Hepatitis E Infection

Hepatitis E infection an update:

Dr.T.V.Rao MD Hepatitis E infection an update Dr.T.V.Rao MD 1

History as documented:

History as documented Dr.T.V.Rao MD 2 In 1978 there was a vast epidemic of icteric viral hepatitis in the Kashmir Valley involving 52000 cases with 1650 fulminant forms and 1560 deaths. Since serology for hepatitis A and B in these patients was negative and the clinical course and the epidemic type of its spread were not those of post-transfusional non-A non-B hepatitis, MS Khuroo in 1980 suggested that this epidemic of hepatitis might have been caused by another virus.(Am J Med 68:818-23,1980).In 1983 Balayan demonstrated that this virus, at difference of non-A non-B virus, is transmitted by fecal-oral route. He himself ingested fecal suspensions from affected patients and contracted the disease.(Intervirology 20:23-31,1983).By transmitting the disease to monkeys the virus was recovered and its morphology and genome were identified only 12-13 years later in the early nineties .

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A “ Infectious” “ Serum” Viral hepatitis Enterically transmitted Parenterally transmitted F, G, TTV ? other E NANB B D C Viral Hepatitis - Historical Perspectives Dr.T.V.Rao MD 3

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Source of virus feces blood/ blood-derived body fluids blood/ blood-derived body fluids blood/ blood-derived body fluids feces Route of transmission fecal-oral percutaneous permucosal percutaneous permucosal percutaneous permucosal fecal-oral Chronic infection no yes yes yes no Prevention pre/post- exposure immunization pre/post- exposure immunization blood donor screening; risk behavior modification pre/post- exposure immunization; risk behavior modification ensure safe drinking water Type of Hepatitis A B C D E Dr.T.V.Rao MD 4

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Structure of hepatitis e virus:

The virus is icosahedral and nonenveloped. It has a diameter of approximately 34 nanometers, and it contains a single strand of RNA approximately 7.5 kilobases in length. Four HEV genotypes exist, and genotype 1 causes human disease. Structure of hepatitis e virus Dr.T.V.Rao MD 7

Structural character of Hepatitis E virus:

Structural character of Hepatitis E virus HEV is an icosahedral, nonenveloped single stranded RNA virus that is approximately 27 to 34 nm in diameter . It has been 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 The largest ORF consists of 1693 codons; it codes for nonstructural proteins that are responsible for the processing and replication of the virus. The second ORF is composed of 660 codons and codes for structural proteins. The third ORF consists of 123 codons; although it may encode for a structural protein, its function remains undetermined. Dr.T.V.Rao MD 8

Hepatitis e shows different distinct features:

The genomic RNA of HEV exhibits several distinct features compared to the genomic RNA of caliciviruses, including a methylated cap at the 5'-end and an ORF1 with functional domains arranged in a different order. Hepatitis e shows different distinct features Dr.T.V.Rao MD 9

Phylogenetic analysis:

Phylogenetic analysis suggests that there are four genotypes (1 through 4) and up to 24 subtypes . The association of genotypes with clinical features is incompletely understood. However, genotype 1 and 2 appear to be confined to humans while genotype 3 and 4 infect humans and animals. Genotype 3 has been associated with less virulent disease Phylogenetic analysis Dr.T.V.Rao MD 10

Hepatitis E virus Infection:

Hepatitis E (HEV) was not recognized as a distinct human disease until 1980. Hepatitis E is caused by infection with the hepatitis E virus, a non-enveloped, positive-sense, single-stranded RNA virus. Although man is considered the natural host for HEV, antibodies to HEV or closely related viruses have been detected in primates and several other animal species Hepatitis E virus Infection Dr.T.V.Rao MD 11

Unhygienic conditions increase the spread of hepatitis e infections:

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. Unhygienic conditions increase the spread of hepatitis e infections Dr.T.V.Rao MD 12

Hepatitis e infection can be uneventful:

Hepatitis e infection can be uneventful In general, hepatitis E is a self-limiting viral infection followed by recovery. Prolonged viraemia or faecal shedding are unusual and chronic infection does not occur. Occasionally, a fulminant form of hepatitis develops, with overall patient population mortality rates ranging between 0.5% - 4.0%. Fulminate hepatitis occurs more frequently in pregnancy and regularly induces a mortality rate of 20% among pregnant women in the 3rd trimester. Dr.T.V.Rao MD 13

Animals can be reservoirs of infection:

Animals can be reservoirs of infection Domestic animals have been reported as a reservoir for the hepatitis E virus, with some surveys showing infection rates exceeding 95% among domestic pigs. Transmission after consumption of wild boar meat and uncooked deer meat has been reported as well . The rate of transmission to humans by this route and the public health importance of this are however still unclear . A number of other small mammals have been identified as potential reservoirs: the lesser bandicoot rat ( Bandicota bengalensis ), the black rat ( Rattus rattus brunneusculus ) and the Asian house shrew ( Suncus murinus ). A new virus designated rat hepatitis E virus has been isolated . Dr.T.V.Rao MD 14

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

The host range of HEV is ever-expanding. In addition to the animal species from which HEV strains have been genetically identified including domestic and wild pigs, chickens, deer, rabbits, and mongeese, antibodies to HEV have also been detected in many other animal species such as dogs, cats, sheep, goats, rodents, cattle, and non-human primates, suggesting that these animals have been exposed to HEV or a related agent. Can we call hepatitis e an emerging zoonotic infection ??? Dr.T.V.Rao MD 15

Course of infection:

The course of infection has 2 phases, the prodromal phase and the icteric phase. The infection is self-limited. Whether protective immunoglobulin's develop against future reinfection remains unknown. The overall case fatality rate is 4%, though pregnant women and liver transplant recipients may be at substantially higher risk . Course of infection Dr.T.V.Rao MD 16

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17 Transmission HEV is spread by the oral-faecal route Consumption of faecally contaminated drinking water has given rise to epidemic cases, Ingestion of raw or uncooked shellfish has been the source of sporadic cases in endemic areas Most outbreaks associated with faecally contaminated drinking water Dr.T.V.Rao MD

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18 Zoonotic transmission Naturally acquired HEV antibodies have been detected in primates, rodents and swine Swine HEV cross-reacts with antibodies to the human HEV Human hepatitis E has been transmitted under laboratory conditions to various species of primates, pigs, lambs, rats Dr.T.V.Rao MD

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19 Zoonotic transmission Species specific HEV has been demonstrated in pigs with the identification of swine HEV Swine HEV is distinct, but closely related to human HEV strains Swine HEV raises a potential public health concern for zoonosis and xenozoonosis following xenotransplantation with pig organs Dr.T.V.Rao MD

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20 Zoonotic transmission A zoonotic spread of HEV is not excluded Monkeys, pigs, cows, rodents, sheep and goats are susceptible Anti-HEV has been found in a significant proportion, up to 28% in some areas, of healthy individuals in industrialized countries Dr.T.V.Rao MD

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Most outbreaks associated with faecally contaminated drinking water. Several other large epidemics have occurred since in the Indian subcontinent and the USSR, China, Africa and Mexico. In the United States and other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low prevalence of anti-HEV (<2%) has been found in healthy populations. The source of infection for these persons is unknown. Minimal person-to-person transmission. Hepatitis E - Epidemiologic Features Dr.T.V.Rao MD 21

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Incubation period: Average 40 days Range 15-60 days Case-fatality rate: Overall, 1%-3% Pregnant women, 15%-25% Illness severity: Increased with age Chronic sequelae: None identified Hepatitis E - Clinical Features Dr.T.V.Rao MD 22

prodromal phase :

prodromal phase The incubation period ranges from 15 days to 60 days. The course of infection has 2 phases, the prodromal phase and the icteric phase. Prodromal-phase symptoms include the following: Myalgia Arthralgia Fever with mild temperature elevations (25-97%) Anorexia (66-100%) Nausea/vomiting (30-100%) Weight loss (typically 2-4 kg) Dehydration Right upper quadrant pain that increases with physical activity (abdominal pain is reported in 35-80% of patients) Dr.T.V.Rao MD 23

icteric-phase symptoms include the following::

icteric-phase symptoms include the following: Jaundice – This may be difficult to see with some patients’ natural skin color; the serum bilirubin level is higher than 3 mg/dL; scleral icterus is present Dark urine Light-colored stools (20-40%) Pruritus (50%) Other features include the following: Urticarial rash Diarrhea Malaise (95-100%) Dr.T.V.Rao MD 24

Age-, sex-, and race-related demographics :

Hepatitis E predominantly affects persons aged 15-40 years. It may affect younger age groups, but it generally is not recognized and may be subclinical in these populations. No chronic cases have been described. Although hepatitis E is not known to have a predilection for either sex, pregnant women are prone to complications. Hepatitis E has no apparent racial predilection. Age-, sex-, and race-related demographics Dr.T.V.Rao MD 25

No established chronicity in hepatitis e infections ???:

No chronic cases of acute hepatitis E have been reported. The infection is self-limited. Whether protective immunoglobulin's develop against future reinfection remains unknown. The overall case fatality rate is 4%. No established chronicity in hepatitis e infections ??? Dr.T.V.Rao MD 26

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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 excluded If laboratory tests are not available, epidemiologic evidence can help in establishing a diagnosis Dr.T.V.Rao MD

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28 Diagnosis of hepatitis E Acute hepatitis E is diagnosed when the presence of IgM anti-HEV is detected Storage of serum samples is acceptable for several days at 4°C, Anti-HEV will be preserved at – 20°C, A temperature of #-70°C should be preferred when viremia is suspected.42 Dr.T.V.Rao MD

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29 Hepatitis E Virus Infection Typical Serologic Course Weeks after Exposure Titer Symptoms ALT IgG anti-HEV IgM anti-HEV Virus in stool 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Dr.T.V.Rao MD

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30 Diagnosis of Hepatitis E HEV RNA can be detected in acute phase faeces by PCR in approximately 50% of cases Immune electron microscopy is positive in only about 10% of cases The viral proteins pORF2 and pORF3 have been expressed in various recombinant systems and form the basis for diagnostic tests and vaccine studies Dr.T.V.Rao MD

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31 Diagnosis of hepatitis E To confirm the results of EIA or ELISA tests, Western blot assays to detect IgM and IgG anti-HEV in serum can be used PCR tests for the detection of HEV RNA in serum and stool, I mmunofluorescent antibody blocking assays to detect antibody to HEV antigen in serum and liver, Immune electron microscopy to visualize viral particles in faeces Dr.T.V.Rao MD

Higher fatalities in pregnant women:

Among pregnant women, the case fatality rate is 20%, and this rate increases during the second and third trimesters. Reported causes of death include encephalopathy and disseminated intravascular coagulation. The rate of fulminant hepatic failure in infected pregnant women is high. Higher fatalities in pregnant women Dr.T.V.Rao MD 32

Liver transplant patients at risk:

Liver transplant recipients may be at a greater risk for HEV infection, which can lead to chronic hepatitis . However, if the patient has antibodies against HEV, the risk of reactivation is extremely low Liver transplant patients at risk Dr.T.V.Rao MD 33

Prevalence of hepatitis e infection:

Prevalence of hepatitis e infection Hepatitis E is prevalent in most developing countries, and common in any country with a hot climate. It is widespread in Southeast Asia, northern and central Africa, India, and Central America. It is spread mainly through fecal contamination of water supplies or food; person-to-person transmission is uncommon. Outbreaks of epidemic Hepatitis E most commonly occur after heavy rainfalls and monsoons because of their disruption of water supplies. Major outbreaks have occurred in New Delhi, India (30,000 cases in 1955-1956), Burma (20,000 cases in 1976-1977), Kashmir, India (52,000 cases in 1978), Kanpur, India (79,000 cases in 1991), and China (100,000 cases between 1986 and 1988). Dr.T.V.Rao MD 34

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35 Some of the Major Epidemics Place Year Number of cases India Myanmar Kashmir China Somalia Mexico Iran (Kermanshah) Sudan Chad Iraq 1955 1976 1978 1986 1988 1989 1991 2004 2004 2004 30000 20000 52000 100000 11000 4000 Hundreds 4000 1000 hundreds Dr.T.V.Rao MD

Prevention:

Improving sanitation is the most important measure, which consists of proper treatment and disposal of human waste, higher standards for public water supplies, improved personal hygiene procedures and sanitary food preparation. Thus, prevention strategies of this disease are similar to those of many others that plague developing nations, and they require large-scale international financing of water supply and water treatment projects. Prevention Dr.T.V.Rao MD 36

Best options to prevent hepatitis e infections:

Ensuring a clean drinking water supply remains the best preventive strategy. Recombinant vaccines are being developed that may be particularly useful for travellers to disease-endemic areas and for pregnant women. Best options to prevent hepatitis e infections Dr.T.V.Rao MD 37

Immunoglobulin's in 3 rd. trimester reduces mortality:

Protective antibodies after the infection are apparently effective to prevent reinfection even with strains from distant regions but the duration of this protection in humans is still questioned. Immune serum globulin will considerably reduce mortality in the 3rd trimester of pregnanc y but will not block incidence of infection on contact. A vaccine is not yet available. Immunoglobulin's in 3 rd. trimester reduces mortality Dr.T.V.Rao MD 38

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39 Vaccines At present, no commercially available vaccines exist for the prevention of hepatitis E. Several studies for the development of an effective vaccine against hepatitis E are in progress : 1- Recombinant vaccines 2- Subunit HEV vaccines Dr.T.V.Rao MD

A vaccine on trail :

A vaccine based on recombinant viral proteins has been developed and recently tested in a high-risk population (military personnel of a developing country).The vaccine appeared to be effective and safe, but further studies are needed to assess the long-term protection and the cost-effectiveness of hepatitis E vaccination. A vaccine on trail Dr.T.V.Rao MD 40

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41 Vaccines • Recombinant vaccines A 55 kDa recombinant HEV-derived ORF2 protein has been used to vaccinate rhesus monkeys against different strains of hepatitis E. Although primates could still be infected, the vaccine protected them from the symptoms of disease Dr.T.V.Rao MD

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42 Vaccines • Subunit HEV vaccines The direct intramuscular injection of purified plasmid DNA containing the full-length ORF2 of HEV has induced a prolonged humoral immune response (>12 months) To the expressed structural protein ORF2 in 80% and 100% of two separate groups of challenged mice, respectively Dr.T.V.Rao MD

Hepatitis can go into chronic phase in immunosuppressed :

Recent studies indicate that chronic HEV infection may develop in immunosuppressed patients. Acute HEV infection in immunocompromised patients such as organ transplant recipients and cancer patients not only can evolve into chronic hepatitis E, but also can rapidly progress into cirrhosis as well. In some of these patients, anti-HEV antibodies were negative [56] probably because of immune suppression. The contribution of the deficiency of anti-HEV antibodies to the establishing of the chronic infection needs to be established. Hepatitis can go into chronic phase in immunosuppressed Dr.T.V.Rao MD 43

Hepatitis e infection is a concern of developed nations too:

Hepatitis E is no longer just a disease of developing countries. Sporadic cases of human hepatitis E have been reported in both industrialized and developing countries, although epidemics only occur in developing countries of Asia, Africa, and in Mexico . [ Recently , there has been an increased incidence of sporadic hepatitis E cases in industrialized countries, and most are caused by zoonotic genotypes 3 and 4 strains of HEV. Hepatitis e infection is a concern of developed nations too Dr.T.V.Rao MD 44

Hygienic hand wash can save several lives from hepatitis e infections:

Hygienic hand wash can save several lives from hepatitis e infections Dr.T.V.Rao MD 45

Major references :

Major references CDC, Atlanta on Hepatitis E infections WHO/CDS/CSR/EDC/2001.12, Hepatitis E World Health Organization, Department of Communicable Disease Surveillance and, Response Control of communicable diseases, 2000 Dr.T.V.Rao MD 46

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