Viral HepatitisinInfants and Children Ricardo A. Caicedo, M.D. Pediatric Gastroenterology and Nutrition Wake Forest University Baptist Medical Center
Learning Objectives • Recognize the clinical manifestations of viral hepatitis in the pediatric population • Understand the natural history of hepatotropic viral infections in children • Become familiar with the diagnosis and management of pediatric viral hepatitis
Topics • Hepatotropic Viruses • Acute vs. Fulminant vs. Chronic • Hepatitis A virus • Hepatitis B virus • Diagnosis • Natural history • Immunoprophylaxis/management • Hepatitis C virus • Diagnosis • Natural history • Management • Other viral agents www.microscopyu.com
PRIMARY Hepatitis A Virus (HAV) Hepatitis B Virus (HBV) Hepatitis C Virus (HCV) Hepatitis D Virus (HDV) Requires HBV co-infection Hepatitis E Virus (HEV) Hepatitis F Virus (controversial) Hepatitis G Virus (pathogen?) SYSTEMIC Cytomegalovirus (CMV) Epstein-Barr Virus (EBV) HIV Adenovirus Parvovirus B19 Rubella Coxsackievirus B Enteroviruses Human Herpes Viruses Herpes Simplex Virus (HSV) HHV-6 Varicella Zoster Virus (VZV) Hepatotropic Viruses
Acute Viral Hepatitis • Acute hepatocellular injury/inflammation • Reflected by elevated transaminases (AST or SGOT, ALT or SGPT) • Clinical manifestations often include fever, malaise, jaundice, RUQ pain, nausea/vomiting • Typically self-limited and of short duration • Contrast with: chronic, fulminant • Causative agents • HAV (50% of cases in U.S.), HEV • CMV, EBV, VZV
Fulminant Hepatitis • Acute, massive hepatocellular necrosis • Impaired synthetic, excretory, and detoxifying functions of the liver • Cholestasis, ascites, coagulopathy, encephalopathy, multi-system failure • Initially very elevated transaminases • Falling transaminases and rising bilirubin ominous • Hyperammonemia, hypoalbuminemia, prolonged PT, hypoglycemia • Viral agents (50% of cases) • Most cases of fulminant hepatic failure are caused by unidentified agent, presumably viral • HAV, HBV+/-HDV, HCV, HEV • HSV, enteroviruses, EBV, CMV, HHV-6, VZV
Chronic Hepatitis • Prolonged necroinflammatory process • Elevated transaminases for > 4-6 months • Insidious clinical manifestations • Can include cholestasis (jaundice, pruritus), ascites, hypoalbuminemia, coagulopathy, encephalopathy • Can progress to fibrosis and then cirrhosis • Viral agents: HBV (+/- HDV), HCV • Other causes include autoimmune, metabolic disorders (Wilson’s, CF, alpha-1 antitrypsin deficiency), drug/toxin-mediated, idiopathic
Chronic Viral Hepatitis Risk Factors Hochman J, Balistreri WF. Pediatr Rev. 2003; 24:399-410.
Hepatitis A Virus • Causes 33% of acute viral hepatitis in U.S. • NOT a cause of chronic hepatitis • rarely causes fulminant hepatitis (< 1% cases) • Can trigger autoimmune hepatitis in predisposed individuals • Epidemiologic factors • Fecal-oral transmission • Poor hygiene • High population density • Daycare centers and minor epidemics
HAV • Acute, self-limited illness • Fever, malaise, anorexia, vomiting, nausea, abdominal pain, diarrhea • Elevated AST/ALT • Jaundice (conjugated hyperbilirubinemia) usually 1 wk after onset of symptoms • Duration • Age < 6 y: typically, <2 wks • Older children and adults can have prolonged course and often have hepatomegaly • Dx: serology • Anti-HAV IgM • Supportive care
HAV Course Quiros-Tejeira RE. Up to Date v. 14.3, 2006.
HAV Vaccine • Prevents morbidity and mortality associated with HAV infection • Incidence of HAV in U.S. has decreased by 75% since vaccine introduced in 1997 • Because humans are the only known reservoir for HAV, universal immunization strategies could hypothetically eradicate HAV • AAP Recommendation, 2006 • All children age 12-23 months should be immunized • Extended safety data supports incorporation of HAV vaccine into routine childhood immunization schedule
Recommended Standard Childhood Immunization Schedule, 2006 www.cdc.gov/nip/recs/child-schedule.htm
Hepatitis B Virus • Hepadnavirus • Double-stranded DNA • “A retrovirus in disguise” • Multiple genotypes and serotypes • Replication factory • Significant mutation rate • Can “escape” serological detection and/or vaccine • Triggers host immune attack on liver cells • T-cell-mediated hepatocellular lysis • Chronic infection results from ineffective immune response
HBV Epidemiology • Worldwide • Persons infected: 2 billion • Persons with chronic HBV: 350 million • Annual deaths: 1 million • U.S. • Chronic HBV: 1.25 million • Annual deaths: 5000
HBV Transmission • Sexual • High risk: non-monogamous heterosexual and all homosexual encounters • Vertical (maternal-fetal) • Intravenous drug use • Hemodialysis • Blood products • Risk of acquiring HBV from blood transfusion: < 1:60000
HBV Manifestations • Incubation period: 45-160 d • Prodromal “flu-like” illness • Malaise, fatigue, anorexia, nausea, fever • Jaundice • Cholestasis • Elevated AST/ALT • Less common • Fulminant hepatitis: coagulopathy, encephalopathy • 1-5% of HBV cases • Glomerulonephritis, arthritis • Papular acrodermatitis (Giannotti-Crosti)
Screening for HBV • TESTS: HBsAg and anti-HBs • Adolescents who engage in high-risk behaviors • IV or intranasal drug abuse • unprotected sex with an infected partner or > 1 partner • Hx of STD • All internationally adopted children • Immigrants from high-prevalence areas • Africa, SE Asia, the Middle East except Israel, the interior Amazon River basin, Haiti/D.R. • Children living in communities where HBV is endemic • Household contacts of individuals with HBV infection • Infants born to women with HBV infection • If infant got hepatitis B immune globulin and hepatitis B vaccine at birth, followed by two additional immunizations, test at 9-15 m • Unimmunized should be tested as soon as identified
HBV Diagnosis Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.
HBV Diagnosis SEROLOGIC RESPONSES Lok ASF. Up to Date v. 14.3, 2006.
HBsAg: + Anti-HBc: + IgM anti-HBc: + Anti-HBs: - HBsAg: + Anti-HBc: + IgM anti-HBc: - Anti-HBs: - HBV Serology INTERPRETATION:Acute HBV infection INTERPRETATION:Chronic HBV infection
HBsAg: - Anti-HBc: + Anti-HBs: + HBsAg: - Anti-HBc: - Anti-HBs: + HBV Serology INTERPRETATION: Immunity due to natural infection INTERPRETATION: Immunity due to HBV vaccination
HBV Course Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.
HBV Sequelae Risk of Chronic HBV 95% 30% 5% Occurs in 20-50% by age 72 in absence of prevention or tx Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.
Evaluation of HBsAg+ Patients • AST/ALT, T/D bilirubin • PT/INR, albumin • HBV DNA • Anti-HBc, Anti-HBe, HBeAg • Serology for HAV, HCV, HDV • Test for HIV and other STDs • Test household and sexual contacts • If chronic • Ultrasound • Liver biopsy • Alpha feto-protein (AFP) Lin KW, Kirchner JT. Am Fam Physician 2004; 69:75-82.
ManagementPediatric Chronic HBV • Prove chronic infection • > 2 HBsAg+ samples 6 months apart • OR anti-HBc+, IgM anti-HBc – • Follow ALT q 6 months • If > 1.5-2X normal, liver biopsy and consider treatment • Yearly • HBeAg and anti-HBe (look for seroconversion) • Ultrasound and AFP • Immunize • HAV vaccine • All household contacts Jonas MM, NASPGHAN Postgraduate Course, 2005.
HBV Treatment Refer to Pediatric Gastroenterology Lin KW, Kirchner JT. Am Fam Physician 2004; 69:75-82. • GOALS of TREATMENT • Suppress HBV replication • Seroconversion from eAg to e Ab • Prevent long-term sequelae • Interferon-alfa • Lamivudine • Adefovir
PASSIVE: HBIG In conjunction with vaccine Perinatal exposure Occupational exposure (needle stick) Household contact exposed to blood ACTIVE: HBV Vaccine AAP recommends immunizing all newborns Started in 1991 By end of 1990s, rate of acute HBV in children reduced by 75% Taiwan: vaccination program reduced incidence of HBsAg+, HCC, and fulminant hepatitis No objective evidence linking vaccine to multiple sclerosis or autism HBV Immunoprophylaxis
HBV Prophylaxis • NEONATAL • Routine screening of all pregnant women for HBsAg is now mandatory • HBsAg-negative mother: Infant vaccinated at birth; at 1-2 m; at 6-18 m • Infants born to mothers with unknown or known positive HBsAg status: HB immune globulin (HBIG) plus the 1st dose HB vaccine within 12 h of birth, 2nd at 1-2 m; 3rd at 6 m • OTHER • Post-exposure (occupational): for nonvaccinated individuals or absence of documented response • High risk groups • Healthcare workers • Chronic liver disease • Dialysis or chronic parenteral therapy recipients • High risk behaviors (IV drug use, unprotected sex)
Hepatitis C Virus • Discovered 1989 • Post-transfusion “non-A, non-B hepatitis” • RNA flavivirus • Difficult to clear • Genetic heterogeneity • 9 known genotypes • Rapid mutation rate • Exists as mixture of closely related mutants (quasi-species) within an individual host
HCV Epidemiology • Prevalence • Adults: 2% • Children: 0.2%, Adolescents: 0.4% • Transmission • Maternal-fetal • Mother HCV+: 5% risk • Mother co-infected with HIV: 15% risk • All infants born to HCV-infected mothers should be tested for anti-HCV Ab after 12 m of age • Blood transfusion • Screening blood products has reduced risk to <1:100,000 • Other risk factors • High risk sexual behavior • IV drug abuse • Tattooing, body piercing
HCV Sequelae Mild systemic illness; usually without jaundice C = Chronic; chronic infection develops in most patients with HCV
HCV Diagnosis Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.
HCV Management • No immunoprophylaxis available • Screen for and vaccinate vs. HAV & HBV • Avoid hepatotoxins • Acetaminophen, alcohol • Follow-up at regular intervals • Follow LFT • AFP, ultrasound (screen for HCC) • Treatment in selected patients • Prevent progression to cirrhosis • If HCV identified during acute stage - eradication • Pegylated-interferon (choice in adults) • PEG-IFN + ribavirin (multicenter pediatric trial) • Liver transplantation: indicated for cirrhosis or HCC
Viral HepatitisConsultation with Pediatric GI Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.
Breastfeeding • HBsAg+ mothers • can breastfeed as long as neonate has received HBIG and vaccine within 12 h of birth • HCV+ mother is not contraindication to breastfeeding • Data re: transmission in human milk is limited
CMV • Usually acute self-limited hepatitis • Mononucleosis syndrome with fever • Typically anicteric • Transaminases peak at 200s at 2-3 wks • Dx: IgM, antigenemia, PCR • Rarely causes fulminant hepatitis • Can treat with ganciclovir or foscarnet • More severe cases • Immunocompromised • Chronic liver disease
EBV • Classic infectious mononucleosis syndrome • Fever, sore throat, fatigue • Cerv. lymphadenopathy, splenomegaly • Liver insult secondary to infected T cells • Mild anicteric hepatitis in most cases • Dx = EBV serology, PCR • Fulminant course (1:3000 cases) • Severe hepatitis, bone marrow failure
North American Society for Pediatric Gastroenterology, Hepatology and Nutrition www.naspghan.org www.cdhnf.org www.hepb.org www.aasld.org