Viral Hepatitis in Infants and Children Ricardo A

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 – Diagnosis – Natural history – Management • Other viral agents www. microscopyu. com

Hepatotropic Viruses 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 B 19 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 – 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 Ig. M • 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)

Papular acrodermatitis

Screening for HBV • TESTS: HBs. Ag 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 • • HBs. Ag: + Anti-HBc: + Ig. M anti-HBc: + Anti-HBs: INTERPRETATION: Acute HBV infection • • HBs. Ag: + Anti-HBc: + Ig. M anti-HBc: Anti-HBs: INTERPRETATION: Chronic HBV infection

HBV Serology • HBs. Ag: • Anti-HBc: + • Anti-HBs: + INTERPRETATION: Immunity due to natural infection • HBs. Ag: • Anti-HBc: • Anti-HBs: + 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 2050% by age 72 in absence of prevention or tx Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399 -410.

Evaluation of HBs. Ag+ Patients • • AST/ALT, T/D bilirubin PT/INR, albumin HBV DNA Anti-HBc, Anti-HBe, HBe. Ag 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 HBs. Ag+ samples 6 months apart • OR anti-HBc+, Ig. M anti-HBc – • Follow ALT q 6 months • If > 1. 5 -2 X normal, liver biopsy and consider treatment • Yearly • HBe. Ag and anti-HBe (look for seroconversion) • Ultrasound and AFP • Immunize • HAV vaccine • All household contacts Jonas MM, NASPGHAN Postgraduate Course, 2005.

HBV Treatment Lin KW, Kirchner JT. Am Fam Physician 2004; 69: 75 -82. GOALS of TREATMENT - Suppress HBV replication - Seroconversion from e. Ag 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 1990 s, rate of acute HBV in children reduced by 75% • Taiwan: vaccination program reduced incidence of HBs. Ag+, HCC, and fulminant hepatitis – No objective evidence linking vaccine to multiple sclerosis or autism

HBV Prophylaxis • NEONATAL • Routine screening of all pregnant women for HBs. Ag is now mandatory • HBs. Ag-negative mother: Infant vaccinated at birth; at 1 -2 m; at 6 -18 m • Infants born to mothers with unknown or known positive HBs. Ag status: HB immune globulin (HBIG) plus the 1 st dose HB vaccine within 12 h of birth, 2 nd at 1 -2 m; 3 rd 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 (quasispecies) 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 Hepatitis Consultation with Pediatric GI Hochman J, Balistreri WF. Pediatr Rev. 2003; 24: 399 -410.

Breastfeeding • HBs. Ag+ 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 200 s at 2 -3 wks Dx: Ig. M, 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