection.15 Inthis issue of the Journal, Kumar et al.16 also report that HEVaccounted for 19% of acute exacerbations of hepatitis amongasymptomatic hepatitis B ‘carriers’. Further, patients with HEVsuperinfection took a longer time for normalization of liverenzymes compared with patients with spontaneous exacerbationsof chronic hepatitis B.An earlier study from Taiwan showed that chronic hepatitis Bcarriers were at a nine-fold increased risk of fulminant hepatitisthan HBV-non-infected persons when they develop acute hepatitis.17 Recently, a case series of seven patients with fulminant liverfailure due to autochthonous hepatitis E was reported fromFrance.18 By multivariate analysis, chronic liver disease was identifiedas a risk factor for fulminant liver failure when comparedwith 33 patients with mild forms of acute hepatitis E. Furthermore,it is well recognized that hepatitis E may result in fulminanthepatic failure and has a mortality rate of up to 30% in pregnantwomen, especially during the third trimester. Dysregulation ofcytokine production by activated T cells and a decrease in cellularimmunity together with hormonal change during pregnancy hasbeen postulated to influence viral replication and expressionleading to the increased severity of viral hepatitis.19It is also noteworthy that HEV may evolve into chronic hepatitisand even cirrhosis among immunocompromised patients. In a caseseries of acute HEV infection in organ transplant recipients inFrance,20 the authors found that 57% (8/14) of these patientsevolved to chronic hepatitis, as indicated by persistently elevatedliver enzyme levels and detectable HEV-RNA in the serum or stoolfor a mean of 15 months after the acute phase. Liver biopsies fromthese cases revealed features of chronic hepatitis, including portalfibrosis and piecemeal necrosis. They also found that patients whodeveloped chronic hepatitis E had significantly lower total, CD2,CD3, and CD4 lymphocyte counts than those in whom hepatitis Eresolved. These findings are consistent with the proposal that thediminished T-cell response may hinder HEV clearance resulting inpersistent HEV infection. Indeed, a case of rapidly progressivecirrhosis in a renal transplant recipient with chronic hepatitis Einfection has recently been reported.21 Further studies are neededto determine the incidence of chronic HEV infection in transplantrecipients who live in HEV-endemic areas, and among patientswith other immunocompromised conditions.In HEV-endemic areas, provision of safe drinking water andproper disposal of sanitary waste are the mainstays for the preventionof epidemics of hepatitis E. In industrialized regions, wildanimal meat, pig liver and pork should be cooked thoroughlybefore consumption. Personnel working with non-human primates,pigs, cattle, sheep and goats should attend to strict personalhygiene (particularly handwashing) after contact with animals.Recently, an HEV recombinant vaccine using capsid antigen hasbeen developed. The vaccine is probably effective against HEV inall regions, as HEV has only one serotype. Among healthy adultsin Nepal, the vaccine was shown to be safe and its protectiveefficacy against clinically overt hepatitis E infection was 95.5% insubjects who received all three vaccine doses (at 0, 1 and6 months), and 85.7% after two doses.22 Universal pediatric vaccinationin HEV-endemic areas may provide the most effectivemeans to control epidemics and sporadic hepatitis E. Travellers toHEV-endemic regions, and persons who are at high risk of developingfulminant hepatitis E, namely, patients with chronic liverdisease (or chronic HBV or HCV infection even without apparentliver disease), organ-transplant recipients, and pregnant women,may be considered as appropriate candidates to receive HEVvaccine. However, further studies are needed to investigate thesafety and efficacy of the vaccine in these high-risk groups, and theduration of protection conferred by the vaccine.References1 Krawczynski K, Aggarwal R, Kamili S. Hepatitis E virus:epidemiology, clinical and pathologic features, diagnosis, andexperimental models. In: HC, Lemon S, Zuckerman AJ, eds.Viral Hepatitis, 3rd edn. Malden, MA: Blackwell Publishing, 2005;624–34.2 Dalton HR, Thurairajah PH, Fellows HJ et al. Autochthonoushepatitis E in southwest England. J. Viral Hepat. 2007; 14: 304–9.3 Mansuy JM, Peron JM, Abravanel F et al. Hepatitis E in thesouthwest of France in individuals who have never visited anendemic area. J. Med. Virol. 2004; 74: 419–24.4 DL, Yarbrough PO, Vlahov D et al. Seroreactivity tohepatitis E virus in areas where the disease is not endemic. J. Clin.Microbiol. 1997; 35: 1244–7.5 Meng XJ, Wiseman B, Elvinger F et al. Prevalence of antibodies tohepatitis E virus in veterinarians working with swine and in normalblood donors in the United States and other countries. J. Clin.Microbiol. 2002; 40: 117–22.6 Clayson ET, Innis BL, Myint KS et al. Detection of hepatitis E virusinfections among domestic swine in the Kathmandu Valley of Nepal.Am. J. Trop. Med. Hyg. 1995; 53: 228–32.7 Banks M, Bendall R, Grierson S, Heath G, J, Dalton HR.Human and porcine hepatitis E virus strains, UK. Emerg. Infect. Dis.2004; 10: 953–5.8 Meng XJ, Halbur PG, Shapiro MS et al. Genetic and experimentalevidence for cross-species infection by swine hepatitis E virus. J.Virol. 1998; 72: 9714–21.9 Tei S, Kitajima N, Takahashi K, Mishiro S. Zoonotic transmissionof hepatitis E from deer to human beings. Lancet 2003; 362:371–3.10 Chau TN, Lai ST, Tse C et al. Epidemiology and clinical features ofsporadic hepatitis E as compared with hepatitis A. Am. J.Gastroenterol. 2006; 1001: 292–6.11 Jeyamani R, Ramakrishna B, Eapen CE et al. Subacute hepaticfailure due to hepatitis. J. Gastroenterol. Hepatol. 2008; 23: 879–82.12 Acharya SK, Panda SK, Saxena A, Gupta SD. Acute hepatic failurein India: a perspective from the East. J. Gastroenterol. Hepatol.2000; 15: 473–279.13 Kumar A, Aggarwal R, Nalk SR et al. Hepatitis E virus isresponsible for decompensation of chronic liver disease in anendemic region. Indian J. Gastroenterol. 2004; 23: 59–62.14 Acharya SK, Sharma PK, Singh R et al. Hepatitis E virus infectionin patients with cirrhosis is associated with rapid decompensationand death. J. Hepatol. 2007; 46: 387–94.15 Ke WM, Li XJ, LN Y et al. Etiological investigation of fatal liverfailure during the course of chronic hepatitis in southeast China.J. Gastroenterol. 2006; 41: 347–51.16 Kumar M, Sharma BC, Sarin SK. Hepatitis E virus as an etiology ofacute exacerbation of previously unrecognized asymptomatic patientswith hepatitis B virus-related chronic liver disease. pls extend refdetails. J. Gastroenterol. Hepatol. 2008; 23: 883–7.17 Chu CM, Liaw YF. Increased incidence of fulminant hepatic failurein previously unrecognized HBsAg carriers with acute hepatitisindependent of etiology. Infection 2005; 33: 136–9.18 Peron JM, Bureau C, Poirson H et al. Fulminant liver failure fromacute autochthonous hepatitis E in France: description of sevenpatients with acute hepatitis E and encephalopathy. J. Viral. Hepat.2007; 14: 298–303.19 Jilani N, Das BC, Husain SA et al. Hepatitis E virus infection andfulminant hepatic failure during pregnancy. J. Gastroenterol.Hepatol. 2007; 22: 672–82.20 Kamar N, Silves J, Mansuy JM et al. Hepatitis E virus and chronichepatitis in organ-transplant recipients. N. Engl. J. Med. 2008; 358:811–17.21 Gerolami R, Moal V, Colson P. Chronic hepatitis E with cirrhosisin a kidney-transplant recipient. N. Engl. J. Med. 2008; 358: 859–10.22 Shrestha MP, RM, Joshi DM et al. Safety and efficacy of arecombinant hepatitis E vaccine. N. Engl. J. Med. 2007; 356: 895–903.