Hepatitis D & E

Hepatitis E Dr. Sachin VermaMD (Medicine), FICM, FCCSConsultant Internal Medicine & Critical CareIvy Hospital Mohali 71

Hepatitis E virus: An important pathogen in tropical and subtropical regions

Source ofvirusfecesblood/blood-derivedbody fluidsblood/blood-derivedbody fluidsblood/blood-derivedbody fluidsfecesRoute oftransmissionfecal-oralpercutaneouspermucosalpercutaneouspermucosalpercutaneouspermucosalfecal-oralChronicinfectionnoyesyesyesnoPreventionpre/post-exposureimmunizationpre/post-exposureimmunizationblood donorscreening;risk behaviormodificationpre/post-exposureimmunization;risk behaviormodificationensure safedrinkingwaterType of HepatitisABCDE3 Introduction1978: epidemic of icteric viral hepatitis in the Kashmir Valley involving 52000 cases with 1650 fulminant forms and 1560 deaths.

1980: MS Khuroo suggested that this epidemic of hepatitis might have been caused by new virus .(Am J Med 68:818-23,1980).1983 : Balayan demonstrated that this virus, at difference of non-A non-B virus, is transmitted by fecal-oral route. (Intervirology 20:23-31,1983).

1991 : By transmitting the disease to monkeys the virus was recovered and its morphology and genome were identified Structure of hepatitis e virusicosahedral and nonenvelopedDiameter of approximately 34 nanometersSingle strand of RNA approximately 7.5 kilobases in length.

Classified as the single member of the genus herpesvirus in the family Herpesviridae

Three large opening reading frames (ORFs) of the positive-sense RNA of HEV have been described

Phylogenetic analysisFour genotypes

Upto 24 subtypes .

Epidemiology of Hepatitis ECentral and South-East Asia, North and West Africa, and in MexicoCommon in hot climate areasporadic cases of hepatitis E - south-east and central Asia, the Middle East, northern and western Africa, and North America

The highest rates of infection occur in regions where low standards of sanitation promote the transmission of the virus. Epidemics of hepatitis E have been reported in Central and South-East Asia, North and West Africa, and in Mexico, especially where faecal contamination of drinking water is common. However, sporadic cases of hepatitis E have also been reported elsewhere and serological surveys suggest a global distribution of strains of hepatitis E of low pathogenicity. hepatitis E is responsible for up to 70% of acute hepatitis cases in countries such as Saudi Arabia, Vietnam, Indonesia, Malaysia, and Nepal.

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Major outbreaksKashmir: 52,000 cases in 1978

Kanpur :79,000 cases in 1991

China :100,000 cases between 1986 and 1988

Recent outbreaks2004 : Chad, 1,442 reported cases and 46 deaths.

2004: Sudan, 6,861 cases and 87 deaths.

2011: minor outbreak reported in Tangail, Bangladesh.

June,2012 : an outbreak was reported in Ichalkaranji, Maharashtra.3232 cases and 18 deathsand 3 died in Shirol taluka of Kolhapur Maharashtra

Mode of TransmissionSpreadfaecal-oral route

Food and waterborne disease

Ingestion of raw or uncooked shellfish has been the source of sporadic cases in endemic areas

Risk factorpoor sanitation

HEV strains have been genetically identified including domestic and wild pigs, chickens, deer, rabbits, mongeese, dogs, cats, sheep, goats, rodents, cattle, and non-human primates,

Can we call hepatitis e an emerging zoonotic infection ???

Hepatitis E - Clinical FeaturesIncubation period:Average 40 daysRange 15-60 daysCase-fatality rate:Overall, 1%-3%Pregnant women, 15%-25%Illness severity:Increased with ageChronic sequelae:???? Classic presentation:Infectious HepatitisPhase 1 - Viral replication; Patients are asymptomatic during this phase.Phase 2 Prodromal Phase 3 - Icteric phasePhase 4 - Convalescent phase; symptoms and icterus resolve. Liver enzymes return to normal.

Severe cases may cause fulminant hepatitis

Hepatitis E and chronicity

Reports of presence of HEV RNA and chronic hepatitis in liver and kidney transplant recipients

Total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed.*

*Kamar N, Selves J, Mansuy JM, Ouezzani L, Pron JM, Guitard J, Cointault O, Esposito L, Abravanel F, Danjoux M, Durand D, Vinel JP, Izopet J, Rostaing L.N Engl J Med. 2008 Feb

Kamar N, Selves J, Mansuy JM, Ouezzani L, Pron JM, Guitard J, Cointault O, Esposito L, Abravanel F, Danjoux M, Durand D, Vinel JP, Izopet J, Rostaing L.N Engl J Med. 2008 Feb Higher fatalities in pregnant womenCase fatality rate is 20%, and this rate increases during the second and third trimesters. Reported causes of death include encephalopathy , disseminated intravascular coagulation and fulminant hepatic failure

Liver transplant patients at riskHEV infection can lead to chronic hepatitis. If the patient has antibodies against HEV, the risk of reactivation is extremely low

HEV has emerged as the leading identified cause of autochthonous acute hepatitis among adults

Colson P, MoalV, MotteA, et al.,EASL 2011; abstract A-343Incidence of HEV infection in Solid organ transplantation: 1% after liver transplantation in the Netherlands and in France[Haagsmaetal.,2009;Kamaretal.,2008] 4.5% in kidney transplant recipients in France [Kamaretal.,2008].

0.4-3.4 % in liver transplant recipients in the Netherlands, Germany and Spain [Haagsmaetal.,2009;Pischkeetal.,2010;Butietal.,2010].

Furthermore,in these previous studies, progression toward chronicity occurred in about 60% of kidney-transplant recipients infected with HEV.

HEV and HIV

The Rate of Anti-HEV seropositivity increased with the progression of HIV infection, reaching 43.3% in AIDS patients and 38.1% in those who died from AIDS.The Rate of Anti-HEV seropositivity increased with the progression of HIV infection, reaching 43.3% in AIDS patients and 38.1% in those who diet from AIDS.26

The percentages of HBcAb, HBsAg, anti-HCV and anti HEV (58.5, 14.5, 58.5 and 6.6% respectively) were significantly higher in HIV-positive patients than in control groups.27

Diagnosis of hepatitis E

Hepatitis E should be suspected in outbreaks of waterborne hepatitis occurring in:Developing countries,Especially if the disease is more severe in pregnant women,Or if hepatitis A has been excludedIf laboratory tests are not available, epidemiologic evidence can help in establishing a diagnosis

Acute hepatitis E is diagnosed when the presence of IgM anti-HEV is detected

Storage of serum samples is acceptable for several days at 4C Anti-HEV will be preserved at 20C,HEV RNA can be detected in acute phase in serum or faeces by PCR in approximately 50% of cases. Can be detected 2 wks before and 2 wks after the onset of symptoms

Immune electron microscopy is positive in only about 10% of cases

To confirm the results of EIA or ELISA tests, Western blot assays to detect IgM and IgG anti-HEV in serum can be used

Are Anti-HEV antibodies protective? Antibodies at onset of outbreak and attack rate Anti hev +ve 0/46 ( 0%) Anti hev ve 23/63( 37%)

Infusion of convalescent plasma into nave animals induced protection against disease (but not infection) In vitro neutralization of HEV by anti-HEV antibodies PreventionImproving sanitation is the most important measure consists of proper treatment and disposal of human waste higher standards for public water supplies improved personal hygiene proceduressanitary food preparation.

Best option to prevent hepatitis E infectionClean drinking water

Immunoglobulin's in 3 rd. trimester reduces mortality

Immune serum globulin will considerably reduce mortality in the 3rd trimester of pregnancy

Vaccines At present, no commercially available vaccine Vaccines on trial

Recombinant vaccine

Subunit vaccine

Recombinant vaccinesA 55 kDa recombinant HEV-derived ORF2 protein has been used to vaccinate rhesus monkeys

Although primates could still be infected, the vaccine protected them from the symptoms of disease

Subunit HEV vaccinesThe direct intramuscular injection of purified plasmid DNA containing the full-length ORF2 of HEV has induced a prolonged humoral immune response (>12 months)

DNA immunization

ORF2 was injected as an expression plasmid directly into muscle resulted in moderate anti- pORF2 titres in mice

Combined vaccine against hepatitis A and hepatitis E Results showed that the combined vaccine could induce neutralizing antibodies against both hepatitis A virus (HAV) and hepatitis E virus (HEV) effectively in mice.

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