Viral hepatitis in children

An overview of pediatric viral hepatitis; pathophysiology, diagnosis, management and prevention.. Hepatitis A, B, C, D and E.

1. VIRAL HEPATITIS Dr Joyce Mwatonoka 3 rd Year Resident Pediatrics and Child Health March 2021

2. Introduction Viral hepatitis s a systemic infection affecting the liver predominantly with primary inflammation of the liver by any of a heterogeneous group of hepatotropic viruses At least 5 pathogenic hepatotropic viruses recognized to date: hepatitides A (HAV), B (HBV), C (HCV), D (HDV), and E (HEV) viruses

3. Cont… Many other viruses (and diseases) can cause hepatitis, usually as 1 component of a multisystem disease These include HSV, CMV, EBV, varicella -zoster virus, HIV, rubella, adenoviruses, enteroviruses , parvovirus B19, and arboviruses

4. Cont… In most pediatric patients , the acute phase causes no or mild clinical disease Morbidity is related to rare cases of ALF in susceptible pts, and to the chronic disease state and attendant complications that 3 of these viruses ( hepatitides B, C, and D) can cause

5. ISSUES COMMON TO ALL FORMS OF VIRAL HEPATITIS

6. Clinical presentation Jaundice Tender hepatomegally Splenomegaly and lymphadenopathy may be present Extrahepatic sxs (rashes, arthritis) are more readily seen in HBV and HCV infections Clinical signs of altered sensorium or hyper- reflexia ( onset of encephalopathy and ALF)

7. Differential Diagnoses V aries with age of presentation; In the newborn period ; I nfection is a common cause of conjugated hyperbilirubinemia ; can be bacterial agent (e.g., E coli, Listeria , syphilis) or a nonhepatotropic virus ( e.g.HSV , enteroviruses , CMV)

8. Cont… Metabolic ( α1 antitrypsin deficiency, cystic fibrosis, tyrosinemia ) Anatomic causes ( biliary atresia , choledochal cysts) and inherited forms of intrahepatic cholestasis should always be excluded

9. In later childhood; E xtrahepatic obstruction (gallstones, primary sclerosing cholangitis , pancreatic pathology), I nflammatory conditions (autoimmune hepatitis, juvenile rheumatoid arthritis, Kawasaki disease) Infection (EBV, varicella , malaria, leptospirosis , syphilis) I mmune dysregulation ( hemophagocytic lymphohistiocytosis ), I nfiltrative disorders (malignancies) T oxins and medications, metabolic disorders (Wilson disease, cystic fibrosis)

10. Common Biochemical Profiles in the Acute Infectious Phase 1. Cytopathic injury to the hepatocytes ; rise in serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) -Take weeks to return to normal unlike bilirubin NB ; The magnitude of enzyme elevation does not correlate with the extent of hepatocellular necrosis and has little prognostic value

11. Cont… 2. Cholestasis , defined by elevated serum conjugated bilirubin levels Markers of cholestasis ; -serum alkaline phosphatase (ALP) -5′-nucleotidase - γ- glutamyl transpeptidase - urobilinogen

12. Cont… Improvement tends to parallel the acute hepatitis phase Absence of cholestatic markers does not rule out progression to chronicity in HCV or HBV infections

13. Cont… 3. Synthetic dysfunction is reflected by a combination of; A bnormal protein synthesis (prolonged PT, high INR, low serum albumin levels) M etabolic disturbances (hypoglycemia, lactic acidosis, hyperammonemia ) P oor clearance of medications H epatic encephalopathy

14. HEPATITIS A VIRUS (HAV) Member of picornavirus family, RNA virus Host; humans and other primates T he most prevalent hepatotropic virus R esponsible for most forms of acute and benign hepatitis F ulminant hepatic failure can occur, but it is rare (<1%) and occurs more often in adults than in children

15. Cont… HAV is highly contagious Transmission is almost always by person-to-person contact through the fecal–oral route Perinatal transmission occurs rarely M ean incubation period is approx 3 wk Fecal excretion of the virus starts late in the incubation period, reaches its peak just before the onset of sxs , and resolves by 2 wk after the onset of jaundice in older subjects

16. Clinical Manifestations of HAV Often an anicteric illness, clinically indistinguishable from other forms of viral gastroenteritis, particularly in young children M ore likely to be symptomatic in adults, in pts with liver disorders and immunocompromised An acute febrile illness with anorexia, nausea, malaise, vomiting, and jaundice The typical duration of illness is 7-14 days

17. Cot… May have regional lymphadenopathy and splenomegally B one marrow may be moderately hypoplastic ( aplastic anemia) U lceration of the GIT can occur, especially in fatal cases Though rarely; a cute pancreatitis, myocarditis , nephritis, arthritis and vasculitis

18. Treatment HAV infection is usually self-limited Treatment consists of supportive care Full clinical and biochemical recovery is observed within 3 months in 85% of pts, and complete recovery is observed by 6mo in nearly all patients

19. Prevention;Vaccine 2 inactivated vaccines (HAVRIX and VAQTA) Approved for children older than 12 mo Administered IM in a 2-dose schedule, with the 2nd dose given 6-12 mo after the 1st dose Seroconversion rates in children exceed 90% after an initial dose and approach 100% after the 2nd dose; protective antibody titer persists for >10 yr in the vast majority of pts

20. Cont… HAV vaccine may be administered simultaneously with other vaccines A combination HAV and HBV vaccine is approved in adults older than age 18 yr For healthy persons at least 12 mo old, vaccine is preferable to Ig for preexposure and postexposure prophylaxis

21. Prognosis Excellent Px , with no long-term sequelae The only feared complication is ALF

22. HEPATITIS B VIRUS (HBV) HBV is a member of the Hepadnaviridae family, DNA virus HBV has 8 genotypes (A-H). A is pandemic, E in Africa Four genes have been identified: the S (surface), C (core), X, and P (polymer) genes The surface of the virus includes particles designated hepatitis B surface antigen ( HBsAg )

23. Cont… The inner portion of the virion contains HBcAg , the nucleocapsid that encodes the viral DNA, and a nonstructural Ag called hepatitis B e antigen ( HBeAg ), a nonparticulate soluble antigen derived from HBcAg by proteolytic self-cleavage HBeAg serves as a marker of active viral replication and usually correlates with HBV DNA levels Replication of HBV occurs predominantly in the liver but also occurs in the lymphocytes, spleen, kidney, and pancreas

24. Epidemiology Areas of highest prevalence of HBV infection are sub-Saharan Africa, China, parts of the Middle East, the Amazon basin, and the Pacific Islands

25. Acute infection The dx of acute HBV infection is based upon the detection of HBsAg and IgM antibody to hepatitis B core antigen (anti- HBc ) Hepatitis B immune globulin and hepatitis B vaccine should be administered to all household and sexual contacts who are not known to be immune

26. Cont… HBV is present in high concentrations in blood, serum, and serous exudates and in moderate concentrations in saliva, vaginal fluid, and semen Efficient transmission occurs through blood exposure and sexual contact

27. Risk factors for HBV infection and modes of transmission; No risk factors are identified in approximately 40% of cases The most important risk factor for acquisition of HBV remains perinatal exposure to an HBsAg -positive mother

28. Mother-to-child transmission HBsAg -positive and HBeAg -positive and/or a high HBV viral load, have greatest risk of transmission Up to 90% of these infants become chronically infected if untreated Transmission may occur in utero ( 2.5% ) , at the time of birth (commonest), or after birth

29. Cont… Immunoprophylaxis with hepatitis B immunoglobulin (HBIG) and the HBV immunization, given within 12 hr of delivery is very effective in preventing infection and protects > 95% of neonates born to HBsAg-positve mothers

30. Cont… However, despite the proper use of prophylaxis, transmission can still occur Among women with a high viral load, antiviral therapy for the mother can further reduce the risk of transmission

31. Cont… Breastfeeding;  does not appear to increase the risk of transmission Paternal transmission; In a study conducted in Taiwan, the HBV infection rate was 65% among neonates born to HBsAg -negative mothers and HBsAg -positive fathers; believed to result from close contact Application of hepatitis B virus genotyping and phylogenetic analysis in intrafamilial transmission of hepatitis B virus. Lin CL, Kao JH, Chen BF, Chen PJ, Lai MY, Chen DS  Clin Infect Dis. 2005;41(11):1576. 

32. Cont… Transfusion;  The WHO suggests screening with both HBsAg and hepatitis B core antibody (anti- HBc ) In the US residual risk of HBV transmission after screening for both ranged from approx 1 in 280,000 to 1 in 357,000 donations  With addition of HBV DNA screening

33. Cont… In adolescents ; IV drug use, contaminated needles, sexual contact, institutional care, and intimate contact with carriers

34. Cont… After infection, the incubation period ranges from 45-160 days , with a mean of approximately 120 days Sxs begin an average of 3months (range 2-5mo) after exposure to HBV Sxs typically last for several weeks but can persist for up to 6mo 70% subclinical ( anicteric ), <1% fulminant dse

35. Chronic HBV HBsAg positive for more than 6mo Approximately 30-50% of pts with chronic HBV infection have a past history of acute hepatitis Many pts with chronic HBV are asymptomatic (unless they have decompensated cirrhosis or have extrahepatic manifestations) Nonspecific symptoms such as fatigue

36. Extrahepatic manifestations Are thought to be mediated by circulating immune complexes The two major extrahepatic complications of chronic HBV are polyarteritis nodosa and glomerular disease HBV can induce both membranous nephropathy and, less often, membranoproliferative glomerulonephritis

37. Cont… The typical presentation is with nephrotic range proteinuria Approximately 30-60% of children with HBV-related membranous nephropathy undergo spontaneous remission The efficacy of antiviral therapy is uncertain

38. Labs ;

39. Treatment of HBV Rx of acute HBV is mainly supportive Indications for admission; coagulopathy , deep jaundiced, hepatic encephalopathy Antiviral treatment; not required in acute Indications for Rx ; fulminant hepatitis B, fibrosis on liver biopsy, post-liver transplant, immunocompromised , concomitant infection with hepatitis C or D virus, preexisting liver disease

40. Cont… Rx of chronic HBV infection is in evolution; no one drug currently achieves consistent, complete eradication of the virus Lack of reliable long-term outcome data on which to base treatment recommendations The goal of Rx is to reduce viral replication defined by having undetectable HBV DNA in the serum and development of anti- HBe , termed seroconversion

41. Cont… The development of anti- HBe transforms the disease into an inactive form, thereby decreasing infectivity, active liver injury and inflammation, fibrosis progression, and the risk of hepatocellular carcinoma Rx should be individualized and done under the care of a experienced pediatric gastroenterologist

42. Cont… Entecavir,tenofovir ,  lamivudine ,  adefovir  or  telbivudine  used in acute infection If unclear the pt has acute HBV or an acute exacerbation of chronic HBV, entecavir or tenofovir is preferred since these agents have a higher barrier to resistance Treatment can be stopped after confirmation (two consecutive tests 4 weeks apart) that the patient has cleared HBsAg

43. Complications Acute liver failure with coagulopathy , encephalopathy, and cerebral edema occurs more commonly with HBV than the other hepatotropic viruses Liver cirrhosis Primary hepatocellular carcinoma

44. HEPATITIS C VIRUS (HCV) HCV is a single-stranded RNA virus, classified as a separate genus within the Flaviviridae family, with marked genetic heterogeneity It has 6 major genotypes and numerous subtypes Genotype 1b is the commonest genotype in the US and is the least responsive to the currently available medications

45. Epidemiology HCV infection is the most common cause of chronic liver disease in adults and causes Approx 170 million people worldwide are estimated to be infected with HCV Approx. 85% of infected adults remain chronically infected In children, seroprevalence of HCV is 0.2% in those < 11 yr and 0.4% in children age 11 yr or older

46. Transmission The mechanisms underlying vertical transmission of HCV are poorly understood Intrauterine transmission during pregnancy and infection at the time of delivery are both possible In most infants, HCV RNA levels only become detectable several weeks after birth, suggesting perinatal infection

47. Cont… A study involving 20 pregnant women (HCV antibody and RNA positive), infants tested atleast by 18months of age; The pooled transmission rate was 5.8% among women with HCV monoinfection and 10.8% among those with HCV/HIV coinfection Vertical transmission of hepatitis C virus: systematic review and meta-analysis. Benova L, Mohamoud YA, Calvert C, Abu- Raddad LJ  Clin Infect Dis. 2014;59(6):765. Epub 2014 Jun 13

48. Established risk factors Maternal HCV viremia during pregnancy or at the time of delivery and with concomitant HIV infection Maternal IV drug use Peripheral blood mononuclear cell infection (serves as a vector for the HCV or because the viral variant of HCV that infects PBMCs is able to interact with and overcome the immune cells of the placenta)

49. Possible risk factors for transmission Invasive prenatal testing  Prolonged rupture of membranes  Obstetric procedures 

50. Clinical manifestations Newborns with HCV infection usually are asymptomatic Although progression to chronicity occurs in most infants with vertically acquired HCV, liver disease usually is mild throughout childhood

51. Cont… One of the largest series with long-term follow-up of children with perinatally acquired HCV included 266 children who were followed for a median of 4.2 years 20% cleared the infection at a median age of 15 months, whereas 80% had chronic infection Most children with chronic infection were asymptomatic Three broad modalities in the natural history of vertically acquired hepatitis C virus infection. European Paediatric Hepatitis C Virus Network  Clin Infect Dis. 2005;41(1):45. 

52. Diagnosis Detection of antibodies to HCV antigens or detection of viral RNA; neither can predict the severity of liver disease Anti-HCV is not a protective antibody and does not confer immunity In children born to infected mothers; check an anti-HCV antibody test after 18 months of age

53. Treatment The natural history of HCV infection in children is still being defined It is believed that children have a higher rate of spontaneous clearance than adults (up to 45% by age 19 yr) Peginterferon (Schering), IFN-α2b , and ribavirin are approved by the FDA for use in children older than 3 yr of age with HCV hepatitis

54. Cont… Treatment should be considered for all children infected with genotypes 2 and 3 , because they have an 80-90% response rate to therapy with peginterferon and ribavirin If the child has genotype 1b virus, the treatment choice remains more controversial

55. Cont… Rx should be considered for pts with evidence of advanced fibrosis or injury on liver biopsy The currently approved treatment consists of 48 wk of peginterferon and ribavirin (stop if still detectable on viral PCR at 24 wk of therapy) Rx of children with normal biochemical profile and mild histologic inflammation should be reserved to a clinical study context

56. Cont… Factors associated with a higher likelihood of response are; Age younger than 12 yr, Genotypes 2 and 3, and, in Pts with genotype 1b, an RNA titer of <2 million copies/ mL of blood Viral response (PCR at weeks 4 and 12 of treatment)

57. Prevention Identifying and treating HCV-infected women prior to conception Antiviral therapy during pregnancy is not an option since the safety and efficacy have not been evaluated

58. HEPATITIS D VIRUS (HDV) Is the smallest known animal virus, is considered defective because it cannot produce infection without concurrent HBV infection Its outer coat is composed of excess HBsAg from HBV. The inner core of the virus is single-stranded circular RNA that expresses the HDV antigen

59. Epidemiology HDV can cause a coinfection , or superinfection with HBV Transmission usually occurs by intrafamilial or intimate contact in areas of high prevalence, which are primarily developing countries The incubation period for HDV superinfection is approximately 2-8 wk ; with coinfection , it is similar to that of HBV infection

60. Pathogenesis Liver pathology in HDV hepatitis has no distinguishing features except that damage is usually quite severe In contrast to HBV, HDV causes injury directly by cytopathic mechanisms The most severe cases of HBV infection appear to result from coinfection of HBV and HDV

61. Clinical Manifestations The sxs are similar to, but usually more severe than those of the other hepatotropic viruses In coinfection , acute hepatitis, which is much more severe than for HBV alone, is common, but low risk of developing chronic hepatitis In superinfection , acute illness is rare and chronic hepatitis is common. Hihgest risk of ALF. Hepatitis D should be considered in any child with ALF

62. Diagnosis By detecting IgM antibody to HDV ; the Abs to HDV develop approximately 2-4 wk after coinfection and approximately 10 wk after a superinfection A test for anti-HDV antibody is commercially available PCR assays for viral RNA are available as research tools

63. Treatment Supportive The treatment is mostly based on controlling and treating HBV infection, without which HDV cannot induce hepatitis Pegylated interferon alfa ( IFNa ) Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr , Bzowej NH, Wong JB  Hepatology . 2018;67(4):1560. 

64. HEPATITIS E VIRUS (HEV) RNA virus Transmission is fecal-oral The highest prevalence of HEV infection has been reported in the Indian subcontinent, the Middle East, Southeast Asia, and Mexico, especially in areas with poor sanitation

65. Cont… The clinical illness associated with HEV infection is similar to that of HAV but is often more severe As with HAV, chronic illness does not occur Tends to affect older patients, with a peak age between 15 and 34 yr HEV is a major pathogen in pregnant women, in whom it causes ALF with a high fatality incidence

66. Dx Antibodies to HEV particles IgM and IgG assays are available to distinguish between acute and resolved infections IgM antibody becomes positive after approximately 1 wk of illness Viral RNA can be detected in stool and serum by PCR.

67. Prevention A recombinant hepatitis E vaccine

68. Thank You For Your Attention!