Hepatitis A and E

Hepatitis A And E In Nepal

1. Viral Hepatitis A and E Int. Dr. Amit Poudel

2. A “Infectious” “Serum” Viral hepatitis Enterically transmitted Parenterally transmitted other E “NANB” B D C VIRAL HEPATITIS

3. Hepatitis A

4. is an acute infectious disease of the liver caused by the hepatitis A virus ( HAV) formerly known as infectious hepatitis

5. HEPATITIS A VIRUS nonenveloped 27-nm, RNA virus , Hepatovirus genus , picornavirus family heat, acid, and ether-resistant virion contains four capsid polypeptides, designated VP1 to VP4 , despite the recognition of four genotypes affecting humans, all strains of this virus are immunologically indistinguishable and belong to one serotype.

6. Inactivation of viral activity can be achieved by boiling for 1 minute, by contact with formaldehyde and chlorine, by ultraviolet irradiation

7. incubation period of 4 weeks. (15-45 days) replication is limited to the liver the virus is present in the liver, bile, stool and blood during the late incubation period and acute preicteric phase of illness. Despite persistence of virus in the liver, viral shedding in feces , viremia , and infectivity diminish rapidly once jaundice becomes apparent.

8. PATHOGENESIS After ingestion, the HAV survives gastric acid, moves to the small intestine and reaches the liver via the portal vein Replicates in hepatocyte cytoplasm Not a Cytopathic virus Immune mediated cell damage more likely Once mature the HAV travels through sinusoids and enters bile canaliculi , released into the small intestine and systemic circulation, excreted in feces

9. has a worldwide distribution. The highest seropositivity is observed in adults in urban Africa, Asia, and South America. Acquisition in early childhood is the norm in these nations and is usually asymptomatic . transmitted almost exclusively by the fecal -oral route Factors predisposing humans to early acquisition include overcrowding , poor sanitation, and lack of a reliable clean water resource.

10. CONCENTRATION OF HEPATITIS A VIRUS IN VARIOUS BODY FLUIDS Source: Viral Hepatitis and Liver Disease 1984;9-22 J Infect Dis 1989;160:887-890 Feces Serum Saliva Urine 10 10 2 10 4 10 6 10 8 10 10 Body Fluids Infectious Doses per mL

11. HEPATITIS A VIRUS TRANSMISSION Close personal contact (e.g., household contact, sex contact, child day-care centers) Contaminated food, water (e.g., infected food handlers) Blood exposure (rare) (e.g., injection drug use, rarely by transfusion)

12. RISK FACTORS ASSOCIATED WITH REPORTED HEPATITIS A,

13. SYMPTOMS Appears in two different phases Prodrome Patients may have mild flu like symptoms of anorexia, nausea and vomiting, fatigue, malaise, low-grade fever (usually <39.5°C), myalgia, and mild headache. Smokers often lose their taste for tobacco

14. Icteric phase Dark urine appears first ( bilirubinuria ). Pale stool soon follows Jaundice -(70-85%) adults. Abdominal pain (40%). Itch (pruritus ) Arthralgias and skin rash,

15. SIGNS Hepatomegaly is common. Jaundice or scleral icterus may occur. Patients may have a fever with temperatures of up to 40°C.

16. LAB STUDIES Anti–hepatitis A virus immunoglobulin M The diagnosis of acute HAV infection is based on serologic testing for IgM antibody to HAV. are positive at the time of onset of symptoms and usually accompany the first rise in alanine aminotransferase (ALT) level. This test is sensitive and specific, and results remain positive for 3-6 months after the primary infection and for as long as 12 months in 25% of patients. False-positive results are uncommon and should be considered in the event that anti-HAV IgM persists. IgM persists in patients with relapsing hepatitis for the duration of this pattern of disease.

17. Anti–hepatitis A virus immunoglobulin G Anti-HAV IgG appears soon after IgM and generally persists for many years. The presence of anti-HAV IgG in the absence of IgM indicates past infection or vaccination rather than acute infection. IgG provides protective immunity

18. Liver enzymes Rises of levels in ALT and aspartate aminotransferase (AST) assays are sensitive for this disease. Levels may exceed values of 10,000 mIU /mL, with ALT levels generally greater than AST levels . Levels usually return to reference ranges over 5-20 weeks. Rises in alkaline phosphatase accompany the acute disease and may progress during the cholestatic phase of the illness following the rises in transaminase levels.

19. Hepatic synthetic function Bilirubin level rises soon after the onset of bilirubinuria and follows rises in ALT and AST levels. Levels may be impressively high and can remain elevated for several months; persistence beyond 3 months indicates cholestatic HAV infection. Older individuals have higher bilirubin levels. Both direct and indirect fractions increase because of hemolysis , which often occurs in acute HAV infection. Modest falls in serum albumin level may accompany the illness.

20. Prothrombin time Prothrombin time usually remains within or near the reference range. Significant rises should raise concern and support closer monitoring. In the presence of encephalopathy, an elevated prothrombin time has ominous implications ( eg , fulminant hepatic failure). CBC count Mild lymphocytosis is not uncommon. Pure red cell aplasia and pancytopenia may rarely accompany infection. Indices of low-grade hemolysis are not uncommon.

21. MEDICAL CARE For acute cases, therapy is generally supportive, with no specific treatment for acute uncomplicated illness. Locating the primary source and preventing further outbreaks are paramount. Initial therapy often consists of bed rest. Returning to work should probably be delayed for 10 days after the onset of jaundice The patient should probably not work during the acute phase of the illness . Diet : Encourage an adequate diet. Patients should avoid alcohol and medications that may accumulate in liver disease. Otherwise, no specific dietary restrictions are necessary

22. CRITERIA FOR HOSPITAL ADMISSION Age > 45 years Fever > 38.5˚C since 72 hours accompanied with vomiting and clinical signs of dehydration and renal insufficiency. Clinical signs of hepatic encephalopathy (flapping tremor, coma) Hemorrhagic manifestations Ascitis Consumption of more than 3g of paracetamol , aspirin during the past week . Anemia or leucopenia Obese or post-partum patient Cirrhosis and/or cardiopathy and/or chronic renal insufficiency Patient with HIV/AIDS

23. SURGICAL CARE Consider patients with fulminant hepatic failure for referral for liver transplantation. Recurrent disease after transplantation has not been reported. Selection of patients who require transplantation may be difficult because 60% of them recover from fulminant failure without a need for transplantation Late referral has ominous implications, with the accompanying comorbidities ( eg , renal failure, coagulopathy, cerebral edema ) and waiting times contributing to poor outcomes.

24. Complications: Death is rare, occurring in fewer than 0.2% of cases,frequent in elderly patients and in those with underlying liver disease. . Prolonged cholestasis characterized by a protracted period of jaundice (>3 mo ) and resolves without intervention . Acute renal failure, interstitial nephritis, pancreatitis , red blood cell aplasia, agranulocytosis ,

25. bone marrow aplasia , transient heart block, Guillain-Barré syndrome, acute arthritis, Still disease, Lupus like syndrome, Sjögren syndrome Autoimmune hepatitis

26. Relapsing HAV infection occurs in 3-20% of patients with acute HAV infection and uncommonly takes the form of multiple relapses. Following a typical acute course of HAV infection, a remission phase occurs, with partial or complete resolution of clinical and biochemical manifestations. The initial flare usually lasts 3-6 weeks; relapse occurs after a short period (usually <3 wk ) and mimics the initially presentation, although it usually is clinically milder. A tendency to greater cholestasis. Vasculitic skin rashes and nephritis During relapses, shedding of virus can be detected. IgM antibody test +. . Liver transplantation has been performed in patients with this condition when signs of significant decompensation have occurred . Corticosteroid treatment has been shown to improve the clinical course, although the course is generally benign without treatment.

27. PREVENTING HEPATITIS A Hygiene (e.g., hand washing) Sanitation (e.g., clean water sources) Hepatitis A vaccine (pre-exposure) Immune globulin (pre- and post-exposure)

28. PREPARATION OF INACTIVATED HEPATITIS A VACCINES Cell culture adapted virus grown in human fibroblasts Purified product inactivated with formalin Adsorbed to aluminum hydroxide adjuvant

29. Highly immunogenic 97%-100% of children, adolescents, and adults have protective levels of antibody within 1 month of receiving first dose; essentially 100% have protective levels after second dose Highly efficacious In published studies, 94%-100% of children protected against clinical hepatitis A after equivalent of one dose HEPATITIS A VACCINES

30. HEPATITIS A VACCINES Age Volume 2-Dose Schedule Vaccine ( yrs ) Dose (mL) ( mos ) HAVRIX ® # 2-18 720 (EL.U.*) 0.5 0, 6-12 >18 1,440 1.0 0, 6-12 VAQTA ® ## 2-18 25 (U**) 0.5 0, 6-18 >18 50 1.0 0, 6-12 * EL.U. – Enzyme-linked immunosorbent assay (ELISA) units ** Units # has 2-phenoxyethanol as a preservative ## has no preservative Recommended Dosages of Hepatitis A Vaccines

31. Most common side effects Soreness/tenderness at injection site - 50% Headache - 15% Malaise - 7% No severe adverse reactions attributed to vaccine Safety in pregnancy not determined – risk likely low Contraindications - severe adverse reaction to previous dose or allergy to a vaccine component No special precautions for immunocompromised persons SAFETY OF HEPATITIS A VACCINE

32. DURATION OF PROTECTION AFTER HEPATITIS A VACCINATION Persistence of antibody At least 5-8 years among adults and children Efficacy No cases in vaccinated children at 5-6 years of follow-up Mathematical models of antibody decline suggest protective antibody levels persist for at least 20 years Other mechanisms, such as cellular memory, may contribute

33. Decreased antibody concentration: Concurrent administration of IG Presence of passively-transferred maternal antibody Age Chronic liver disease Decreased seroconversion rate: HIV infection May be related to degree of immunosuppression Liver transplantation FACTORS ASSOCIATED WITH DECREASED IMMUNOGENICITY TO HEPATITIS A VACCINE

34. USE OF HEPATITIS A VACCINE FOR INFANTS Safe and immunogenic for infants without maternal antibody Presence of passively-acquired maternal antibody blunts immune response all respond, but with lower final antibody concentrations Age by which maternal antibody disappears is unclear still present in some infants at one year probably gone in vast majority by 15 months

35. Approved by the FDA in United States for persons > 18 years old Contains 720 EL.U. hepatitis A antigen and 20 μ g . HBsAg Vaccination schedule: 0,1,6 months Immunogenicity similar to single-antigen vaccines given separately Can be used in persons > 18 years old who need vaccination against both hepatitis A and B Formulation for children available in many other countries COMBINED HEPATITIS A HEPATITIS B VACCINE

36. Pre-exposure travelers to intermediate and high HAV-endemic regions Post-exposure (within 14 days) Routine household and other intimate contacts Selected situations institutions (e.g., day-care centers) common source exposure (e.g., food prepared by infected food handler) HEPATITIS A PREVENTION IMMUNE GLOBULIN

37. Hepatitis E

38. Hepatitis E is an acute disease caused by hepatitis E virus that usually manifest as acute jaundice. Previously labeled epidemic or enterically transmitted non-A, non-B hepatitis is an enterically transmitted self-limited infection. Hallmarks of the disease are high attack-rate in young adults and high mortality in pregnant women spread by fecally contaminated water within endemic areas Outbreaks can be epidemic and individual. It has many similarities with hepatitis A.

39. HEPATITIS E VIRUS discovered during electron microscopy of feces contaminated with enteric non-A, non-B hepatitis round , non-enveloped virus -30 nm. The genome of the virus is a single stranded, positive–sense RNA of approximately 7.2 kb . consists of a short 5’ untranslated region ( UTR) followed by three partially overlapping open reading frames (ORFs: ORF1, ORF2, and ORF3), and then a short 3’UTR terminated by a poly (A) tract

40. ORF1 encodes viral non-structural proteins , ORF2 encodes the capsid protein, ORF3 encodes a small phosphorylated protein

41. classified tentatively into four major genetic groups (genotype 1-4) Genotype 1 is further segregated into five subgroups, subtypes 1a to 1e. The predominant HEV genotype seen in Nepal is 1a . Genotype 1c was observed only during 1996 to 1998 Study of 250 HEV isolates from Nepal over ten years period from 1986 to 2006 showed some genetic changes in hepatitis E virus of subtype 1a

42. NEPAL AND HEPATITIS E The first documented epidemic hepatitis in Nepal occurred in the Kathmandu valley in 1973 affected more than 10,000 people, mostly young adults in the age group of 16 to 35 years age Another epidemic of hepatitis occurred in the valley in 1981 to 1982 was identified as epidemic non-A, non-B hepatitis. reoccurred in the valley in 1987 - HEV was isolated from stool of a patient .

43. Between 1985 and 1986 five localized focal outbreaks of non-A, non-B hepatitis occurred in different institutions like Central jail, police training center , Military hospital and two localities in Kathmandu. These outbreaks were caused by local sewerage contamination of the drinking water As the adult population of Nepal has solid immunity against HAV (99% has anti-HAV IgG ), the common occurrence of acute infectious jaundice mainly affecting adults pointed to the presence of hepatitis E in the country at least since early 20 th century .

44. In April 2014 there was an outbreak in Nepal, Biratnagar Municipality with over 6,000 locals infected and at least 9 dead Prevalence of Hepatitis E (in percentage) among patient with Acute Hepatitis in Kathmandu valley from 1996 to 2005

45. INCUBATION PERIOD ranges from 15 days to 60 days

46. MORTALITY/MORBIDITY: The overall case fatality rate is 4%. The case fatality rate among pregnant women is 20%, which increases during the second and third trimesters . Reported causes of death include encephalopathy and disseminated intravascular coagulation. The rate of fulminant hepatic failure in infected pregnant women is high.

47. AGE predominantly affects those aged 15-40 years. may affect younger age groups but generally is not recognized and may be subclinical. No chronic cases have been described.

48. SYMPTOMS Appears in two different phases Prodromal-phase Myalgia Arthralgia Fever with mild temperature elevations (25-97%) Anorexia (66-100%) Nausea/vomiting (30-100%) Weight loss (typically 2-4 kg) Dehydration Right upper quadrant pain that increases with physical activity

49. Icteric-phase symptoms include the following: Jaundice Dark urine Light- colored stools (20-40%) Pruritus (50%) Urticarial rash Diarrhea

50. SIGNS Right upper quadrant tenderness Possible enlarged liver (palpable edges) Possible splenomegaly Possible transient spider angiomata

51. LAB STUDIES Western blot and enzyme immunoassays detect anti-HEV antibodies by using the antigenic domains from ORF-2 and ORF-3. Assays of ORF-2 are more sensitive. Testing to detect anti-HEV immunoglobulin M ( IgM ) and immunoglobulin G ( IgG ) differentiates acute and chronic infection. The IgM titer falls rapidly after infection, becoming virtually undetectable within 6 months. Anti-HEV IgG persists for longer than 6 months, although its actual duration of positivity is unknown. IgG anti-HEV appears to afford protection against reinfection.

52. Symptoms ALT IgG anti-HEV IgM anti-HEV Virus in stool 1 2 3 4 5 6 7 8 9 10 11 12 13 TYPICAL SEROLOGIC COURSE Titer Weeks after Exposure

53. AMINOTRANSFERASE LEVELS (AST, ALT) are elevated several days before the onset of symptoms generally return to normal within 1-2 months after the peak severity of the disease has passed. Elevations can be associated with underlying liver disease or exposure to other hepatotoxins . Whether the magnitude of elevation correlates with the histological severity is not clear

54. Serum bilirubin elevations occur in both the total and direct fractions. Hemolysis is unusual. In most cases, bilirubin levels take longer to return to normal than aminotransferase levels. Many patients develop a mild leukocytosis. If associated with fever, bacteremia should be suspected. More commonly, WBC counts are decreased. Differential counts may show atypical cells and lymphocytosis

55. IMAGING STUDIES Abdominal ultrasonography is recommended. It helps rule out biliary obstruction in cases with significant nausea, vomiting, or fever. It can demonstrate the presence of an enlarged liver; echo texture is heterogeneous and coarsened. It can demonstrate splenomegaly, if present.

56. HEPATITIS E IN PREGNANCY High incidence of death from acute hepatic failure in pregnant women is recognized as a distinct characteristic feature of hepatitis E .. Pregnant women are not found to be more prone to HE , but the incidence of AHF is higher among pregnant women during the epidemics It was more common in 3rd trimester (41%), compared to 1 st trimester (20 %) or 2 nd trimester (26 %). Majority of patients with AHF are young (78% were aged below 25 years age ) and prime- gravida (70%)

57. The common complications noted among the patients with AHF during 1973 epidemic were Coagulopathy with bleeding tendency (75.6%), Hypoglycemia (41 %), hyperventilation (17%), cerebral edema and edema of legs.

58. Mortality correlated with the period of gestation . There was no death in first trimester. The mortality in 2nd and 3rd trimesters was 16.6% 32.4% respectively. Highest incidence of death occurred in the immediate postpartum period. Fetal loss among the infected pregnant women, which included abortion , stillbirth and maternal death before delivery was seen.

59. MEDICAL CARE: predominantly preventive, relying on clean drinking water, good sanitation, and proper personal hygiene. Travelers to endemic areas should avoid drinking water or other beverages that may be contaminated and should avoid eating uncooked shellfish. Care should be taken while preparing uncooked fruits or vegetables. Boiling water may prevent infection, but the effectiveness of chlorination is unknown.

60. No immunoprophylaxis is available. Immunoglobulin from infected patients is not effective in preventing outbreaks or sporadic cases. Prototype vaccines are being developed using animal models. this is hindered by an inability to maintain the virus in cell cultures. Once infection occurs, therapy is limited to support. Provide patients with adequate hydration and electrolyte repletion.

61. Hospitalization is indicated only for patients unable to maintain oral intake .

62. DIET: The acute illness may result in anorexia, nausea, and vomiting, predisposing patients to dehydration. These symptoms tend to be worse in the afternoon or evening. Patients should attempt to ingest significant calories in the morning. As they improve, frequent small meals may be better tolerated. Neither multivitamins nor specific dietary requirements are required

63. ACTIVITY: Patients should be allowed to function at whatever levels they can tolerate. No evidence indicates that bedrest hastens recovery. It actually may retard recovery.

64. Thank you