VIRAL HEPATITIS Kolářová M., Autumn 2017 1970 1960A“Infectious” “Serum” Viral hepatitis Enterically transmitted Parenterally transmitted other E “NANB” B D;1977 C VIRAL HEPATITIS HISTORICAL PERSPECTIVE VIRAL HEPATITIS A HEPATITIS A VIRUS HEPATITIS A VIRUS • RNA Picornavirus  Single serotype worldwide  Acute disease and asymptomatic infection • No chronic infection  Protective antibodies develop in response to infection - confers lifelong immunity HEPATITIS A - CLINICAL FEATURES •Jaundice by <6 yrs <10% age group: 6-14 yrs 40%-50% >14 yrs 70%-80% •Rare complications: Fulminant hepatitis Cholestatic hepatitis Relapsing hepatitis •Incubation period: Average 30 days Range 15-50 days •Chronic sequelae: None 0 1 2 3 4 5 6 7 8 9 10 11 12 13 Week Response Clinical illness ALT IgM IgG HAV in stool Infection Viremia EVENTS IN HEPATITIS A VIRUS INFECTION CONCENTRATION OF HEPATITIS A VIRUS IN VARIOUS BODY FLUIDS Source: Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:887-890 Feces Serum Saliva Urine 100 102 104 106 108 1010 BodyFluids Infectious Doses per mL Is estimated that in 2013 HAV caused 14 900 deaths. The severity of clinical disease associated with HAV infection increases with increasing age; jaundice occurs among less than:  10% of children younger than 6 years of age,  40%-50% of older children, and  70%-80% of adults. Complications of hepatitis A include fulminant hepatitis, in which the case fatality rate can be greater than 50% despite medical interventions such as liver transplantation; cholestatic hepatitis, with very high bilirubin levels that can persist for months; and relapsing hepatitis, in which exacerbations can occur weeks to months after apparent recovery. Chronic infection does not occur following HAV infection. GEOGRAPHIC DISTRIBUTION OF HEPATITIS A VIRUS INFECTION ACUTE HEPATITIS A CASE DEFINITION FOR SURVEILLANCE Clinical criteria • Any person with a discrete onset of symptoms (e.g. fatigue, abdominal pain, loss of appetite, intermittent nausea and vomiting) • AND at least one of the following three: • — Fever; • — Jaundice; • — Elevated serum aminotransferase levels. Laboratory criteria • At least one of the following three: • — Detection of hepatitis A virus nucleic acid in serum or stool; • — Hepatitis A virus specific antibody response; • — Detection of hepatitis A virus antigen in stool. Epidemiological criteria • At least one of the following four: • — Human-to-human transmission; • — Exposure to a common source; • — Exposure to contaminated food/drinking water; • — Environmental exposure. Case classification • A. Probable case: Any person meeting the clinical criteria with an epidemiological link • B. Confirmed case: Any person meeting the clinical and the laboratory criteria  Close personal contact (e.g., household contact, sex contact, child daycare centers) • Contaminated food, water (e.g., infected food handlers) • Blood exposure (rare) (e.g., injection drug use, rarely by transfusion) HEPATITIS A VIRUS TRANSMISSION Unknown 46% Contact of day- care child/employee 6% Other Contact 8% Child/employee in day-care 2% Food- or waterborne outbreak 4% Injection drug use 6% Sexual or Household Contact 14% Men who have sex with men 10% International travel 5% RISK FACTORS ASSOCIATED WITH REPORTED HEPATITIS A, 1990-2000, UNITED STATES Source: NNDSS/VHSP PREVENTING HEPATITIS A • Hygiene (e.g., hand washing) • Sanitation (e.g., clean water sources) • Hepatitis A vaccine (pre-exposure) • Immune globulin (pre- and post-exposure) PREPARATION OF INACTIVATED HEPATITIS A VACCINES • Cell culture adapted virus grown in human fibroblasts • Purified product inactivated with formalin • Adsorbed to aluminum hydroxide adjuvant • Highly immunogenic • 97%-100% of children, adolescents, and adults have protective levels of antibody within 1 month of receiving first dose; essentially 100% have protective levels after second dose • Highly efficacious • In published studies, 94%-100% of children protected against clinical hepatitis A after equivalent of one dose HEPATITIS A VACCINES DURATION OF PROTECTION AFTER HEPATITIS A VACCINATION • Persistence of antibody • At least 5-8 years among adults and children • Efficacy – No cases in vaccinated children at 5-6 years of follow-up • Mathematical models of antibody decline suggest protective antibody levels persist for at least 20 years • Other mechanisms, such as cellular memory, may contribute VIRAL HEPATITIS B The hepatitis B virus is a DNA virus belonging to the Hepadnaviridae family of viruses. VIRAL HEPATITIS TYPE B Hepatitis B virus, HBV, Hepadnavirus, the so-called Dane particle with a core (formed by DNA, DNA polymerase, and a nucleocapsid protein with the hepatitis B core antigen (HBcAg) and a coat of hepatitis B surface antigen (HBsAg) ). The whole virus is infectious with a diameter of 42 nm. Two months in the ende of incubation period, the sick or carriers. Parenteral transmission - blood, blood products and inoculation of the infectious material are of principal significance in the transmission. Professional risk to medical personnel (injury by needle - transmission in 7 - 30 %, contaminated instruments, blood transfusions - transmission in 90 %). i.v. drug addicts - injury during tattooing, possibly other minute injuries of the skin and mucosa. By sexual intercourse in homosexuals, bisexuals, and prostitutes. Vertical - perinatal transmission from mother to child when the mother is the virus carrier or the sick person. About 95 % of newborns infect intranatally and 5 % intrauterinely. General General The source of infection Route of transmission Susceptibility Etiology: Preventive measures: VIRAL HEPATITIS TYPE B Preventive measures: Health education - to emphasize the extent of risk Observance of epidemic measures in medical establishments. Handling biological material and contaminated instruments, consistent disinfection and sterilization, application of single-use needles and syringes, use of closed hemodialysis systems, smoking and drinking in workplaces with biological material is forbidden. Postexposure prophylaxis - passive and active immunization (newborns). Examination of blood-donors - exclusion of HBsAg carriers from blood donation Designation and inspection of sanitary-epidemic measures in non-medical establishments (hair-dressing salons, barber shops, etc.) Active immunization in persons with a high risk of infection (stated by public notice) . . The disease occurs worldwide. In 2013, HBV caused: 686 000 deaths, including 68 600 deaths from fulminant hepatitis, 300 000 deaths from hepatocellular carcinoma 317 400 deaths from cirrhosis with a very high burden among an estimated 280 million carriers (prevalence 3,7 %). The symptoms can vary greatly and many of those infected with HBV never develop any symptoms at all. Those who do get symptoms (30-50% of cases) usually suffer from tiredness, loss of appetite, abdominal discomfort, nausea, vomiting and fever. The vast majority of healthy adults who get acute hepatitis B will recover with no liver damage in 4–12 weeks but the death rate can reach 2% in the elderly. Chronic infection is most likely to develop in young babies. * Incubation period: Average 60-90 days Range 45-180 days * Clinical illness <5 yrs, <10% (jaundice): >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 Outcome of HBV Infection Infection Asymptomatic Symptomatic acute hepatitis B Resolved Immune Chronic infection Asymptomatic Cirrhosis Liver cancer Resolved Immune Chronic infection Asymptomatic Cirrhosis Liver cancer Weeks after Exposure Symptoms HBeAg anti-HBe Total anti-HBc IgM anti-HBc anti-HBsHBsAg 0 4 8 12 16 20 24 28 32 36 52 100 Titer Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course 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 Weeks after Exposure Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course • Sexual • Parenteral • Perinatal HBV Modes of Transmission Low/Not High Moderate Detectable semen serum vaginal fluid blood wound exudates urine feces sweat tears breast milk Concentration of HBV in Various Body Fluids  Prevent perinatal HBV transmission  Routine vaccination of all infants  Vaccination of children in high-risk groups  Vaccination of adolescents — all children up through age 18  Vaccination of adults in high-risk groups Strategy Elimination of HBV Transmission, • Licensed in 1982; currently recombinant (in US) • 3 dose series, typical schedule 0, 1-2, 4-6 months - no maximum time between doses (no need to repeat missed doses or restart) • Protection ~30-50% dose 1; 75% - 2; 96% - 3; • lower in older, immunosuppressive illnesses (e.g., HIV, chronic liver diseases, diabetes), obese, smokers Hepatitis B Vaccine • Routine infant • Ages 11-15 “catch up”, and through age 18(VFC eligible) • Over 18 – high risk – Occupational risk (HCWs) – Hemodyalisis patients – All STD clinic clients – Multiple sex partners or prior STD – Inmates in Correctional settings – MSM – IDU – Institution for developmental disability • Pre-vaccination testing – if cost effective • Post-vaccination testing – 1-2 months after last shot, if establishing response critical (HCW) Hepatitis B Vaccination ACIP Recommendations VIRAL HEPATITIS C VIRAL HEPATITIS TYPE C BHepatitis C virus is a RNA-virus measuring 50 nm. It is classed into a separate genus, Hepacavirus of the Flaviviridae family. Long-term in viremia (in the ende IP), chronic infections. Parenteral transmission. Sporadically, vertical and sexual transmissions were reported carrier or the sick person. Susceptibility is general. The source of infection Route of transmission Susceptibility Etiology: Preventive measures: The same as for HBV, exclusive immunization. Features of Hepatitis C Virus Infection Incubation period Average 6-7 weeks Range 2-26 weeks Acute illness (jaundice) Mild (<20%) Case fatality rate Low Chronic infection 60%-85% Chronic hepatitis 10%-70% (most asx) Cirrhosis <5%-20% Age- related Chronic Hepatitis C Factors Promoting Progression or Severity • Increased alcohol intake • Age > 40 years at time of infection • HIV co-infection • Other – Male gender – Chronic HBV co-infection Serologic Pattern of Acute HCV Infection with Recovery Symptoms +/Time after Exposure Titer anti-HCV ALT Normal 0 1 2 3 4 5 6 1 2 3 4 YearsMonths HCV RNA Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection Symptoms +/Time after Exposure Titer anti-HCV ALT Normal 0 1 2 3 4 5 6 1 2 3 4 YearsMonths HCV RNA Exposures Known to Be Associated With HCV Infection • Injecting drug use • Transfusion, transplant from infected donor • Occupational exposure to blood – Mostly needle sticks • Iatrogenic (unsafe injections) • Birth to HCV-infected mother • Sex with infected partner – Multiple sex partners Injecting Drug Use and HCV Transmission • Highly efficient – Contamination of drug paraphernalia, not just needles and syringes • Rapidly acquired after initiation – 30% prevalence after 3 years – >50% after 5 years • Four times more common than HIV Posttransfusion Hepatitis C 0 5 10 15 20 25 30 1965 1970 1975 1980 1985 1990 1995 2000 Year %ofRecipientsInfected All volunteer donors HBsAg Donor Screening for HIV Risk Factors Anti-HIV ALT/Anti-HBc Anti-HCV Improved HCV Tests Adapted from HJ Alter and Tobler and Busch, Clin Chem 1997 Occupational Transmission of HCV • Inefficient by occupational exposures • Average incidence 1.8% following needle stick from HCV-positive source – Associated with hollow-bore needles • Case reports of transmission from blood splash to eye; one from exposure to non-intact skin • Prevalence 1-2% among health care workers – Lower than adults in the general population – 10 times lower than for HBV infection HCV Related to Health Care Procedures • Recognized primarily in context of outbreaks – Chronic hemodialysis – Hospital inpatient setting – Private practice setting – Home therapy • Unsafe injection practices – Reuse of syringes and needles – Contaminated multiple dose medication vials Perinatal Transmission of HCV • Transmission only from women HCV-RNA positive at delivery – Average rate of infection 6% – Higher (17%) if woman co-infected with HIV – Role of viral titer unclear • No association with – Delivery method – Breastfeeding • Infected infants do well – Severe hepatitis is rare Sexual Transmission of HCV • Case-control, cross sectional studies – Infected partner, multiple partners, early sex, non-use of condoms, other STDs, sex with trauma, BUT – MSM no higher risk than heterosexuals • Partner studies – Low prevalence (1.5%) among long-term partners • infections might be due to common percutaneous exposures (e.g., drug use), BUT – Male to female transmission more efficient • more indicative of sexual transmission Sexual Transmission of HCV • Occurs, but efficiency is low – Rare between long-term steady partners – Factors that facilitate transmission between partners unknown (e.g., viral titer) • Accounts for 15-20% of acute and chronic infections • Sex is a common behavior – Large chronic reservoir provides multiple opportunities for exposure to potentially infectious partners Household Transmission of HCV • Rare but not absent • Could occur through percutaneous/mucosal exposures to blood – Contaminated equipment used for home therapies • IV therapy, injections – Theoretically through sharing of contaminated personal articles (razors, toothbrushes) Other Potential Exposures to Blood • No or insufficient data showing increased risk – intranasal cocaine use, tattooing, body piercing, acupuncture, military service • No associations in acute case-control or population-based studies • Cross-sectional studies in highly selected groups with inconsistent results – Temporal relationship between exposure and infection usually unknown – Biologically plausible, but association or causal relationship not established Sources of Infection for Persons With Hepatitis C Sexual 15% Other 1%* Unknown 10% Injecting drug use 60% Transfusion 10% (before screening) * Nosocomial; iatrogenic; perinatal Source: Centers for Disease Control and Prevention Occupational 4% Reduce or Eliminate Risks for Acquiring HCV Infection • Screen and test donors • Virus inactivation of plasma-derived products • Risk-reduction counseling and services – Obtain history of high-risk drug and sex behaviors – Provide information on minimizing risky behavior, including referral to other services – Vaccinate against hepatitis A and/or hepatitis B • Safe injection and infection control practices MMWR 1998;47 (No. RR-19) Reduce Risks for Disease Progression and Further Transmission • Identify persons at risk for HCV and test to determine infection status – Routinely identify at risk persons through history, record review • Provide HCV-positive persons – Medical evaluation and management – Counseling • Prevent further liver damage • Prevent transmission to others HCV Testing Routinely Recommended • Ever injected illegal drugs • Received clotting factors made before 1987 • Received blood/organs before July 1992 • Ever on chronic hemodialysis • Evidence of liver disease • Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood • Children born to HCV-positive women Based on increased risk for infection Based on need for exposure management Postexposure Management for HCV • IG, antivirals not recommended for prophylaxis • Follow-up after needlesticks, sharps, or mucosal exposures to HCV-positive blood – Test source for anti-HCV – Test worker if source anti-HCV positive • Anti-HCV and ALT at baseline and 4-6 months later • For earlier diagnosis, HCV RNA at 4-6 weeks – Confirm all anti-HCV results with RIBA • Refer infected worker to specialist for medical evaluation and management Routine HCV Testing of Uncertain Need • Recipients of transplanted tissue • Intranasal cocaine or other non-injecting illegal drug users • History of tattooing, body piercing • History of STDs or multiple sex partners • Long-term steady sex partners of HCV-positive persons Not confirmed as risk factor/prevalence low or unknown Confirmed risk factor but prevalence of infection low Mother-to-Infant Transmission of HCV • Postexposure prophylaxis not available • No need to avoid pregnancy or breastfeeding – Consider bottle feeding if nipples cracked/bleeding • No need to determine mode of delivery based on HCV infection status • Test infants born to HCV-positive women – >15-18 months old – Consider testing any children born since woman became infected – Evaluate infected children for CLD Persons with One Long-Term Steady Sex Partner Sexual Transmission of HCV • Do not need to change their sexual practices • Should discuss with their partner – Risk (low but not absent) of sexual transmission – Counseling and testing of partner should be individualized • May provide couple with reassurance • Some couples might decide to use barrier precautions to lower limited risk further Persons with High-Risk Sexual Behaviors Sexual Transmission of HCV • At risk for sexually transmitted diseases, e.g., HIV, HBV, gonorrhea, chlamydia, etc. • Reduce risk – Limit number of partners – Use latex condoms – Get vaccinated against hepatitis B – MSMs also get vaccinated against hepatitis A Other Transmission Issues • HCV not spread by kissing, hugging, sneezing, coughing, food or water, sharing eating utensils or drinking glasses, or casual contact • Do not exclude from work, school, play, childcare or other settings based on HCV infection status VIRAL HEPATITIS D Hepatitis D (Delta) Virus HBsAg RNA d antigen • Coinfection –severe acute disease –low risk of chronic infection • Superinfection –usually develop chronic HDV infection –high risk of severe chronic liver disease Hepatitis D - Clinical Features • Percutanous exposures –injecting drug use • Permucosal exposures –sex contact Hepatitis D Virus Modes of Transmission HBV - HDV Coinfection Typical Serologic Course Time after Exposure Titer anti-HBs Symptoms ALT Elevated Total anti-HDV IgM anti-HDV HDV RNA HBsAg HBV - HDV Superinfection Typical Serologic Course Time after Exposure Titer Jaundice Symptoms ALT Total anti-HDV IgM anti-HDV HDV RNA HBsAg Geographic Distribution of HDV Infection HDV Prevalence High Intermediate Low Very Low No Data Taiwan Pacific Islands • HBV-HDV Coinfection Pre or postexposure prophylaxis to prevent HBV infection • HBV-HDV Superinfection Education to reduce risk behaviors among persons with chronic HBV infection Hepatitis D - Prevention VIRAL HEPATITIS E Hepatitis E Virus Hepatitis E - Clinical Features • 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 Virus Infection Typical Serologic Course Weeks after Exposure Titer 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 • Most outbreaks associated with fecally contaminated drinking water • Minimal person-to-person transmission • U.S. cases usually have history of travel to HEV-endemic areas Hepatitis E Epidemiologic Features Geographic Distribution of Hepatitis E Outbreaks or Confirmed Infection in >25% of Sporadic Non-ABC Hepatitis • Avoid drinking water (and beverages with ice) of unknown purity, uncooked shellfish, and uncooked fruit/vegetables not peeled or prepared by traveler • IG prepared from donors in Western countries does not prevent infection • Unknown efficacy of IG prepared from donors in endemic areas • Vaccine? Prevention and Control Measures for Travelers to HEV-Endemic Regions Key characteristics of HAV, HBV, HCV, HDV, HEV A B C D E Causative agent Picornaviridae Hepadnaviridae Raviviridae Deltaviridae Hepeviridae RNA DNA RNA RNA RNA Incubation period 2 – 6 weeks 2 - 6 months 2 - 6 months 3-7 weeks 2 - 10 weks Characteristic of acute hepatitis Case fatality increases with age Acute hepatitis more common in adults Acute hepatitis uncommon, almost never fulminant Superinfection with HDV in chronic heptitis B may lead to fulminnat disease High case fatality in pregnant women -10-20 %; other 1 -2 % Biomarker of recent infection IgM anti-HAV IgM anti-HBc None IgM anti-HDV IgM anti-HEV Chronic infection none Chronic infection leading to sequelae Chronic infection leading to sequelae Chronic hepatitis that copmlicated chronic hepatitis B Very rare Cirrhosis and hepatocelular Ca No Yes; 0,1 -1,0 % are fulminant Yes; 50 % can be fulminant Yes; 5 - 20 % can be fulminant NO The period of infectivity last 2 weeks of incubation period last 2 months of incubation period last 2 months of incubation period ?? ??first day of acute stage entire period of acute stageentire period of acute stage chronic disease, carriers chronic disease, carriers Infectious biological material faeces blood blood blood faeces viremia - 1. day of illnes genital secretions genital secretions meat of animals Mode of transmission Person-to person Perinatal Blodborne Blodborne Waterborne Foodborne Bloodborne Perinatal Foodborne Waterborne Sexual Sexual Person-to person Inactivated hepatitis A vaccines are Active (recombinant