ABOUT ACUTE SEVERE HEPATITIS…

1. ABOUT ACUTE SEVERE HEPATITIS… Gerkens A, François E, Lucidi V, Moreno C, Donckier V, Bourgeois N, Mathieu A, Adler M Hôpital Erasme BASL – 11.12.2009

2. CASE REPORT

3. 28-year old ♀ • Past history:- • Lifestyle: Caucasian, married, a 10-months-old son Policewoman, no recent travels No tobacco, alcohol, drugs, allergies Contraception: IUD Vaccination against HAV and HBV (Twinrix®)  2nd injection late february 2009

4. Early march: Nausea, asthenia • 15 d later: Jaundice with abnormal liver tests  Hôpital Tivoli ↑ Bilirubin, ↓ PT  Hôpital Erasme

5. Clinical examination: Jaundice

6. Blood analysis: • Coagulation: PT 30%, factor V 24 % • Liver tests: T Bili 18 mg/dl (direct), PAL 244 UI/L, γGT 146 UI/L, ALAT 818 UI/L, ASAT 574 UI/L, LDH 269 UI/L • Serologies: HAV IgG, Ac Anti HBs, EBV IgG, HZV IgG, HSV: + HCV, HEV, HIV, Toxo, CMV: - • Immunology: IgG 1,8 g/dl, ANA, ANCA, AMA, SMA, LKM, LC1, SLA: - • Metabolism (lipids, glucids, thyroïd, iron and urinary cupper) and α1antitrypsin: N

7. Liver US doppler: N • TVLB: • HVG: 2 mmHg • Histology:

11. Histologic diagnosis: Autoimmune hepatitis

12. Hepatology 2008

13. Evolution:  Steroids started • Clinico-biochemical deterioration in 48h: - hepatic encephalopathy grade 3  4 - ↓ PT (15 % ) • Listed < fulminant hepatitis • MARS on 30.03.09 • Transplanted on 31.03.09

14. Analysis of the explant liver

18. CD138

19. 6 month later: No clinical symptoms Normal liver enzymes

20. Autoimmune hepatitis ...Vaccine related ? (

21. DISCUSSION

22. Autoimmune hepatitis (AIH) • Pathogenese: • Triggering factors: toxins, medications, infectious agents • Autoantigens • Genetic predisposition • Immunoregulatory networks Krawitt, EL. N Engl J Med 2006

23. Vaccination: another trigger ? Case report 1 ♂ 35 y AIH several days following serial immunizations (typhoïd, HAV, Diphteria/Tetanos, oral polio and mumps, measles and rubella) administrated on a single occasion Veerappan, GR. Digestive Diseases and Sciences 2005

24. Vaccination: another trigger ? case report 2 ♀ 31 y AIH 11 days after hepatitis A virus and yellow fever vaccines Perumalswami, P. Seminars in liver disease 2009

25. Vaccines & autoimmune diseases (AID) • Why vaccines are incriminated in AID ? • Theoretical background • Vaccines components • Incriminated vaccines

26. Theoretical background Infection Induce / trigger AID Genetically predisposed individuals Ag specific / non-specific way (molecular mimicry) Fail-safe mechanism (infection-induced autoimmunity)  apply to host response tovaccination Wraith, D. The Lancet 2003

27. Vaccines components • Inactive / Attenuated • Adjuvants • Preservative agents • Other components

28. Incriminated vaccines • A/New Jersey/8/76 swine - flu vaccine • Guillain-Barré syndrome • 1-3/100 000, • 5w after vaccination, • RR 7.6 Schonberger, LB. Am J Epidemiol 1977 • MMR vaccination • Idiopathic thrombocytopenic purpura • 1/30 000 • Ac anti-platelets Jonville-Bera, AP. Pediatr Infect Dis J 1996

29. Incriminated vaccines • Hepatitis B Vaccination • Multiple sclerosis: 2 cases reported Herroelen, L. The Lancet 1991 35 cases 1991-1997, 8w after vacc. Gout, O. Rev Neurol 1998 • Systemic erythematosus lupus: 10 cases related Agmon-Levin N, Lupus 2009 • Haemophilus influenza type B (Hib) • Type 1 diabetes if given at ≥ 2 month Classen, JB. BMJ 1999

30. Vaccines & autoimmune diseases (AID) • How to establish the causal relation ? • Case-controle studies • WHO criteria: Consistency, Strenght, Specificity, Temporal relation • Biologic plausibility Identification of known biological markers of the identified AID in others vaccinee • Coincidence background cases Wraith, D. The Lancet 2003

31. Case-contole studies • Association between type 1 diabetis and Hemophilus influenza type B vaccination: birth control study Karvonen, M. BMJ 1999 • Vaccinations and the risk of relapse in multiple sclerosis Confavreux, C. N Engl J Med 2001 • Hepatitis B vaccination and the risk of multiple sclerosis Ascherio, A. N Engl J Med 2001 • Hepatitis B vaccination and first central nervous system demyelinating events: Reanalysis of a case control study using the self-controlled case serie method Hocine, MN. Vaccine 2007 • Risk of incident autoimmune diseases after vaccination : a large cohort study in the UK General Practice Research database Egbring, M. AASLD 2009

32. Coincidence background cases • Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccinesBlack, S. The Lancet, October 2009 • Human papillomavirus immunisation of adolescent girls and anticipated reporting of immune-mediated adverse events Callreus, T. Vaccine 2009

33. Conclusions Vaccination  Cause of AIH ? • Temporal relation: Yes • Causal relation: No  Impossible to be established on individual basis  Clinical event has multiple or unknown causes

36. Case report Discussion • Autoimmune hepatitis (AIH) • Definition • Epidemiology • Pathogenesis • Vaccination: an other trigger for AIH ? • 2 other case reports • Vaccination and Autoimmune diseases (AID) • Why vaccines are incriminated in AID ? • Theoretical background • Vaccine components • Incriminated vaccines • How to establish the causal relation ? • Case-controle study • Biologic plausibility • Coincidence background cases Conclusion

37. CONCLUSIONS (2) • Age-groups of autoimmune disorders = targets for vaccination programmes • Increasing number of vaccination • Better knowledge of mechanisms - by wich autoimmune responses are generated - how they might (not) lead to AID  Real risk of vaccine-associated autoimmunity

39. Pathophysiology of AIH Liver injury in a patient with autoimmune hepatitis is the result of a cell-mediated immunologic attack. This attack is directed against genetically predisposed hepatocytes. Aberrant display of human leukocyte antigen (HLA) class II on the surface of hepatocytes facilitates the presentation of normal liver cell membrane constituents to antigen-processing cells. These activated cells, in turn, stimulate the clonal expansion of autoantigen-sensitized cytotoxic T lymphocytes. Cytotoxic T lymphocytes infiltrate liver tissue, release cytokines, and help to destroy liver cells. The reasons for the aberrant HLA display are unclear. It may be initiated or triggered by genetic factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection),and chemical agents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid). The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed as the triggering autoantigens. Some patients appear to be genetically susceptible to developing autoimmune hepatitis. This condition is associated with the complement allele C4AQO and with the HLA haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients. HLA DR3-positive patients are more likely than other patients to have aggressive disease, which is less responsive to medical therapy; these patients are younger than other patients at the time of their initial presentation. HLA DR4-positive patients are more likely to develop extrahepatic manifestations of their disease.

40. Association between type 1 diabetis and Hemophilus influenza type B vaccination: birth control studyKarvonen, M. BMJ 1999 • 10-y follow-up study of more than 100 000 Finnish children involved in a clinical trial of the Hib vaccine:  No increased risk of diabetes when children who had received 4 doses of vaccine at age 3, 4, 6 and 14-18 month were compared 1 dose at age 2 years

41. Vaccinations and the risk of relapse in multiple sclerosisConfavreux, C.N Engl J Med 2001 • Case-crossover study • Vaccinations: mono or multivalent / first adm. or booster • 643 relapse: - 2.3% vaccinated during the 2-month risk period - 2.8 - 4.O% vaccinated during 1 or more of the 4 control periods  RR: 0,71 (95% CI 0.4 -1.26)  No increase in the specific short term risk of relapse associated with the HBVax

42. Hepatitis B vaccination and the risk of multiple sclerosis Ascherio, A. N Engl J Med 2001 • 121 700 nurses < 1976 • 116 671 nurses < 1989  192 MS with 645 controls • RR MS associated with HBVax at any time before the onset of the disease: 0.7 (95% CI:0.5-1.6) • RR MS associated with HBVax 2 y before the onset of the disease: 0.9 (95% CI:0.3-1.8) • no assoc between HBVax and development ofMS

43. Hepatitis B vaccination and first central nervous system demyelinating events: Reanalysis of a case control study using the self-controlled case serie methodHocine, MN. Vaccine 2007 • Led to similar results: no strong association between HB vaccination and a first episod of CNS demyel. disease or MS and HBVax between 2 months or 1 year after vaccination • Analyse based on all cases (matched and unmatched): -Relative incidence of first demyel. event =1.35 (95% CI 0.66-2.79) for 0-2 m post HBVax =1.78 (95% CI 0.97-3.27) for 2m-1y post HBVax • Assoc between HBVax and first demyel. Event with indefinite post HBVax risk period  2.29 y after • Appreciable reduction in possible biases/ gain in power

44. AASLD 2009 Autoimmune disease: RA, HLAB27 associated rheumatoïd disease, Rheumatoïd collagenosis, GN, Polyradiculoneuritis Exposed cohort: Unexposed cohort n 38277 (6 to 60 y) 112185 AID 23 55 RA 12 m 0.06% 0.05% RR associated HBVax: 1.23 (95% intervalle confidence) No significantassociation between HBVac and the studied AID

45. Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccinesBlack, S. The Lancet, October 2009 • Comparing observed rates with expected rates:  21.5 Guillain-Barré syndrome / 10 millions vaccinated  5.75 sudden death / " " "  86.3 optic neuritis / " " ♀ "  pregnant ♀: 397 spont. abortion / 1 million " would be expected to occur within 6 weeks of vaccination as « COINCIDENCE BACKGROUND CASES » ! Age, sex, ethnic, geographical and seasonal characteristics (eg: priority groups in the H1N1 influenza vaccine) ! Methods used to develop these rates

46. Human papillomavirus immunisation of adolescent girls and anticipated reporting of immune-mediated adverse events.Callréus T, Svanström H, Nielsen NM, Poulsen S, Valentiner-Branth P, Hviid A • Vaccine. 2009 May 14;27(22):2954-8. Epub 2009 Mar 13. • Division of Vaccine, Statens Serum Institut, Copenhagen, Denmark. • Determining incidence rates of potential adverse events before and after an immunisation programme is initiated, provides a useful framework for the evaluation of vaccine safety concerns. Human papillomavirus vaccination (HPV) of adolescent girls has recently been introduced in Denmark. Using a nationwide hospitalisation registry we estimated incidence rates of immune-mediated disorders before HPV vaccination in a cohort of 418,289 Danish girls aged 12-15 years. We further estimated the expected number of cases of immune-mediated disorders occurring in temporal relationship to a hypothetical HPV vaccination schedule purely by chance. Our results and analytical approach provides a framework for the evaluation of adverse event reports following immunisation of adolescent girls.

47. New-generation vaccines 1° Autoimmune manifestations linked to infectious disease targeted by the vaccine (eg, group A streptococcal disease) 2° Potential molecular and immunologic mimicry between vaccine Ag and host components 3° Use of ad hoc experimental models of AID 4° Appropriate immunological investigations (eg, autoimmune serology) phase I-III clinical trials 5° Clinical surveillance of potential AI adverse effects and appropriate laboratory tests

48. Ag specific Way Wraith, D. The Lancet 2003

49. Ag non-specific way Wraith, D. The Lancet 2003

50. Le squalène = produit intermédiaire du métabolisme du cholestérol, présent chez tous les organismes supérieurs (dont l’homme) dans divers sites, dont le sang ; il est un composant majeur de divers aliments, dont l’huile d’olive, avec une absorption de 60 à 80 % de la dose ingérée. La quantité injectée dans le vaccin est inférieure à égale à la quantité résorbée journalièrement par voie digestive. Aucune étude animale n’a montré de foeto ou embryotoxicité de ce produit naturel, qui disparaît en quelques jours du site de l’injection. Le squalène utilisé provient de foies de requins : sa contamination par de la vitamine A est au maximum de 0,33 mg/dose, largement inférieure à la dose quotidienne maximale pour la femme enceinte qui est de 3mg. Une analyse erronée des données avait attribué au squalène une responsabilité dans des problèmes de santé survenus après la guerre du Golfe, jusqu’au moment où on s’est rendu compte que les vaccins administrés aux soldats n’avaient jamais contenu de squalène… Les anticorps anti squalène, survenant naturellement chez de nombreuses personnes, et de manière croissante avec l’âge, n’ont pu être corrélés avec la survenue d’une pathologie ou l’emploi d’un vaccin contenant dusqualène.