An OverviewTerry Kotrla, MS,

MT(ASCP)BB

Unit 4Part 4 Hepatitis A-E

Viruses

BackgroundViral hepatitis caused by infection by any of at least

five distinct viruses.Hepatitis A, B and C most common ones identified

in US.Produce acute illness characterized by:

NauseaMalaiseAbdominal painDark urineJaundice

HBV and HCV can become chronic, associated with increased risk of chronic liver disease and hepatocellular carcinoma.

AA“ Infectious”

“ Serum”

Viral hepatitis

Entericallytransmitted

Parenterallytransmitted

F, G, TTV? other

EE

NANBNANB

BB DD CC

Viral Hepatitis - Historical Perspectives

Source ofvirus

feces blood/blood-derived

body fluids

blood/blood-derived

body fluids

blood/blood-derived

body fluids

feces

Route oftransmission

fecal-oral percutaneouspermucosal

percutaneouspermucosal

percutaneouspermucosal

fecal-oral

Chronicinfection

no yes yes yes no

Prevention pre/post-exposure

immunization

pre/post-exposure

immunization

blood donorscreening;

risk behaviormodification

pre/post-exposure

immunization;risk behaviormodification

ensure safedrinking

water

Summary of Viral Hepatitis

A B C D E

Hepatitis A Virus

Hepatitis A VirusRNA virusHumans only natural hostCan be stable in environment for months.Children younger than 6 years of age may have

asymptomatic infection (70%).Older children and adults usually symptomatic,

jaundice occurring in 70%.

Transmitted by close personal contact

(e.g., household contact, sex contact, child day care centers)

Contaminated food, water(e.g., infected food handlers, raw shellfish)

Blood exposure (rare)(e.g., injecting drug use, transfusion)

Hepatitis A Virus Transmission

Incubation period: Average 28 days

Range 15-50 days Jaundice by age group: <6 yrs, <10%

6-14 yrs, 40%-50%

>14 yrs, 70%-80%

Complications: Fulminant hepatitisCholestatic

hepatitisRelapsing

hepatitis Chronic sequelae: None

Hepatitis A - Clinical Features

FecalHAV

Symptoms

0 1 2 3 4 5 6 12

24

Hepatitis A Infection

Total anti-HAV

Titer ALT

IgM anti-HAV

Months after exposure

Typical Serological Course

EndemicityDisease

RatePeak Age

of Infection Transmission Patterns

High Low to High

Early childhood

Person to person;outbreaks uncommon

Moderate High Late childhood/

young adults

Person to person;food and waterborne outbreaks

Low Low Young adults Person to person;food and waterborne outbreaks

Very low Very low Adults Travelers; outbreaks uncommon

Global Patterns of Hepatitis A Virus Transmission

Prevalence of Antibody to HAV 2006

Laboratory Diagnosis

Acute infection is diagnosed by the detection of IgM anti-HAV in serum by EIA.

Generally detectable 5-10 days before onset of symtpoms.

May persist for up to 6 months.

Past infection is determined by the detection of IgG anti-HAV by EIA. Appears during convalescence.

Present in serum forever, confers lifelong immunity.

PCR helpful during outbreaks to determine common source.

Many cases occur in community-wide outbreaks No risk factor identified for most cases Highest attack rates in 5-14 year olds Asymptomatic children serve as source of infection

Persons at increased risk of infectionTravelersHomosexual menInjecting drug users

Hepatitis A Vaccination

StrategiesEpidemiologic Considerations

Pre-exposureTravelers to intermediate and high

HAV-endemic regionsPost-exposure (within 14 days)

RoutineHousehold and other intimate contactsSelected situationsInstitutions (e.g., day care centers)Common source exposure (e.g., food prepared by

infected food handler)

Hepatitis A Prevention - Immune Globulin

Hepatitis B Virus

• Incubation period: Average 60-90 daysRange 45-180 days

Clinical illness (jaundice): <5 yrs, <10%5 yrs, 30%-50%

Acute case-fatality rate: 0.5%-1% Chronic infection: <5 yrs, 30%-90%

5 yrs, 2%-10% Premature mortality from

chronic liver disease: 15%-25%

Hepatitis B - Clinical Features

Hepatitis B Diseases DNA virus

May cause:

Chronic Persistent Hepatitis – asymptomatic

Chronic Active Hepatitis – symptomatic exacerbations of disease

Cirrhosis of liver

Hepatocellular Carcinoma

Liver failure

Death

Symptoms

HBeAg anti-HBe

Total anti-HBc

IgM anti-HBc anti-HBsHBsAg

0 4 8 12 16 20 24 28 32 36 52 100

Acute HBV Infection with RecoveryTypical Serologic Course

Weeks after Exposure

Titer

IgM anti-HBc

Total anti-HBc

HBsAg

Acute(6 months)

HBeAg

Chronic(Years)

anti-HBe

0 4 8 12 16 20 24 28 32 36 52 Years

Weeks after Exposure

Titer

Progression to Chronic HBV Infection - Serology

Symptomatic Infection

Chronic Infection

Age at Infection

Chronic Infection (%)

Sym

pto

matic In

fection

(%)

Birth 1-6 months 7-12 months 1-4 years Older Childrenand Adults

0

20

40

60

80

100100

80

60

40

20

0

Outcome of Hepatitis B Virus Infection

by Age at Infection

Ch

ron

ic In

fect

ion

(%

)

High (>8%): 45% of global populationlifetime risk of infection >60%early childhood infections common

Intermediate (2%-7%): 43% of global populationlifetime risk of infection 20%-60%infections occur in all age groups

Low (<2%): 12% of global populationlifetime risk of infection <20%most infections occur in adult risk groups

Global Patterns of Chronic HBV Infection

Prevalence of Chronic HBV 2006

High ModerateLow/Not

Detectable

blood semen urineserum vaginal fluid feces

wound exudates saliva sweat

tearsbreastmilk

Concentration of Hepatitis B Virus in Various Body Fluids

Sexual - sex workers and homosexuals are particular at risk.

Parenteral - IVDA, Health Workers are at increased risk.

Perinatal - Mothers who are HBeAg positive are much more likely to transmit to their offspring than those who are not. Perinatal transmission is the main means of transmission in high prevalence populations.

Hepatitis B Virus

Modes of Transmission

Diagnosis

A battery of serological tests are used for the diagnosis of acute and chronic hepatitis B infection.

HBsAg - used as a general marker of infection. HBsAb - used to document recovery and/or immunity to HBV

infection. anti-HBc IgM - marker of acute infection. anti-HBcIgG - past or chronic infection. HBeAg - indicates active replication of virus and therefore

infectiveness. Anti-Hbe - virus no longer replicating. However, the patient can still

be positive for HBsAg which is made by integrated HBV. HBV-DNA - indicates active replication of virus, more accurate than

HBeAg especially in cases of escape mutants. Used mainly for monitoring response to therapy.

Treatment

Interferon - for HBeAg positive carriers with chronic active hepatitis. Response rate is 30 to 40%.

Lamivudine - a nucleoside analogue reverse transcriptase inhibitor. Well tolerated, most patients will respond favorably. However, tendency to relapse on cessation of treatment. Another problem is the rapid emergence of drug resistance.

Successful response to treatment will result in the disappearance of HBsAg, HBV-DNA, and seroconversion to HBeAg.

Prevention

Vaccination - highly effective recombinant vaccines are now available. Vaccine can be given to those who are at increased risk of HBV infection such as health care workers. It is also given routinely to neonates as universal vaccination in many countries.

Hepatitis B Immunoglobulin - HBIG may be used to protect persons who are exposed to hepatitis B. It is particular efficacious within 48 hours of the incident. It may also be given to neonates who are at increased risk of contracting hepatitis B i.e. whose mothers are HBsAg and HBeAg positive.

Other measures - screening of blood donors, blood and body fluid precautions.

hypervariableregion

capsid envelope

protein

protease/helicase

RNA-dependent

RNA polymerase

c22

5’

core

E1 E2 NS2

NS3

33c

NS4

c-100

NS5

3’

Hepatitis C Virus

Incubation period: Average 6-7 wks

Range 2-26 wks

Clinical illness (jaundice): 30-40% (20-30%)

Chronic hepatitis: 70%

Persistent infection: 85-100%

Immunity: No protective antibody response identified.

Hepatitis C - Clinical Features

Chronic Hepatitis C Infection

RNA virusThe spectrum of chronic hepatitis C infection is

essentially the same as chronic hepatitis B infection.

All the manifestations of chronic hepatitis B infection may be seen, albeit with a lower frequency i.e. chronic persistent hepatitis, chronic active hepatitis, cirrhosis, and hepatocellular carcinoma.

Symptoms

anti-HCV

ALT

Normal

0 1 2 3 4 5 6 1 2 3 4

Hepatitis C Virus InfectionTypical Serologic Course

Titer

Months

Years

Time after Exposure

Transfusion or transplant from infected donor

Injecting drug use

Hemodialysis (years on treatment)

Accidental injuries with needles/sharps

Sexual/household exposure to anti-HCV-positive contact

Multiple sex partners

Birth to HCV-infected mother

Risk Factors Associated with

Transmission of HCV

Prevalence of Hepatitis C Infection

Laboratory Diagnosis

HCV antibody - generally used to diagnose hepatitis C infection. Not useful in the acute phase as it takes at least 4 weeks after infection before antibody appears.

HCV-RNA - various techniques are available e.g. PCR and branched DNA. May be used to diagnose HCV infection in the acute phase. However, its main use is in monitoring the response to antiviral therapy.

HCV-antigen - an EIA for HCV antigen is available. It is used in the same capacity as HCV-RNA tests but is much easier to carry out.

Viral LoadDone by PCRNegative defined as less than 100

copies/mL200,000 to 1,000,000 low1,000,000 to 5,000,000 medium5,000,000 to 25,000,000 highabove 25,000,000 very high

Treatment for HCVTreatment based on HCV viral load.

InterferonMay be considered for patients with chronic

active hepatitis.Response rate is around 50% but 50% of

responders will relapse upon withdrawal of treatment.

RibavirinLess experience than with interferon.Recent studies suggest combination of

interferon and ribavirin.

Prevention of Hepatitis CScreening of blood, organ and tissue

donors.High-risk behavior modification.Blood and body fluid precautions.

HBsAg

RNA

antigen

Hepatitis D (Delta) Virus

Hepatitis D Clinical FeaturesRNA virusCoinfection with Hepatitis B required

Severe, acute diseaseLow risk of chronic infection

Super infectionUsually develop chronic HDV infectionHigh risk of severe chronic liver diseaseMay present as an acute hepatitis.

Heptaitis D Virus Modes TransmissionPercutaneous exposureInjecting (IV) drug use.Permucosal exposureSexual contact

anti-HBs

Symptoms

ALT Elevated

Total anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

HBV - HDV Coinfection Serology

Time after Exposure

Titer

Jaundice

Symptoms

ALTTotal anti-HDV

IgM anti-HDV

HDV RNA

HBsAg

HBV - HDV SuperinfectionTypical Serologic

Course

Time after Exposure

Titer

Hepatitis D PreventionBecause HDV requires HBV for replication

pre- or postexposure prophylaxis to prevent HBV infection.

No product exists to prevent HDV superinfection in persone with chronic HBV infection.

Educate to reduce risk behaviors among persons with chronic HBV infecion.

Hepatitis E Virus

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

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

Typical Serologic Course of HEV Infection

Titer

Weeks after Exposure

Hepatitis E FeaturesRNA virusUncommon in US, associated with travel.Spread by fecal-oral route.Most outbreaks associated with fecal

contamination of drinking water.Large epidemics still occur

Prevention and Control MeasuresTravelers to HEV Endemic regions should

use caution.Avoid

drinking water and beverages with ice, uncooked shellfish and uncooked fruit or vegetables which are not

peeled or prepared by travelerIG prepared from donors in Western

countries does not prevent infection.Unknown efficacy of IG prepared from

donors in endemic areas.Vaccine?

Diagnosis and Treatment of HEVDiagnosis

Suspect based on travel history to endemic area and negative serologic markers for HAV, HBV, and HCV

Testing for presence of antibody to HEV.Detection of HEV RNA.

TreatmentNo specific treatment available, most people

recover completely.Fatality rate <4%Pregnant women much more serious, 10-30%

fatal, especially in 3rd trimester.

Distribution of HEV Infection, 2008

The End