Hepatitis virus Overview of Hepatitis Virus Virus Virus group Nucleic Mode of infection Severity acid (chronicity) HAV Enterovirus RNA Fecal-oral +(acute) 72(heptovirus) HBV hepadnavirus DNA Percutaneous; ++(chronic) Permucosal HCV Flavivirus RNA Blood(transfusion- + (chronic) associated) HDV B-dependent RNA blood + (chronic) small virus HEV Calicivirus RNA Fecal-oral +(acute) HGV ? RNA Blood ? Viral Hepatitis - Overview Type of Hepatitis A B C D E Source of feces blood/ blood/ blood/ feces virus blood-derived blood-derived blood-derived body fluids body fluids body fluids Route of fecal-oral percutaneous percutaneous percutaneous fecal-oral transmission permucosal permucosal permucosal Chronic no yes yes yes no infection Prevention pre/post- pre/post- blood donor pre/post- ensure safe exposure exposure screening; exposure drinking immunization immunization risk behavior immunization; water modification risk behavior modification Human cytomegalovirus Epstein-Barr virus Herpes simplex virus Yellow fever virus Rubella. Hepatitis A virus Structure Small, non- enveloped icosahedral particle, 27 nm in diameter ssRNA Replication Unlike other picornaviruses, however, HAV is not cytolytic and is released by exocytosis. Laboratory isolates of HAV have been adapted to growth in primary and continuous monkey kidney cell lines, but clinical isolates are very difficult to grow in cell culture. Resistance Stable to: acid at pH 3 Solvents(ether,chloroform) detergents saltwater,groundwater(months) drying(stable) temperature 4℃: weeks 56℃for 30minutes: stable 61℃for 20minutes: partial inactivation Resistance Inactivated by: chlorine treatment of drinking water formalin(0.35%,37℃,72hours) acetic acid(2%,4hours) B-propiolactone丙内酯(0.25%,1hours) Ultraviolet radiation(2μW/㎝2/min) Hepatitis A Virus Transmission Virus can be transmitted via fecal-oral route ingestion of contaminated food and water can cause infection HAV in shellfish is from sewage-contaminated water Virus can be transmitted by food handlers, day- care workers, and children. Concentration of Hepatitis A Virus in Various Body Fluids Feces Body Fluid Serum Saliva Urine 100 102 104 106 108 1010 Infectious Doses per ml Source: Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:887-890 Geographic Distribution of HAV Infection Anti-HAV Prevalence High Intermediate Low Very Low Age-specific Mortality Due to Hepatitis A Age group Case-Fatality (years) (per 1000) <5 3.0 5-14 1.6 15-29 1.6 30-49 3.8 >49 17.5 Total 4.1 Source: Viral Hepatitis Surveillance Program, 1983-1989 Hepatitis A - Clinical Features Average 30 days Incubation period Range 15-50 days Jaundice by <6 yrs <10% age group 6-14 yrs 40%-50% >14 yrs 70%-80% Hepatitis A - Clinical Features Milder disease than Hepatitis B; asymptomatic infections are very common, especially in children. Adults, especially pregnant women, may develop more severe disease no chronic form of the disease. Complications: Fulminant hepatitis is rare: 0.1% of cases Pathogenesis Pathogenesis of HAV HAV replicates slowly in the liver without producing apparent cytopathological effects (CEPs). In the absence of cytolysis, the virus readily establishes a persistent infection. Jaundice, resulting from damage to the liver Antibody is detected and cell-mediated immune responses to the virus For example An epidemic of HAV that occurred in Shanghai, China, in 1988 in which 300,000 people were infected with the virus resulted from eating Anadara subcrenata obtained from a polluted river. Time course of HAV infection Immunity Antibody protection against reinfection is lifelong Laboratory Diagnosis Viral particles in the stool, by electron microscopy Specific IgM in serum PCR HAV-specific sequences in stool Treatment, Prevention and Control Prophylaxis with immune serum globulin given before or early in the incubation period A killed HAV vaccine has been approved and is available for use in children and adults at high risk for infection. A live HAV vaccine has been developed in China. Hepatitis B virus Introduction approximately 350 million people are infected globally with HBV. Structure Small, enveloped DNA The genome: a small, circular, partly double-stranded DNA of 3200 base Although a DNA virus, it encodes a reverse transcriptase and replicates through an RNA intermediate. Structure Dane particle, is 42 nm in diameter. Resist to treatment with: ether, a low pH, freezing, and moderate heating. This helps transmission from one person to another. Decoy Particles HBsAg-containing particles are released into the serum of infected people and outnumber the actual virions. Spherical or filamentous They are immunogenic and were processed into the first commercial vaccine against HBV. Structure HBcAg HBsAg HBeAg 15-25nm 42nm HBsAg 20×20×200nm 28nm HBcAg DNA HBeAg Replication HBV has a very defined tropism for the liver. Its small genome also necessitates economy, as illustrated by the pattern of its transcription and translation. In addition, HBV replicates through an RNA intermediate and produces and release antigenic decoy particles. Replication The entire genome can also be integrated into the host cell chromatin. HBsAg, but not other proteins, can often be detected in the cytoplasm of cells containing integrated HBV DNA. The significance of the integrated DNA in the replication of the virus is not known, but integrated viral DNA has been found in hepatocellular carcinomas. Global Patterns of Chronic HBV Infection High (>8%): 45% of global population – lifetime risk of infection >60% – early childhood infections common Intermediate (2%-7%): 43% of global population – lifetime risk of infection 20%-60% – infections occur in all age groups Low (<2%): 12% of global population – lifetime risk of infection <20% – most infections occur in adult risk groups High-risk groups for HBVinfection People from endemic regions Babies of mothers with chronic HBV Intravenous drug abusers People with multiple sex partners Hemophiliacs and other patients requiting blood and blood product treatments Health care personnel who have contact with blood Residents and staff members of institutions for the mentally retarded Concentration of Hepatitis B Virus in Various Body Fluids High Blood ,Serum, Wound exudates Moderate Semen, vaginal and menstrual secretions, Saliva, amniotic fluid Low/Not Urine , Feces, Sweat , Tears , Breast milk Detectable What determines the development of chronic vs. acute infection Age (chronic infections decrease with increasing age) Sex: Syndrome: Males : Females Chronic Infection: 1.5 : 1 Cirrhosis: 3:1 PHC: 6:1 Route of infection (oral/sexual infections give rise to less chronic cases than serum infection Hepatitis B - Clinical Features • Incubation period: Average 60-90 days Range 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% 100 Outcome of Hepatitis B Virus Infection 100 by Age at Infection Symptomatic Infection (%) Chronic Infection (%) 80 80 60 60 Chronic Infection 40 40 20 20 Symptomatic Infection 0 0 Birth 1-6 months 7-12 months 1-4 years Older Children and Adults Age at Infection Pathogenesis(1) The virus starts to replicate within 3 days of its acquisition, Symptoms may not be observed for 45 days of longer, depending on the infectious dose, the route of infection, and the person. Pathogenesis(2) Hypoimmune response. IFN↓,HLA-I↓→CTL↓(An insufficient T-cell response ) Cell mediated immunopathogenic damage. CTL →acute hepatitis/chronic hepatitis Pathogenesis (3) Immune complexes formed between HBsAg and anti- HBs contribute to the development of hypersensitivity reactions, leading to problems such as vasculitis血管炎, arthralgia关节痛, rash, and renal damage. Pathogenesis(4) Pathogenic damage caused by autoimmunity liver specific protein(LSP) Viral variation HBeAg Clinical Syndromes Major eterminants of acute and chronic HBV infection Acute Infection Symptoms of Acute Infection Clinical outcomes of acute hepatitis B infection The serological events associated with the typical course of acute HBV disease Typical Serologic Course Acute Hepatitis B Virus Infection with Recovery Symptoms HBeAg anti-HBe Total anti-HBc Titer HBsAg IgM anti-HBc anti-HBs 0 4 8 12 16 20 24 28 32 36 52 100 Weeks after Exposure Chronic Infection Chronic hepatitis occurs in 5% to 10% of people with HBV infections, usually after mild or inapparent initial disease. Detected by the finding of elevated liver enzyme levels Development of the chronic HBV carrier state Typical Serologic Course Progression to Chronic HBV Infection Acute Chronic (6 months) (Years) HBeAg anti-HBe HBsAg Total anti-HBc Titer IgM anti-HBc 0 4 8 12 16 20 24 28 32 36 52 Years Weeks after Exposure Primary Hepatocellular Carcinoma The WHO estimates that 80% of all cases of PHC can be attributed to chronic HBV infections. HBV may induce PHC by promoting continued liver repair and cell growth in response to tissue damage or by integrating into the host chromosome and stimulating cell growth directly. Lab. Diagnosis The initial diagnosis of hepatitis can be made on the basis of the clinical symptoms and the presence of liver enzymes in the blood. The serology of infection describes the course and the nature of the disease. Acute and chronic HBV infect. Can be distinguished by the presence of HBsAg and HBeAg in the serum and the pattern of Ab to the individual HBV antigens. Diagnosis During the symptomatic phase of infection, detection of antibodies to HBeAg and HBsAg is obscured because the antibody is complexed with antigen in the serum. The best way to diagnose a recent acute infection, especially during the period when neither HBsAg nor anti-HBs can be detected, is to measure IgM anti-HBc. Diagnosis Detection of serum HBVDNA: nucleic hybridization; PCR. Detection of viral DNA polymerase. Treatment Interferon-alpha may be effective for treating a chronic HBV infection. Hepatitis B immune globulin may be administered within a week of exposure and to newborn infants of HBsAg-positive mothers. Elimination of Hepatitis B Virus Transmission Objectives • Prevent chronic HBV Infection • Prevent chronic liver disease • Prevent primary hepatocellular carcinoma • Prevent acute symptomatic HBV infection Elimination of Hepatitis B Virus Transmission Strategy • Prevent perinatal围产期的HBV transmission • Routine vaccination of all infants • Vaccination of children in high-risk groups • Vaccination of adolescents – all unvaccinated children at 11-12 years of age – “high-risk” adolescents at all ages • Vaccination of adults in high-risk groups 病毒抗原抗体系统检测结果分析 HBsAg HBeAg 抗- HBs 抗- HBe 抗- HBc 结果分析 ＋ － － － － HBV感染或无症状携带 者 ＋ ＋ － － － 急性或慢性乙型肝炎， 或无症状携带者 ＋ ＋ － － ＋ 急性或慢性乙型肝炎 （ 传染性强，“大三阳”） ＋ － － ＋ ＋ 急性感染趋向恢复 （ “小三阳”） － － ＋ ＋ ＋ 既往感染恢复期 － － ＋ ＋ － 既往感染恢复期 － － － － ＋ 既往感染或“窗口期” － － ＋ － － 既往感染或接种过疫苗 Hepatitis C Virus Introduction The major cause of parenterally transmitted non A non B hepatitis. It eluded identification for many years. In 1989, the genome was cloned from the serum of an infected chimpanzee. 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 75%-85% Chronic hepatitis 70% (most asx) Cirrhosis 10%-20% Mortality from CLD 1%-5% (chronic liver disease ) Common characteristics Putative Togavirus related to the Flavi and Pesti viruses.Thus probably enveloped. Has a ssRNA genome Does not grow in cell culture, but can infect Chimpanzees Transmission Blood transfusions, blood products organ donation Intravenous drug abusers community acquired: mechanism unclear. ? Vertical transmission ? sexual intercourse Epidemiology Causes a milder form of acute hepatitis than does hepatitis B But 50% individuals develop chronic infection, following exposure. Incidence endemic world-wide; high incidence in Japan, Italy and Spain Clinical syndromes HCV can cause acute infections but is more likely to establish chronic infections. Viremia Chronic persistent hepatitis Chronic active hepatitiw Cirrhosis Liver failure Chronic Hepatitis C Factors Promoting Progression or Severity Increased alcohol intake Age > 40 years at time of infection HIV co-infection ?Other – Male gender – Other co-infections (e.g., HBV) Serologic Pattern of Acute HCV Infection with Recovery anti-HCV Symptoms +/- HCV RNA Titer ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection anti-HCV Symptoms +/- HCV RNA Titer ALT Normal 0 1 2 3 4 5 6 1 2 3 4 Months Years Time after Exposure HCV Prevalence by Selected Groups United States Hemophilia Injecting drug users Hemodialysis STD clients Gen population adults Surgeons, PSWs Pregnant women Military personnel 0 10 20 30 40 50 60 70 80 90 Average Percent Anti-HCV Positive Laboratory diagnosis 1) Serology Reliable serological tests have only recently become available. HCV-specific IgG indicates exposure, not infectivity 2) PCR detects viral genome in patient's serum Treatment, Prevention, and Control Recombinant interferon-alpha is the only known effective treatment for HCV. Illicit drug abuse and transfusion are the most identifiable sources of HCV viruses. Hepatitis D virus Introduction Defective virus which requires Hepatitis B virus as a helper virus in order to replicate. Infection only occurs in patients who are already infected with Hepatitis B. Structure Virus particle 36 nm in diameter encapsulated with HBsAg, derived from HBV Delta antigen is associated with virus particles ssRNA genome Hepatitis D (Delta) Virus d antigen HBsAg RNA Replication Transcription and replication of the HDV genome are unusual. Specifically, the host cell’s RNA polymerase II makes an RNA copy, replicates the genome, and makes mRNA. Geographic Distribution of HDV Infection Taiwan Pacific Islands HDV Prevalence High Intermediate Low Very Low No Data Pathogenesis Spread in blood, semen, and vaginal secretion. It can replicate and cause disease only in people with active HBV infections. Replication of the delta agent results in cytotoxicity and liver damage. Clinical Syndromes Increases the severity of HBV infections. Fulminant hepatitis Hepatitis D - Clinical Features • Coinfection –severe acute disease –low risk of chronic infection • Superinfection –usually develop chronic HDV infection –high risk of severe chronic liver disease HBV - HDV Coinfection Symptoms Typical Serologic Course ALT Elevated anti-HBs Titer IgM anti-HDV HDV RNA HBsAg Total anti-HDV Time after Exposure HBV - HDV Superinfection Jaundice Typical Serologic Course Symptoms Total anti-HDV ALT Titer HDV RNA HBsAg IgM anti-HDV Time after Exposure Laboratory Diagnosis Detect the delta antigen of antibodies ELISA and RIA Hepatitis D - Prevention • 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 E Virus Structure and Genome 30-32nm non-enveloped particle s/s (+)sense RNA genome , ~7.5Kb. Genetic organization similar (not identical) to Caliciviruses 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 Geographic Distribution of Hepatitis E Hepatitis E - Epidemiologic Features • Most outbreaks associated with fecally contaminated drinking water • Minimal person-to-person transmission Prevention and Control Measures for Travelers to HEV-Endemic Regions • 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? Epidemiology The delta agent infects children and adults with underlying HBV infection, and people who are persistently infected with both HBV and HDV are a source for the virus.