hepatitis e infection

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


• 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


• 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

FOR ARTICLES OF ACADEMIC INTEREST ON

INFECTIOUS DISEASES FOLLOW ME ON

• Created by Dr.T.V.Rao MD for ‘e’ learning resources for Medical Professionals in

Developing World • Email

• [email protected]

DR.T.V.RAO MD 48

hepatitis e infection

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