hepatitis e infection
DESCRIPTION
Hepatitis E InfectionTRANSCRIPT
Dr.T.V.Rao MD
HEPATITIS E INFECTION
AN UPDATE
DR.T.V.RAO MD 1
HISTORY AS DOCUMENTED
DR.T.V.RAO MD 2
• In 1978 there was a vast epidemic of icteric viral hepatitis in the Kashmir Valley involving 52000 cases with 1650 fulminant forms and 1560 deaths. Since serology for hepatitis A and B in these patients was negative and the clinical course and the epidemic type of its spread were not those of post-transfusional non-A non-B hepatitis, MS Khuroo in 1980 suggested that this epidemic of hepatitis might have been caused by another virus.(Am J Med 68:818-23,1980).In 1983 Balayan demonstrated that this virus, at difference of non-A non-B virus, is transmitted by fecal-oral route. He himself ingested fecal suspensions from affected patients and contracted the disease.(Intervirology 20:23-31,1983).By transmitting the disease to monkeys the virus was recovered and its morphology and genome were identified only 12-13 years later in the early nineties.
A “Infectious”
“Serum”
Viral hepatitis
Enterically
transmitted
Parenterall
y
transmitted F, G, TTV
? other
E
NANB
B D C
Viral Hepatitis - Historical Perspectives
DR.T.V.RAO MD 3
Source of
virus
feces blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
blood/
blood-derived
body fluids
feces
Route of
transmission
fecal-oral percutaneous
permucosal
percutaneous
permucosal
percutaneous
permucosal
fecal-oral
Chronic
infection
no yes yes yes no
Prevention pre/post-
exposure
immunization
pre/post-
exposure
immunization
blood donor
screening;
risk behavior
modification
pre/post-
exposure
immunization;
risk behavior
modification
ensure safe
drinking
water
Type of Hepatitis
A B C D E
DR.T.V.RAO MD 4
DR.T.V.RAO MD 5
DR.T.V.RAO MD 6
• The virus is icosahedral
and nonenveloped. It
has a diameter of
approximately 34
nanometers, and it
contains a single strand
of RNA approximately
7.5 kilobases in length.
Four HEV genotypes
exist, and genotype 1
causes human disease.
STRUCTURE OF HEPATITIS E VIRUS
DR.T.V.RAO MD 7
STRUCTURAL CHARACTER OF HEPATITIS E
VIRUS
• HEV is an icosahedral, nonenveloped single stranded RNA virus that is
approximately 27 to 34 nm in diameter . It has been classified as the single
member of the genus herpesvirus in the family Herpesviridae Three large
opening reading frames (ORFs) of the positive-sense RNA of HEV
have been described
• The largest ORF consists of 1693 codons; it codes for nonstructural proteins
that are responsible for the processing and replication of the virus.
• The second ORF is composed of 660 codons and codes for structural
proteins.
• The third ORF consists of 123 codons; although it may encode for a
structural protein, its function remains undetermined.
DR.T.V.RAO MD 8
• The genomic RNA of
HEV exhibits several
distinct features
compared to the
genomic RNA of
caliciviruses, including
a methylated cap at the
5'-end and an ORF1
with functional domains
arranged in a different
order.
HEPATITIS E SHOWS DIFFERENT
DISTINCT FEATURES
DR.T.V.RAO MD 9
• Phylogenetic analysis suggests
that there are four genotypes (1
through 4) and up to 24 subtypes
. The association of genotypes
with clinical features is
incompletely understood.
However, genotype 1 and 2
appear to be confined to humans
while genotype 3 and 4 infect
humans and animals. Genotype
3 has been associated with less
virulent disease
PHYLOGENETIC ANALYSIS
DR.T.V.RAO MD 10
• Hepatitis E (HEV) was not
recognized as a distinct human
disease until 1980. Hepatitis E is
caused by infection with the
hepatitis E virus, a non-
enveloped, positive-sense,
single-stranded RNA virus.
• Although man is considered the
natural host for HEV, antibodies
to HEV or closely related viruses
have been detected in primates
and several other animal species
HEPATITIS E VIRUS INFECTION
DR.T.V.RAO MD 11
• The highest rates of infection occur
in regions where low standards of
sanitation promote the transmission
of the virus. Epidemics of hepatitis E
have been reported in Central and
South-East Asia, North and West
Africa, and in Mexico, especially
where faecal contamination of
drinking water is common. However,
sporadic cases of hepatitis E have
also been reported elsewhere and
serological surveys suggest a global
distribution of strains of hepatitis E
of low pathogenicity.
UNHYGIENIC CONDITIONS INCREASE THE
SPREAD OF HEPATITIS E INFECTIONS
DR.T.V.RAO MD 12
HEPATITIS E INFECTION CAN BE
UNEVENTFUL
• In general, hepatitis E is a self-limiting viral infection
followed by recovery. Prolonged viraemia or faecal
shedding are unusual and chronic infection does not
occur.
• Occasionally, a fulminant form of hepatitis develops,
with overall patient population mortality rates ranging
between 0.5% - 4.0%. Fulminate hepatitis occurs
more frequently in pregnancy and regularly
induces a mortality rate of 20% among
pregnant women in the 3rd trimester. DR.T.V.RAO MD 13
ANIMALS CAN BE RESERVOIRS OF
INFECTION
• Domestic animals have been reported as a reservoir for the
hepatitis E virus, with some surveys showing infection rates
exceeding 95% among domestic pigs. Transmission after
consumption of wild boar meat and uncooked deer meat has
been reported as well. The rate of transmission to humans by
this route and the public health importance of this are however
still unclear.
• A number of other small mammals have been identified as
potential reservoirs: the lesser bandicoot rat (Bandicota
bengalensis), the black rat (Rattus rattus brunneusculus) and
the Asian house shrew (Suncus murinus). A new virus
designated rat hepatitis E virus has been isolated.
DR.T.V.RAO MD 14
• The host range of HEV is ever-
expanding. In addition to the
animal species from which HEV
strains have been genetically
identified including domestic and
wild pigs, chickens, deer, rabbits,
and mongeese, antibodies to
HEV have also been detected in
many other animal species such
as dogs, cats, sheep, goats,
rodents, cattle, and non-human
primates, suggesting that these
animals have been exposed to
HEV or a related agent.
CAN WE CALL HEPATITIS E AN EMERGING
ZOONOTIC INFECTION ???
DR.T.V.RAO MD 15
• The course of infection has 2
phases, the prodromal phase
and the icteric phase. The
infection is self-limited.
Whether protective
immunoglobulin's develop
against future reinfection
remains unknown. The overall
case fatality rate is 4%,
though pregnant women and
liver transplant recipients may
be at substantially higher risk.
COURSE OF INFECTION
DR.T.V.RAO MD 16
17
Transmission
• HEV is spread by the oral-faecal route
• Consumption of faecally contaminated drinking water has given rise to epidemic cases,
• Ingestion of raw or uncooked shellfish has been the source of sporadic cases in endemic areas
• Most outbreaks associated with faecally contaminated drinking water
DR.T.V.RAO MD
18
Zoonotic transmission • Naturally acquired HEV antibodies
have been detected in primates, rodents and swine
• Swine HEV cross-reacts with antibodies to the human HEV
• Human hepatitis E has been transmitted under laboratory conditions to various species of primates, pigs, lambs, rats
DR.T.V.RAO MD
19
Zoonotic transmission
• Species specific HEV has been demonstrated in pigs with the identification of swine HEV
• Swine HEV is distinct, but closely related to human HEV strains
• Swine HEV raises a potential public health concern for zoonosis and xenozoonosis following xenotransplantation with pig organs
DR.T.V.RAO MD
20
Zoonotic transmission • A zoonotic spread of HEV is not
excluded
• Monkeys, pigs, cows, rodents, sheep and goats are susceptible
• Anti-HEV has been found in a significant proportion, up to 28% in some areas, of healthy individuals in industrialized countries
DR.T.V.RAO MD
Most outbreaks associated with faecally contaminated drinking water.
Several other large epidemics have occurred since in the Indian subcontinent and the USSR, China, Africa and Mexico.
In the United States and other nonendemic areas, where outbreaks of hepatitis E have not been documented to occur, a low prevalence of anti-HEV (<2%) has been found in healthy populations. The source of infection for these persons is unknown.
Minimal person-to-person transmission.
Hepatitis E -
Epidemiologic Features
DR.T.V.RAO MD 21
Incubation period: Average 40 days
Range 15-60 days
Case-fatality rate: Overall, 1%-3%
Pregnant women,
15%-25%
Illness severity: Increased with age
Chronic sequelae: None identified
Hepatitis E - Clinical Features
DR.T.V.RAO MD 22
PRODROMAL PHASE • The incubation period ranges from 15 days to 60 days. The course of infection has 2 phases,
the prodromal phase and the icteric phase.
• Prodromal-phase symptoms include the following:
• Myalgia
• Arthralgia
• Fever with mild temperature elevations (25-97%)
• Anorexia (66-100%)
• Nausea/vomiting (30-100%)
• Weight loss (typically 2-4 kg)
• Dehydration
• Right upper quadrant pain that increases with physical activity (abdominal pain is reported in 35-80% of patients)
DR.T.V.RAO MD 23
ICTERIC-PHASE SYMPTOMS INCLUDE
THE FOLLOWING:
• Jaundice – This may be difficult to see with some patients’
natural skin color; the serum bilirubin level is higher than 3
mg/dL; scleral icterus is present
• Dark urine
• Light-colored stools (20-40%)
• Pruritus (50%)
• Other features include the following:
• Urticarial rash
• Diarrhea
• Malaise (95-100%)
DR.T.V.RAO MD 24
• Hepatitis E predominantly affects
persons aged 15-40 years. It
may affect younger age groups,
but it generally is not recognized
and may be subclinical in these
populations. No chronic cases
have been described. Although
hepatitis E is not known to have
a predilection for either sex,
pregnant women are prone to
complications. Hepatitis E has no
apparent racial predilection.
AGE-, SEX-, AND RACE-RELATED
DEMOGRAPHICS
DR.T.V.RAO MD 25
• No chronic cases of
acute hepatitis E have
been reported. The
infection is self-limited.
Whether protective
immunoglobulin's
develop against future
reinfection remains
unknown. The overall
case fatality rate is 4%.
NO ESTABLISHED CHRONICITY IN
HEPATITIS E INFECTIONS ???
DR.T.V.RAO MD 26
27
Diagnosis of hepatitis E
• Hepatitis E should be suspected in outbreaks
of waterborne hepatitis occurring in:
• Developing countries,
• Especially if the disease is more severe in
pregnant women,
• Or if hepatitis A has been excluded
• If laboratory tests are not available,
epidemiologic evidence can help in
establishing a diagnosis
DR.T.V.RAO MD
28
Diagnosis of hepatitis E
• Acute hepatitis E is diagnosed when the
presence of IgM anti-HEV is detected
• Storage of serum samples is acceptable for
several days at 4°C,
• Anti-HEV will be preserved at – 20°C,
• A temperature of #-70°C should be preferred
when viremia is suspected.42
DR.T.V.RAO MD
29
Hepatitis E Virus Infection
Typical Serologic Course
Weeks after Exposure
Tit
er
Symptoms
ALT
IgG anti-HEV
IgM anti-HEV
Virus in stool
0 1 2 3 4 5 6 7 8 9 10 11 12 13
DR.T.V.RAO MD
30
Diagnosis of Hepatitis E
• HEV RNA can be detected in acute phase
faeces by PCR in approximately 50% of cases
• Immune electron microscopy is positive in
only about 10% of cases
• The viral proteins pORF2 and pORF3 have
been expressed in various recombinant
systems and form the basis for diagnostic
tests and vaccine studies
DR.T.V.RAO MD
31
Diagnosis of hepatitis E
• To confirm the results of EIA or ELISA tests,
Western blot assays to detect IgM and IgG
anti-HEV in serum can be used
• PCR tests for the detection of HEV RNA in
serum and stool,
• Immunofluorescent antibody blocking assays
to detect antibody to HEV antigen in serum
and liver,
• Immune electron microscopy to visualize
viral particles in faeces DR.T.V.RAO MD
• Among pregnant women,
the case fatality rate is
20%, and this rate
increases during the
second and third trimesters.
Reported causes of death
include encephalopathy
and disseminated
intravascular coagulation.
The rate of fulminant
hepatic failure in infected
pregnant women is high.
HIGHER FATALITIES IN PREGNANT
WOMEN
DR.T.V.RAO MD 32
• Liver transplant
recipients may be at a
greater risk for HEV
infection, which can
lead to chronic
hepatitis. However, if
the patient has
antibodies against HEV,
the risk of reactivation
is extremely low
LIVER TRANSPLANT PATIENTS AT RISK
DR.T.V.RAO MD 33
PREVALENCE OF HEPATITIS E INFECTION
• Hepatitis E is prevalent in most developing countries, and
common in any country with a hot climate. It is widespread in
Southeast Asia, northern and central Africa, India, and Central
America. It is spread mainly through fecal contamination of
water supplies or food; person-to-person transmission is
uncommon. Outbreaks of epidemic Hepatitis E most commonly
occur after heavy rainfalls and monsoons because of their
disruption of water supplies. Major outbreaks have occurred in
New Delhi, India (30,000 cases in 1955-1956), Burma (20,000
cases in 1976-1977), Kashmir, India (52,000 cases in 1978),
Kanpur, India (79,000 cases in 1991), and China (100,000
cases between 1986 and 1988).
DR.T.V.RAO MD 34
35
Some of the Major Epidemics Place Year Number of cases
India
Myanmar
Kashmir
China
Somalia
Mexico
Iran (Kermanshah)
Sudan
Chad
Iraq
1955
1976
1978
1986
1988
1989
1991
2004
2004
2004
30000
20000
52000
100000
11000
4000
Hundreds
4000
1000
hundreds DR.T.V.RAO MD
• Improving sanitation is the
most important measure,
which consists of proper
treatment and disposal of
human waste, higher
standards for public water
supplies, improved personal
hygiene procedures and
sanitary food preparation.
Thus, prevention strategies of
this disease are similar to
those of many others that
plague developing nations,
and they require large-scale
international financing of water
supply and water treatment
projects.
PREVENTION
DR.T.V.RAO MD 36
• Ensuring a clean
drinking water supply
remains the best
preventive strategy.
Recombinant vaccines
are being developed
that may be particularly
useful for travellers to
disease-endemic areas
and for pregnant
women.
BEST OPTIONS TO PREVENT HEPATITIS E
INFECTIONS
DR.T.V.RAO MD 37
• Protective antibodies after the
infection are apparently effective to
prevent reinfection even with strains
from distant regions but the duration of
this protection in humans is still
questioned. Immune serum
globulin will considerably
reduce mortality in the
3rd trimester of
pregnancy but will not block
incidence of infection on contact. A
vaccine is not yet available.
IMMUNOGLOBULIN'S IN 3 RD. TRIMESTER
REDUCES MORTALITY
DR.T.V.RAO MD 38
39
Vaccines • At present, no commercially
available vaccines exist for the prevention of hepatitis E.
• Several studies for the development of an effective vaccine against hepatitis E are in progress :
1- Recombinant vaccines
2- Subunit HEV vaccines DR.T.V.RAO MD
• A vaccine based on
recombinant viral proteins
has been developed and
recently tested in a high-
risk population (military
personnel of a developing
country).The vaccine
appeared to be effective
and safe, but further
studies are needed to
assess the long-term
protection and the cost-
effectiveness of hepatitis E
vaccination.
A VACCINE ON TRAIL
DR.T.V.RAO MD 40
41
Vaccines • Recombinant vaccines
• A 55 kDa recombinant HEV-derived ORF2 protein has been used to vaccinate rhesus monkeys against different strains of hepatitis E.
• Although primates could still be infected, the vaccine protected them from the symptoms of disease
DR.T.V.RAO MD
42
Vaccines • Subunit HEV vaccines
• The direct intramuscular injection of purified plasmid DNA containing the full-length ORF2 of HEV has induced a prolonged humoral immune response
(>12 months)
• To the expressed structural protein ORF2 in 80% and 100% of two separate groups of challenged mice, respectively
DR.T.V.RAO MD
• Recent studies indicate that chronic
HEV infection may develop in
immunosuppressed patients. Acute
HEV infection in
immunocompromised patients such
as organ transplant recipients and
cancer patients not only can evolve
into chronic hepatitis E, but also can
rapidly progress into cirrhosis as
well. In some of these patients, anti-
HEV antibodies were negative [56]
probably because of immune
suppression. The contribution of the
deficiency of anti-HEV antibodies to
the establishing of the chronic
infection needs to be established.
HEPATITIS CAN GO INTO CHRONIC PHASE IN
IMMUNOSUPPRESSED
DR.T.V.RAO MD 43
• Hepatitis E is no longer just a
disease of developing countries.
Sporadic cases of human
hepatitis E have been reported in
both industrialized and
developing countries, although
epidemics only occur in
developing countries of Asia,
Africa, and in Mexico.[Recently,
there has been an increased
incidence of sporadic hepatitis E
cases in industrialized countries,
and most are caused by zoonotic
genotypes 3 and 4 strains of
HEV.
HEPATITIS E INFECTION IS A CONCERN OF
DEVELOPED NATIONS TOO
DR.T.V.RAO MD 44
HYGIENIC HAND WASH CAN SAVE SEVERAL
LIVES FROM HEPATITIS E INFECTIONS
DR.T.V.RAO MD 45
MAJOR REFERENCES
• CDC, Atlanta on Hepatitis E infections
• WHO/CDS/CSR/EDC/2001.12, Hepatitis E
World Health Organization, Department of
Communicable Disease Surveillance and,
Response
• Control of communicable diseases, 2000
DR.T.V.RAO MD 46
DR.T.V.RAO MD 47
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DR.T.V.RAO MD 48