Viral Hepatitis in Infants 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 Management Other viral agents www.microscopyu.com

Hepatotropic Viruses PRIMARY SYSTEMIC 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)

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 Dx: serology Supportive care 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 Replication factory 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 U.S. 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 Vertical (maternal-fetal) Intravenous drug use 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)

Papular acrodermatitis

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.

HBV Serology HBsAg: + Anti-HBc: + IgM anti-HBc: + Anti-HBs: - HBsAg: + INTERPRETATION: Acute HBV infection INTERPRETATION: Chronic HBV infection

HBV Serology HBsAg: - Anti-HBc: + Anti-HBs: + HBsAg: - Anti-HBc: - INTERPRETATION: Immunity due to natural infection INTERPRETATION: Immunity due to HBV vaccination

HBV Course Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399-410.

Occurs in 20-50% by age 72 in absence of prevention or tx 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.

Management Pediatric 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.

Refer to Pediatric Gastroenterology 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

HBV Immunoprophylaxis 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 Prophylaxis NEONATAL OTHER 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 RNA flavivirus Difficult to clear 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 Transmission Maternal-fetal 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 C = Chronic; chronic infection develops in 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 Hepatitis Consultation 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