Viral Hepatitis in Children DR. HOSSAIN IBRAHIM AGEEL PEDIATRIC GASTROENTEROLOGIST PEDIATRIC DEPARTMENT KFCH JAZAN

Viral Hepatitis in Children DR. HOSSAIN IBRAHIM AGEEL PEDIATRIC GASTROENTEROLOGIST PEDIATRIC DEPARTMENT KFCH JAZAN

General Concepts Hepatitis = 'inflammation of the liver'. Virus causes: Hepatotropic and non-hepatotropic Hepatotropic viruses: HAV, HBV, HCV, HDV, HEV, HGV

Classification of Hepatitis Viruses VIRUS FAMILY DNA or RNA ENVELOPE HAV Picornaviridae RNA* No HBV Hepadnaviridae DNA** Yes HCV Flaviviridae RNA* Yes HDV Deltaviridae RNA* Yes HEV Hepeviridae RNA* No HGV Flaviviridae RNA* Yes *Single strand ** Double strand

Hepatitis A Virus Infection Worldwide infection Transmission of hepatitis A virus: Fecal-oral route Close personal contact Contaminated water and food Parentral (rare) Incubation: 15-50 days (mean 28)

Pathogenesis HAV infection is biphasic process: Non-cytopathic stage Cytopathic stage Hepatocellular damage is immune mediated process and not direct cytopathic effect by hepatitis A virus.

Clinical manifestations HAV infection is an acute self-limited illness General nonspecific symptoms (fever, malaise, anorexia, vomiting, nausea, abdominal pain and diarrhea) Jaundice Choluria (bilirubin in urine) Mild hepatomegaly Symptomatic hepatitis: 30% of infected children younger than six years. 70 80% in older children and adults infected with HAV

Atypical presentations Hepatic manifestations: Relapsing hepatitis (3-20%) Acute liver failure (<1%) Cholestasic hepatitis (30% of adult). Autoimmune hepatitis. Extra-hepatic manifestations (common) An evanescent rash (11%) Arthralgias (14%)

Atypical presentations Extra-hepatic manifestations (rare) Vasculitis Arthritis Optic neuritis Transverse myelitis Encephalitis Bone marrow suppression

Diagnosis Serologic tests: Anti HAV IgM : indicates an acute infections Anti HAV IgG : indicates resolved infections or vaccine induced immunity. Other techniques: HAV detection in stool and body fluids by electron microscopy. HAV RNA detection in stool, body fluids, serum and liver tissues by PCR.

Treatment Self-limited disease, rarely requires hospitalization Only supportive measures in uncomplicated cases: Bed rest. Control fever. Increased fluid intake versus intravenous fluids. No particular diet is needed. Limit hepatotoxic medications, be cautious with acetaminophen. Children with HAV infection should be away for 1 wk. Identify the index case for preventive measures

Treatment If complicated with acute liver failure: Hospitalization Aggressive supportive therapy Early transfer to liver transplantation center. If HAV triggered secondary disorders Treat the specific disease

Prevention and Prophylaxis General measures: Adherence to sanitary practices (hand washing). Heating food appropriately. Avoidance of water or food from endemic areas. Active immunization: Two hepatitis A vaccines (inactivated vaccines) HAVRIX (in1995) VAQTA (in 1996) Passive immunization: Polyclonal serum immunoglobulin (IgG)

Hepatitis A Vaccines Inactivated whole virus vaccines Pediatric and adult formulations : Pediatric formulations vaccines approved for persons 12 months through 18 years Adult formulations approved for persons 19 years and older

Adult Hepatitis A Vaccines 1 dose ( >95% seropositive ) booster dose 6-18 months after first dose ( 100% seropositive ) Children and Adolescents 1 dose ( >97% seropositive ) booster dose 6-18 months after first dose ( 100% seropositive )

Hepatitis A Vaccines Formulation Pediatric: Age Dose Adult: Age Dose HAVRIX 1 18 years 0.5 ml 19 years 1.0 ml VAQTA 1 18 years 0.5 ml 19 years 1.0 ml

Polyclonal serum immunoglobulin (IgG) Available since 1940s Passive immunity lasts for up to six months Effective if administered within 2 weeks post-exposure Dose is 0.02 ml per kg IM

Structure of Hepatitis B Virus Virion is 42 nm in diameter Consists of : An envelop contains viral derived surface proteins also known as HBsAg Nucleocapsid contains hepatitis core protein or hepatitis Bc antigen(hbcag) Hepatitis Be protein (HBeAg) Partially ds circular DNA viral genome. Viral DNA polymerase Others

Genotype A B C D E F G H Hepatitis B genotypes Geographic Regions North America, Western Europe, Central Africa China, Indonesia, Vietnam, Taiwan East Asia, Korea, China, Japan, Taiwan, Polynesia, Vietnam Mediterranean area, Middle East, India Nigeria, West Africa Alaska, Polynesia North America, France Central America

Pathogenesis of HBV Infection Two mechanisms: immune-mediated liver injury which is related to cytotoxic T cell-mediated lysis of infected hepatocytes. Direct cytotoxic liver injury may occur when the viral load is very high

Epidemiology Prevalence of hepatitis B virus infection Categories Low Intermediate High Areas Western United States, Canada, Europe, Australia, and New Zealand Mediterranean Countries, Japan, Central Asia, Middle East, Latin and South America Southeast Asia, China, Sub- Saharan Africa Rate 0.1 2% 3 5% 10 20%

Concentration of Hepatitis B Virus in Various Body Fluids High Moderate Low/Not Detectable blood semen urine serum vaginal fluid feces wound exudates saliva sweat tears breastmilk

Transmissions and High Risk Groups Modes of Transmission Perinatal Horizontal Parentral Sexual High Risk Groups Infants born to HBeAg-positive mothers Household Close Contacts Injection drug users, Health care workers, Hemodialysis patients, Recipients of blood products Heterosexuals and homosexuals

Incubation Period of HBV Average: 60 90 days Range: 45 180 days

Clinical manifestations Acute Infection: Asymptomatic Symptomatic : Prodromal (serum sickness like syndrome, Constitutional (anorexia, nausea, jaundice, right upper quadrant pain, fatigue) Occasionally develops acute fulminant hepatitis and Gianotti-Crosti syndrome.

Clinical manifestations Chronic Infection: Asymptomatic Vague right upper quadrant pain and fatigue Occasionally associated with extrahepatic manifestation including polyarteritis nodosa and glomerulonephropathy

Investigations Laboratory tests: Complete blood count with platelets Liver biochemical tests including AST, ALT, total bilirubin, alkaline phosphatase, albumin. Prothrombin time. Tests for HBV infectivity and immunity including HBsAg and HBsAb. Tests for HBV replication including HBeAg and HBeAb. Screen for hepatocellular carcinoma with abdominal ultrasound and serum alpha fetoprotein. Liver biopsy for patients who meet criteria of chronic hepatitis and who are considered for treatment

Serologic responses to hepatitis B Virus infection

Progression to chronic state 90% if perinatal acquisition 20-50% if acquired between 1-5 years of age. <5% if acquired in adult

Tests HBsAg Anti-HBc Anti-HBs HBsAg Anti-HBc Anti-HBs HBsAg Anti-HBc Anti-HBs HBsAg Anti-HBc IgM anti-hbc Anti-HBs HBsAg Anti-HBc IgM anti-hbc Anti-HBs Results Negative Negative Negative Negative Positive Positive Negative Negative Positive Positive Positive Positive Negative Positive Positive Negative Negative Interpretation Susceptible Immune due to natural infection Immune due to hepatitis B vaccination Acutely infected Chronically infected

Natural Course of Chronic Hepatitis B Infection Phase 1 Phase 2 Phase 3 Phase 4 Immune Tolerance State Immune Active Inactive Carrier Reactivation State Lack of effective immune response and exhibit immune tolerance Immune-mediated viral clearance Low replication state Subsequent reactivation of chronic hepatitis

Phase Immune Tolerant Immune Active Inactive Carrier (latent) Reactivation Phases of Chronic Hepatitis B Infection Labs and Histology ALT Normal DNA > 20,000 IU/ml HBeAg +ve Minimal liver inflammation and fibrosis ALT elevated DNA level >20,000 IU/ml HBeAg +ve Liver inflammation & fibrosis develops ALT normal DNA < 2,000 IU/ml or undetectable HBeAg -ve, Anti-HBe +ve No liver inflammation, Fibrosis regress ALT normal or elevated DNA levels increase (>2,000 IU/ml) HBeAg ve HBeAb +ve or -ve Liver biopsy not indicated Antiviral Rx is ineffective. Risk of drug resistance if treated with nucleoside. Liver biopsy is indicated. spontaneous conversion Resolution of infection. Treatment if there is no spontaneous conversion Liver biopsy not indicated Treatment not indicated Up to 20% immune active 20-30% reactivate 20-30% of patients HBeAg-ve chronic HBV Usually 2 nd to mutant virus Liver biopsy is indicated Antiviral therapy indicated

Monitoring of patients Disease activity: ALT every 6-12 months HBeAg and HBeAb every 12 months If HBeAg is +ve, measure HBV DNA. HCC surveillance: Ultrasound of liver every 12 months Alpha fetoprotein every 12 months

Treatment Interferon alfa First line treatment choice. Six month course of interferon alfa-2b, six million units (MU) per m(2) (maximum 10MU) SC. three times a week for 24 weeks. Response rate in 30 40% of patients. Side effects: Flu like symptoms, Bone marrow suppression and changes in personality

Treatment Lamivudine Second line treatment choice Nucleoside analog. Dose: 3 mg per kg of body weight (max. 100 mg) Limited efficacy. Drug resistance with long term use

Treatment Newer agents Pegylated interferon therapy approved for 3 years of age. Adefovir : licensed for use in patient 12 years of age. Tenofovir : licensed for use in patient 12 years of age. Entecavir: licensed for use in patient 16 years of age.

Prevention HBV vaccine Universally recommended for all infants. Series of 3 doses over 6-9 months. Catch up immunizations for older unimmunized children. HBV-exposed family members or closed contacts. HBV immune globulin indication for use Infants born to HBsAg positive mothers. Post exposure prophylaxis within 24 hours of exposure if no past vaccine.

Prevention Other measures Household contacts: Avoid sharing of tweezers, shavers, toothbrush, nail clippers. Universal precautions for handling abrasions, bleeding, etc.

Hepatitis C Virus

Genotype 1 2 3 4 5 6 Hepatitis C genotypes Geographic Regions United State, Europe United State, Europe India, Far East, Australia Africa, Middle East South Africa Hong Kong, Vietnam, Australia

Mode of transmission Vertical Parentral Sexual

Perinatal transmission Perinatal transmission rates are 5% Rates are increased up to 15 20% if mother is coinfected with HIV. Risk factors: Use of internal fetal monitoring devices Prolonged rupture of membranes (>6 hours) High viral load HIV coinfection Breast feeding and vaginal delivery doesnot increase vertical transmission

Clinical Features Incubation period: 30-150 days Chronic infection will develop in 60-80% of exposed children. Majority of patients are asymptomatic in childhood. End-stage liver disease with decompensated cirrhosis has been described in children. Acute liver failure from HCV infection has not reported in immunocompetent patients. Comorbidities: Glomerulonephritis, Cryoglobulinemia and Autoimmune hepatitis

Diagnosis Check liver panel Screen with HCV IgG antibody after 18 month of age and HCV RNA after 2 month of age. HCV genotype analysis indicated if treatment is being considered.

Treatment Subcutaneous weekly pegylated interferon-alpha injections for 48 weeks (genotypes 1 or 4) or 24 weeks (genotypes 2 or 3), plus oral ribavirin. Treatment response: nondetectable HCV RNA by 24 weeks. Pegylated interferon/ribavirin therapy approved for 3 years of age.

Prevention HCV vaccine: none available. HCV immunoglobulin: none available. Household contacts: avoid sharing of tweezers, shavers, toothbrush, nail clippers. Universal precautions for handling abrasions, bleeding, etc. Screening for hepatocellular carcinoma (HCC): increased risk for HCC in setting of chronic HCV hepatitis.

HEPATITIS D VIRUS Defective interfering virus, requires HBV co-infection Prevalent in Mediterranean basin, North Africa, and South America 10% of HBV infected persons co-infected with HDV More severe infection Diagnosis: Co-infection with acute HBV showed positive IgM anti-hdv while super-infection of chronic HBV showed positive IgG & IgA anti-hdv in addition to serological markers of HBV.

HEPATITIS E VIRUS Incubation period 15-60 days Enteric transmission via fecal-oral route. Endemic in Southeast & Central Asia; Middle East, North and West Africa Acute, self-limited hepatitis Clinical features range from asymptomatic to mild to fulminant picture with high mortality rate in pregnant women in third trimester (20%) Diagnosis: Anti-HEV IgM positive for 2-3 months, Anti-HEV IgG persists long term in haif of patients. Immunoprophylaxis: none

HEPATITIS G VIRUS RNA virus Flaviviridae family with 25% homology with HCV. Parenterally transmitted agent ; can be transmitted perinatally. Clinical significance is uncertain, majority of infected patients without liver disease.