- Viral Infections (RNA)
Hepatitis E virus (HEV), also referred to as enterically transmitted non-A non-B hepatitis virus, has been associated with waterborne outbreaks since 1955. Availability of serological tests for hepatitis A and hepatitis B virus, identified this virus as a different causative agent of acute hepatitis. HEV is endemic in developing countries and associated with poor sanitation and water borne outbreaks. However, in developed countries, traditionally HEV was associated with travelers returning from HEV endemic countries. Zoonotic or food borne transmission has contributed to increase in number of locally acquired cases in developed nations. The epidemiology, pathogenicity and mode of transmission varies with infecting genotype of this virus.Hepatitis E
HEV causes self-limited acute hepatitis. Majority of cases are asymptomatic with rates varying from 50% in developing countries to 67-98% in developed countries. Mean incubation period of hepatitis E is 40 days (15-60 days). Clinical features are non-specific including anorexia, nausea, vomiting, diarrhea, fever, jaundice, hepatomegaly. In developing countries, case fatality rate of up to 4% during outbreaks and maternal mortality rate of ~25% have been reported.
Clinical features of hepatitis E are non-specific and in majority of developed countries diagnosis is based on risk factors including travel to endemic countries or consumption of contaminated food/meat. Different laboratory methods of HEV diagnosis are:
Immune Electron Microscopy
This technique involves use of stool sample treated with serum containing antibodies against HEV. Presence of virus is confirmed by agglutination and detection using electron microscope.
The tests involve detection of HEV IgG, IgM, IgA antibodies or HEV antigen in serum or plasma using enzyme immune assay (EIA). HEV IgG detection indicates previous exposure as the antibody can persist for years and are suitable for seroprevalence studies. Acute HEV cases are diagnosed by detection of HEV IgM, as this class of antibody can persist for 6 months. IgA based assay has been suggested for acute HEV diagnosis with no IgM response. EIA for direct detection of antigen has been developed for early diagnosis of infection.
Nucleic acid amplification assays
Such assays are based on detection of viral
Ribonucleic Acid (RNA)
The biological molecule that contains long chains of nucleotide units of a nitrogenous base, a ribose sugar and a phosphate is known as Ribonucleic acid. RNA is single stranded molecule with ribose, unlike DNA that is double stranded with deoxyribose. Another difference between a DNA and RNA molecule is presence of base uracil instead of thymine in RNA. in blood, which are useful in diagnosis of immunocompromised patients who do not develop antibody responses. Nucleic acid amplification methods include nested RT-PCR, real time PCR. Transcription mediated amplification has been developed for nucleic acid testing for screening of blood.
These tests include detection of increased levels of bilirubin, alanine transaminase, aspartate aminotransferase in acute HEV infection. However, these tests are non-specific as they are detectable in other viral hepatitis.
An in vitro study proposed that the truncated structural protein (p239) of HEV, binds to heparan sulphate proteoglycan receptors. HEV replication involves entry of the virus by
The process of absorption of molecules present outside the cells by the method of engulfment with the cell membrane is known as endocytosis. , uncoating of capsid, translation and replication of RNA Ribonucleic Acid (RNA)
The biological molecule that contains long chains of nucleotide units of a nitrogenous base, a ribose sugar and a phosphate is known as Ribonucleic acid. RNA is single stranded molecule with ribose, unlike DNA that is double stranded with deoxyribose. Another difference between a DNA and RNA molecule is presence of base uracil instead of thymine in RNA. in the host cytoplasm, synthesis of capsid which packages RNA Ribonucleic Acid (RNA)
The biological molecule that contains long chains of nucleotide units of a nitrogenous base, a ribose sugar and a phosphate is known as Ribonucleic acid. RNA is single stranded molecule with ribose, unlike DNA that is double stranded with deoxyribose. Another difference between a DNA and RNA molecule is presence of base uracil instead of thymine in RNA. to virions with subsequent release. HEV pathogenesis has been studied in Cynomolgus macaques intravenously infected with HEV containing bile or faeces. After 2-3 weeks of infection, increase in serum alanine aminotransferases, histopathological changes in liver, appearance of antigen in liver, virus in bile and antibodies against HEV in serum were observed. In general, HEV RNA Ribonucleic Acid (RNA)
The biological molecule that contains long chains of nucleotide units of a nitrogenous base, a ribose sugar and a phosphate is known as Ribonucleic acid. RNA is single stranded molecule with ribose, unlike DNA that is double stranded with deoxyribose. Another difference between a DNA and RNA molecule is presence of base uracil instead of thymine in RNA. appears in blood after 2-3 weeks of infection and persists for 4 weeks whereas in faces is detectable for 6 weeks. HEV IgM appears after 3-4 weeks of infection and declines after 3-6 months. HEV IgG is detectable after 4-5 weeks of infection and can persist for 12 years or more. Biopsies of acute hepatitis E positive patients shows spotty necrosis and portal expansion of infiltrates of lymphocytes and polymorphonuclear leukocytes Leukocytes
The white blood cells of the immune system, that defend the body against infectious diseases and foreign materials are known as leukocytes. , ballooning of hepatocytes, presence of councilman bodies, bile ductular proliferation.
Chronic HEV infection has been reported in solid organ transplant (kidney, liver and pancreas) recipients and in immune suppressive conditions like HIV. HEV can cause non-hepatitis manifestations like pancreatitis, thrombocytopenia, autoimmune phenomena, Guillian-Barré syndrome.
HEV is classified in the family Hepeviridae and the genus Hepevirus. The virus is approximately 30 nm in diameter with icosahedral symmetry. HEV is stable in bile due to absence of envelope and thus excreted in faeces.
The HEV genome comprises of single stranded positive sense
Ribonucleic Acid (RNA)
The biological molecule that contains long chains of nucleotide units of a nitrogenous base, a ribose sugar and a phosphate is known as Ribonucleic acid. RNA is single stranded molecule with ribose, unlike DNA that is double stranded with deoxyribose. Another difference between a DNA and RNA molecule is presence of base uracil instead of thymine in RNA. of 7.5 kb in length with three open reading frames (ORFs). ORF1 codes for non-structural proteins, ORF2 codes structural proteins and ORF3 codes cellular proteins. There are four genotypes of HEV which are characterized based on ORFs. Genotype 1 has been reported from Asia and Africa and 2 from Mexico and some African countries. Both genotypes include human strains. Genotypes 3 and 4 infect both humans and swine and are reported globally and in southeast Asia respectively. HEV genotypes 3 and 4 have been isolated from other animals (deer, mongoose, rats, rabbits, cattle or sheep).
Modes of transmission
HEV is commonly known to be transmitted through drinking contaminated water or consumption of raw or uncooked infected meat, especially pork. Other possible modes of transmission include contact with infected animals, blood transfusion, organ transplantation from infected donor and vertical transmission from infected mother to child.
In developing countries such as India, Nepal, Bangladesh, Pakistan and Sudan, HEV outbreaks are commonly associated with faeco-oral transmission. Such a mode of transmission is caused by genotypes 1 and 2.
Food-borne and zoonotic transmission
HEV genotypes 3 and 4 have been reported to be associated with consumption of uncooked meat (pork) in developed countries. In the USA and Germany, genotype 3 has been detected in pig livers sold in grocery stores. Pigs are natural reservoirs of HEV and faceo-oral transmission in pigs can also occur with shedding of infectious HEV. Contact with infected animals is other possible source, as demonstrated by higher prevalence of HEV among pig farm workers.
Ribonucleic Acid (RNA)
The biological molecule that contains long chains of nucleotide units of a nitrogenous base, a ribose sugar and a phosphate is known as Ribonucleic acid. RNA is single stranded molecule with ribose, unlike DNA that is double stranded with deoxyribose. Another difference between a DNA and RNA molecule is presence of base uracil instead of thymine in RNA. has been detected in blood donors in Japan, the UK, Germany, China, Netherland, China, USA, Australia. Cases of transfusion transmission have been reported in the UK, France, Japan and Saudi Arabia. Majority of the cases are associated with genotype 3.
HEV transmission from infected mother to child has been reported to range from 33.33% in India to 100% in United Arab Emirates.
Acute HEV cases are self-limiting and generally do not require treatment. Severe chronic cases and patients receiving immunosuppresive therapy and infected with HEV are treated with ribavirin. Immunosuppressants can increase HEV replication and hence immunosuppressive therapy is reduced in the treatment of hepatitis E. Chronic cases are treated with ribavirin for 3 months at doses of 200 mg. However, ribavirin is contraindicated during pregnancy. Pegylated interferon-α 2a at a dose of 135 µg/week for 3 months can clear HEV
Ribonucleic Acid (RNA)
The biological molecule that contains long chains of nucleotide units of a nitrogenous base, a ribose sugar and a phosphate is known as Ribonucleic acid. RNA is single stranded molecule with ribose, unlike DNA that is double stranded with deoxyribose. Another difference between a DNA and RNA molecule is presence of base uracil instead of thymine in RNA. in chronic cases.
Prevention of HEV infection include improvement of sanitation and safe supply of drinking water. Food borne transmission is preventable by proper cooking of food /meat before consumption. The virus is inactivated by cooking at 71°C for 20 minutes. Although, two vaccines have been developed, neither is licensed for use worldwide. A recombinant vaccine encoding ORF2 of a Pakistani HEV strain was derived from the Sf9 insect cell line using baculovirus (Dyncorp, Rockville. Md., USA). This vaccine was trialed with the Nepalese Army and the efficacy was found to be 95.5% but durability of immunity was unclear. A recombinant vaccine – HEV 239 (Hecolin: Xiamen Innovax Biotech, Xiamen, China) encoding ORF2, expressed in Escherichia coli has been determined to be safe and immunogenic. This vaccine has been approved in China.
Majority of HEV cases are asymptomatic and therefore actual incidence of disease is unknown. In 2005, the global annual disease burden for HEV genotypes 1 and 2 was estimated to be 20.1 million incident infections, which resulted in an estimate of 3.3 million symptomatic cases, 70,000 deaths and 3,000 still births. Burden for HEV genotypes 3 and 4 is not known. HEV seroprevalence of less than 5% to greater than 50% has been reported in different countries. However, seroprevalence does vary with different study population and assays due to variability in sensitivity and specificity. The occurrence of HEV genotypes 1 and 2 in developing countries is associated with waterborne outbreaks. In developed countries, occurrence of hepatitis E is associated with food borne transmission, zoonotic transmission (caused by genotypes 3 and 4) and travelers returning from HEV endemic countries (genotype 1 and 2).
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