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In the name of GOD
HEPATITIS E VIRUS
Presented by
Sajjad Shahmoradi
Introduction
Hepatitis E was not recognized as a distinct clinical entity until 1980 when sensitive and specific tests for antibody to hepatitis A virus (anti-HAV) were first applied to the study of epidemic waterborne hepatitis in India
The first direct experimental evidence for the existence of an additional waterborne hepatitis agent was reported in 1983 by Balayan et al
Classification 1 Initial analysis of the HEV genome revealed three open
reading frames (ORF) nonstructural proteins were localized at the 5 end and structural protein(s) at the 3 end of the genome and subgenomic messenger RNA (mRNA) detected in infected liver tissue were superficially suggestive of a relationship with the caliciviruses
So the virus was classified in the Caliciviridae family
Classification 2
The order of the genes of HEV however is not identical to
that of typical caliciviruses
although the sequence of HEV is not closely related to that of any other recognized virus it most closely resembles the sequences of rubella virusFor these and other reasons HEV was removed from the Caliciviridae family and reclassified as the only member of the genus Hepevirus in the new family Hepeviridae
Morphology bullHepatitis E virus is a nonenveloped spherical particle approximately 30 to 34 nm in diameter with an indefinite surface substructure that is slightly less pronounced than that of the Norwalk agent (a calicivirus) but distinguishable from the smooth featureless surface of hepatitis A virus
bullOn the basis of morphology however HEV cannot be reliably distinguished from other ldquosmall round virusesrdquo found
in feces
Chemistry bullThe virus is relatively stable to acid and mild alkaline Conditions
bullHEV is more heat labile than is HAVbullAlthough not specifically tested HEV is likely to be inactivated by the same agents that inactivate HAV
bullHEV contains an RNA genome enclosed within a capsid that is probably composed of single protein
bull
Genome Structure 1 bullThe HEV genome consists of three overlapping ORF and utilizes all three coding framesbullThe function of only a few viral proteins has been directly demonstratedbullORF1 encodes the following MT Pol Y Pro H X Hel
bullORF2 encodes a protein that contains a typical signal sequence near its 5 end
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
HEPATITIS E VIRUS
Presented by
Sajjad Shahmoradi
Introduction
Hepatitis E was not recognized as a distinct clinical entity until 1980 when sensitive and specific tests for antibody to hepatitis A virus (anti-HAV) were first applied to the study of epidemic waterborne hepatitis in India
The first direct experimental evidence for the existence of an additional waterborne hepatitis agent was reported in 1983 by Balayan et al
Classification 1 Initial analysis of the HEV genome revealed three open
reading frames (ORF) nonstructural proteins were localized at the 5 end and structural protein(s) at the 3 end of the genome and subgenomic messenger RNA (mRNA) detected in infected liver tissue were superficially suggestive of a relationship with the caliciviruses
So the virus was classified in the Caliciviridae family
Classification 2
The order of the genes of HEV however is not identical to
that of typical caliciviruses
although the sequence of HEV is not closely related to that of any other recognized virus it most closely resembles the sequences of rubella virusFor these and other reasons HEV was removed from the Caliciviridae family and reclassified as the only member of the genus Hepevirus in the new family Hepeviridae
Morphology bullHepatitis E virus is a nonenveloped spherical particle approximately 30 to 34 nm in diameter with an indefinite surface substructure that is slightly less pronounced than that of the Norwalk agent (a calicivirus) but distinguishable from the smooth featureless surface of hepatitis A virus
bullOn the basis of morphology however HEV cannot be reliably distinguished from other ldquosmall round virusesrdquo found
in feces
Chemistry bullThe virus is relatively stable to acid and mild alkaline Conditions
bullHEV is more heat labile than is HAVbullAlthough not specifically tested HEV is likely to be inactivated by the same agents that inactivate HAV
bullHEV contains an RNA genome enclosed within a capsid that is probably composed of single protein
bull
Genome Structure 1 bullThe HEV genome consists of three overlapping ORF and utilizes all three coding framesbullThe function of only a few viral proteins has been directly demonstratedbullORF1 encodes the following MT Pol Y Pro H X Hel
bullORF2 encodes a protein that contains a typical signal sequence near its 5 end
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Introduction
Hepatitis E was not recognized as a distinct clinical entity until 1980 when sensitive and specific tests for antibody to hepatitis A virus (anti-HAV) were first applied to the study of epidemic waterborne hepatitis in India
The first direct experimental evidence for the existence of an additional waterborne hepatitis agent was reported in 1983 by Balayan et al
Classification 1 Initial analysis of the HEV genome revealed three open
reading frames (ORF) nonstructural proteins were localized at the 5 end and structural protein(s) at the 3 end of the genome and subgenomic messenger RNA (mRNA) detected in infected liver tissue were superficially suggestive of a relationship with the caliciviruses
So the virus was classified in the Caliciviridae family
Classification 2
The order of the genes of HEV however is not identical to
that of typical caliciviruses
although the sequence of HEV is not closely related to that of any other recognized virus it most closely resembles the sequences of rubella virusFor these and other reasons HEV was removed from the Caliciviridae family and reclassified as the only member of the genus Hepevirus in the new family Hepeviridae
Morphology bullHepatitis E virus is a nonenveloped spherical particle approximately 30 to 34 nm in diameter with an indefinite surface substructure that is slightly less pronounced than that of the Norwalk agent (a calicivirus) but distinguishable from the smooth featureless surface of hepatitis A virus
bullOn the basis of morphology however HEV cannot be reliably distinguished from other ldquosmall round virusesrdquo found
in feces
Chemistry bullThe virus is relatively stable to acid and mild alkaline Conditions
bullHEV is more heat labile than is HAVbullAlthough not specifically tested HEV is likely to be inactivated by the same agents that inactivate HAV
bullHEV contains an RNA genome enclosed within a capsid that is probably composed of single protein
bull
Genome Structure 1 bullThe HEV genome consists of three overlapping ORF and utilizes all three coding framesbullThe function of only a few viral proteins has been directly demonstratedbullORF1 encodes the following MT Pol Y Pro H X Hel
bullORF2 encodes a protein that contains a typical signal sequence near its 5 end
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Classification 1 Initial analysis of the HEV genome revealed three open
reading frames (ORF) nonstructural proteins were localized at the 5 end and structural protein(s) at the 3 end of the genome and subgenomic messenger RNA (mRNA) detected in infected liver tissue were superficially suggestive of a relationship with the caliciviruses
So the virus was classified in the Caliciviridae family
Classification 2
The order of the genes of HEV however is not identical to
that of typical caliciviruses
although the sequence of HEV is not closely related to that of any other recognized virus it most closely resembles the sequences of rubella virusFor these and other reasons HEV was removed from the Caliciviridae family and reclassified as the only member of the genus Hepevirus in the new family Hepeviridae
Morphology bullHepatitis E virus is a nonenveloped spherical particle approximately 30 to 34 nm in diameter with an indefinite surface substructure that is slightly less pronounced than that of the Norwalk agent (a calicivirus) but distinguishable from the smooth featureless surface of hepatitis A virus
bullOn the basis of morphology however HEV cannot be reliably distinguished from other ldquosmall round virusesrdquo found
in feces
Chemistry bullThe virus is relatively stable to acid and mild alkaline Conditions
bullHEV is more heat labile than is HAVbullAlthough not specifically tested HEV is likely to be inactivated by the same agents that inactivate HAV
bullHEV contains an RNA genome enclosed within a capsid that is probably composed of single protein
bull
Genome Structure 1 bullThe HEV genome consists of three overlapping ORF and utilizes all three coding framesbullThe function of only a few viral proteins has been directly demonstratedbullORF1 encodes the following MT Pol Y Pro H X Hel
bullORF2 encodes a protein that contains a typical signal sequence near its 5 end
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Classification 2
The order of the genes of HEV however is not identical to
that of typical caliciviruses
although the sequence of HEV is not closely related to that of any other recognized virus it most closely resembles the sequences of rubella virusFor these and other reasons HEV was removed from the Caliciviridae family and reclassified as the only member of the genus Hepevirus in the new family Hepeviridae
Morphology bullHepatitis E virus is a nonenveloped spherical particle approximately 30 to 34 nm in diameter with an indefinite surface substructure that is slightly less pronounced than that of the Norwalk agent (a calicivirus) but distinguishable from the smooth featureless surface of hepatitis A virus
bullOn the basis of morphology however HEV cannot be reliably distinguished from other ldquosmall round virusesrdquo found
in feces
Chemistry bullThe virus is relatively stable to acid and mild alkaline Conditions
bullHEV is more heat labile than is HAVbullAlthough not specifically tested HEV is likely to be inactivated by the same agents that inactivate HAV
bullHEV contains an RNA genome enclosed within a capsid that is probably composed of single protein
bull
Genome Structure 1 bullThe HEV genome consists of three overlapping ORF and utilizes all three coding framesbullThe function of only a few viral proteins has been directly demonstratedbullORF1 encodes the following MT Pol Y Pro H X Hel
bullORF2 encodes a protein that contains a typical signal sequence near its 5 end
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Morphology bullHepatitis E virus is a nonenveloped spherical particle approximately 30 to 34 nm in diameter with an indefinite surface substructure that is slightly less pronounced than that of the Norwalk agent (a calicivirus) but distinguishable from the smooth featureless surface of hepatitis A virus
bullOn the basis of morphology however HEV cannot be reliably distinguished from other ldquosmall round virusesrdquo found
in feces
Chemistry bullThe virus is relatively stable to acid and mild alkaline Conditions
bullHEV is more heat labile than is HAVbullAlthough not specifically tested HEV is likely to be inactivated by the same agents that inactivate HAV
bullHEV contains an RNA genome enclosed within a capsid that is probably composed of single protein
bull
Genome Structure 1 bullThe HEV genome consists of three overlapping ORF and utilizes all three coding framesbullThe function of only a few viral proteins has been directly demonstratedbullORF1 encodes the following MT Pol Y Pro H X Hel
bullORF2 encodes a protein that contains a typical signal sequence near its 5 end
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Chemistry bullThe virus is relatively stable to acid and mild alkaline Conditions
bullHEV is more heat labile than is HAVbullAlthough not specifically tested HEV is likely to be inactivated by the same agents that inactivate HAV
bullHEV contains an RNA genome enclosed within a capsid that is probably composed of single protein
bull
Genome Structure 1 bullThe HEV genome consists of three overlapping ORF and utilizes all three coding framesbullThe function of only a few viral proteins has been directly demonstratedbullORF1 encodes the following MT Pol Y Pro H X Hel
bullORF2 encodes a protein that contains a typical signal sequence near its 5 end
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Genome Structure 1 bullThe HEV genome consists of three overlapping ORF and utilizes all three coding framesbullThe function of only a few viral proteins has been directly demonstratedbullORF1 encodes the following MT Pol Y Pro H X Hel
bullORF2 encodes a protein that contains a typical signal sequence near its 5 end
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Genome Structure 2
bullThe ORF2-encoded protein contains potential glycosylation sites that are glycosylated in vitro
bullORF3 encodes a protein of only 114 to 115 amino acids
It fractionates with the cellular cytoskeleton
and is probably a viral regulatory protein
bullVirally-expressed ORF3 protein is not required for genome replication viral assembly or infection of
hepatoma cells
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Genome Structure 3
bullIn addition the HEV genome contains two cis-reactive elements (CRE)
bullOne CRE overlaps the 3 end of ORF2 and the 3 noncoding region and is essential for replication
bullThe second CRE may be the promoter for synthesis of the
20 kb subgenomic messenger RNA
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Genome Structure 4
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Genetic Heterogeneity bullThe human HEV strains appear to fall into at least four major genetic groups genotype 1 (Asia North Africa) genotype 2 (Mexico Southern Africa) genotype 3 (North and South America Europe Asia) and genotype 4 (Asia)
bullThus although some evidence indicates that genetic heterogeneity is regionally distributed suggesting that HEV is an old virus that was geographically dispersed in the distant past
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Propagation and Assay in Cell Culture bullVirus infectious for macaques 2nd for Huh 7 cells has been recovered from hepatocarcinoma cell cultures transfected with recombinant RNA indicating that the virus can replicate and produce infectious virus in cultured cells however the virus did not spread within the culture
bullThus HEV can replicate in a limited number of cell lines of hepatic origin but these are not robust systems and HEV remains a difficult virus to study in vitro
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Key Antigens 1
bullHepatitis E virus encodes antigens reactive in IEM enzyme-linked immunosorbent assay (ELISA) Western blot and immunofluorescence microscopy
bullMajor epitopes appear to exist in ORF2 and ORF3bullORF2 is relatively highly conserved In contrast ORF3 is more heterogeneous
bullThus it is not surprising that serologic tests based on ORF2 sequences are broadly reactive whereas tests containing
ORF3 sequences may be more strain-specific
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Key Antigens 2
bullWestern blot assays although specific have been
somewhat less sensitive than ELISA for detecting anti-HEV
bullHEV antigens derived from ORF2 and ORF3 and expressed in E coli have been incorporated into assays that are
commercially available in Europe and Asia
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Key Antigens 3bullThese assays are useful for diagnosing hepatitis E but they have failed to detect infections with some recently discovered genetic variants of HEV
bullThey are not sufficiently sensitive for seroepidemiologic studies
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Serologic Heterogeneity
bullAlthough moderate genetic heterogeneity has been identified among HEV strains evidence for serologic heterogeneity is limited
bullAll human HEV strains studied to date appear to belong to a single serotype
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Host Range 1
bullPrimates found to be susceptible to infection with HEV include Old World species such as chimpanzees macaques and African green monkeys
bullThe course of infection in experimentally infected primates is similar to that in humans
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Host Range 2
bull It is still not clear whether animals serve as a significant reservoir of HEV for infection of humans but rare zoonotic transmission has been documented recently
bullOnly genotypes 3 and 4 strains have been shown to infect both humans and animals
bullIn industrialized countries where the disease is rare or infrequent the genotype associated with disease in humans
is the same as that in the native swine
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Host Range 3
bullThis same pattern is also seen in some developing countries where human disease is more common with the exception of several reports from India and Egypt
bullBecause neither avian nor rat HEV could be transmitted to
rhesus macaques they are unlikely to infect humans
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Infection in Experimental Animals 1 bullPeak viremia and peak shedding of HEV into the feces occurs during the incubation period and early acute phase of diseasebullDetection of HEV antigens in the liver generally precedes or parallels viremia and fecal shedding
bullHistopathologic changes in the liver parallel biochemical evidence of hepatitis
bullEnzyme elevations are usually unimodal but bimodal
curves have also been observed
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Infection in Experimental Animals 3
bullAs in hepatitis A the immune response to hepatitis E in primates appears late in the incubation period or during the acute phase of illness and is characterized by a brisk IgM and IgG anti-HEV response
bullAlso as seen in hepatitis A viremia can persist for some time after the appearance of serum antibodies suggesting
the presence of immune complexes
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Replication 1
bullBecause replication of HEV in cell culture is inefficient
and because HEV is not closely related to any other well-characterized virus little is known about its strategy for
replication bullThe mechanism of attachment entry and uncoating of HEV is unknown but it is assumed that the virus attaches to receptor sites on hepatocytes and possibly cells in the biliary tract and intestine
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Replication 2bullAfter uncoating the 72-kb genome is probably translated via cellular mechanisms that recognize capped RNA
bullReplicative intermediate negative-strand RNA is probably synthesized by the viral polymerase as are subsequent strands of positive sense full-length (genomic and messenger) RNA as well as two bicistronic subgenomic mRNA
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Replication 3
bullNothing is known about the site or mode of assemblyRecombinant hepatitis E capsid protein is proteolytically processed at both ends and self-assembles into viruslike particles that have a diameter approximately two thirds that of native virions
bullNothing is known about release of the virus from infected cells
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Pathogenesis and Pathology 1
bullEntry of the virus into the host is believed to be primarily by the oral routebullThe site of primary replication has not been identified but it is presumed to be in the intestinal tractbullIt replicates in the cytoplasm of hepatocytes and is released into the bile and blood by mechanisms that are not understood
bullViremia was first detected by RT-PCR 22 days after exposure and over a week before onset of disease on day
30
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Pathogenesis and Pathology 2
bullViruslike particles were found by IEM in the feces by 34 days after exposurebull Liver enzyme values peaked on day 46bullAnti-HEV was first detected on day 41 and was still detectable 2 years laterbullAs in hepatitis A specific IgM and IgG immune responses occur early in the disease usually by the time of onset of clinical illness
bullIgM anti-HEV disappears after several months IgG anti-HEV persists but at relatively rapidly decreasing levels
shortly after infection
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Pathogenesis and Pathology 3
bullAnti-HEV of the IgA class has also been detected in the serum of naturally infected individualsbullThe significance of such antibody is unknown
bullVirus found in the feces of infected humans or animals is presumed to be the primary source of infectious virus in the environmentbullThe severity of HEV infections is on average somewhat greater than the severity of HAV infections
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Pathogenesis and Pathology 4
bullMortality of hepatitis E has varied in different reports but has been as high as 1 compared to 02 for hepatitis A
bullMore important however is the severity of hepatitis E in pregnant womenbullThe mortality of hepatitis E in pregnancy increases with each succeeding trimester and may reach 20bullHEV is an uncommon cause of fulminant hepatitis in nonpregnant individuals
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Pathogenesis and Pathology 5
bullModest inflammation consisting predominantly of Kupffer cells and polymorphonuclear leukocytes is seen and the focal lesions
bullCholestatic hepatitis is often present characterized by ballooning hepatocytes cytoplasmic cholestasis and focal cytolytic necrosis
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Pathogenesis and Pathology 6
bullThe discrepancy between the time of appearance of viral replication in the liver and histopathologic and biochemical evidence of hepatitis suggests that HEV is not cytopathic and that the pathogenesis of hepatitis E is immunologically mediatedbullIt is not known whether HEV causes other sequelae or extrahepatic manifestations of infectionbullPremature deliveries with a high infant mortality rate have also been reported
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Hepatitis E and pregnancybullIn pregnant women particularly from certain
geographical areas in India HEV infection is more severe often leading to fulminant hepatic failure and death in a significant proportion of patients
bull In contrast reports from Egypt Europe and the USA have shown that the course and severity of viral hepatitis during pregnancy is not different from that in nonpregnant
women
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
bullThe reasons for the differences in the outcome of HEV in different geographical areas remain unclear but could be the result of early childhood HEV exposures producing long-lasting immunity andor modifying subsequent responses to exposure to the
virusbullAlternatively the predominant HEV genotypes in Egypt could be less virulent than those in Asia
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
bullThe severe liver injury because of HEV infection during pregnancy may be related to one of several possible host factors such as differences in immune and hormonal factors occurring during pregnancy and
genetic and environmental factors
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Clinical Features
bullSensitive serologic tests have revealed that not all HEV infections are clinically apparent
bullHepatitis E never progresses to chronicity
bullRecurrent hepatitis A is not uncommon but comparable recurrence of hepatitis E has not been reported except in
experimental infections of primates
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Clinical Features of Hepatitis EIncubation period 2-10 weeksAdult symptoms and signs1048590 Jaundice 1001048590 Malaise gt951048590 Anorexia gt651048590 Abdominal pain 30-801048590 Hepatomegaly 10-801048590 Nausea amp Vomiting 30-1001048590 Fever 20-901048590 Pruritis 15-60Mortality1048590 Average adult (FHF)1048590 Pregnant woman 15-25
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Diagnosis 1
bullCurrent tests are capable of detecting IgM anti-HEV in up to 90 of acute infections if a serum sample is obtained 1 to 4 weeks after the onset of disease
bullIgM anti-HEV reaches peak titers of 11000 to 110000 during the first 4 weeks after the onset of hepatitis
bullBy 3 months after the onset of disease IgM anti-HEV is no
longer detectable in 50 or more of patients with hepatitis E
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Diagnosis 2
bullIgG anti-HEV peaks in titer (11000 to 1100000) between 2 and 4 weeks after onset of hepatitis and diminishes relatively rapidly thereafter
bullImmunoelectron microscopy is an insensitive test that is positive in only approximately 10 of casesbullMolecular approaches to diagnosis of hepatitis E have replaced IEM
bull RT-PCR is useful for detecting HEV in the blood and feces
during the acute phase of infection
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Diagnosis 3
bullIt has contributed to the identification of new genetic variants of HEV but the the sensitivity of the technique depends on a proper match between the HEV strain and the PCR primers
bullBecause of this serologic approaches to diagnosis remain
the methods of choice
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Treatment
bullNo specific treatment exists for hepatitis EbullSupportive therapy
bullAggressive management of fulminant hepatitis E may reduce the mortality of this complication in pregnant
women
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Epidemiology 1
A major cause of sporadic and epidemic hepatitis
1048590Prominent in India China and North Africa and Mexico
1048590Rare in developed countries
1048590Water-borne little person to person spread
1048590Animal sources are likely (esp Swine and rodents)
1048590Only 5 of adult cases have jaundice
1048590High mortality (15-25) in pregnant women
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Epidemiology 2
1048590Clinical hepatitis E disease normally seen in adults 15ndash40 years old (unlike HAV)
1048590Low seroprevalence in pediatric populations
1048590Infection rate is 2ndash4 times higher than disease rateUS cases usually have history of travel to HEV-endemic areas
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Prevention and Control
bullImproved personal and public hygienebullNo vaccines availablebullRecombinant protein in animal amp human trialsbullImmune serum globulin is ineffective
bullThe high prevalence of anti-HEV in domestic and wild animals even in industrialized countries suggests that possible zoonotic spread of HEV may continue in such
regions despite improved sanitation
Thank you
Thank you
