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

CASE REPORT

28-year old ♀

• Past history: -

• Lifestyle:Caucasian, married, a 10-months-old sonPolicewoman, no recent travelsNo tobacco, alcohol, drugs, allergiesContraception: IUD

Vaccination against HAV and HBV (Twinrix®) 2nd injection late february 2009

• Early march: Nausea, asthenia

• 15 d later: Jaundice with abnormal liver tests Hôpital Tivoli

↑ Bilirubin, ↓ PT Hôpital Erasme

• Clinical examination:

Jaundice

• 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

• Liver US doppler: N

• TVLB:

– HVG: 2 mmHg

– Histology:

• Histologic diagnosis:

Autoimmune hepatitis

Hepatology 2008

• 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

Analysis of the explant liver

CD138

• 6 month later:

No clinical symptoms

Normal liver enzymes

Autoimmune hepatitis

(

...Vaccine related ?

DISCUSSION

Autoimmune hepatitis (AIH)

• Pathogenese:

– Triggering factors: toxins, medications, infectious agents

– Autoantigens– Genetic predisposition– Immunoregulatory networks

Krawitt, EL. N Engl J Med 2006

Case report 1♂ 35 yAIH 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

Vaccination: another trigger ?

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

Vaccines & autoimmune diseases (AID)

• Why vaccines are incriminated in AID ?

– Theoretical background

– Vaccines components

– Incriminated vaccines

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 to vaccination

Wraith, D. The Lancet 2003

Vaccines components

• Inactive / Attenuated

• Adjuvants

• Preservative agents

• Other components

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

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

Vaccines & autoimmune diseases (AID)

• How to establish the causal relation ?

– Case-controle studies WHO criteria:

Consistency, Strenght, Specificity, Temporal relation

– Biologic plausibilityIdentification of known biological markers of the identified

AID in others vaccinee

– Coincidence background cases

Wraith, D. The Lancet 2003

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 sclerosisConfavreux, 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

Coincidence background cases

• Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines

Black, S. The Lancet, October 2009

• Human papillomavirus immunisation of adolescent girls and anticipated reporting of immune-mediated adverse events

Callreus, T. Vaccine 2009

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

Case report

• 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

Discussion

Conclusion

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

Pathophysiology of AIHLiver 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.

Association between type 1 diabetis and Hemophilus influenza type B vaccination:

birth control study Karvonen, 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

Vaccinations and the risk of relapse in multiple sclerosis Confavreux, 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

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 of

MS

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

• 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

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 significant association between HBVac and the studied AID

Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines

Black, 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

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.

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

Wraith, D. The Lancet 2003

Ag specific Way

Ag non-specific way

Wraith, D. The Lancet 2003

• 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 du squalène.

• Le thiomersal est utilisé depuis les années ’30 dans la fabrication des vaccins, et plus particulièrement des flacons multidoses, afin de prévenir toute prolifération bactérienne ou fongique .Ce composé organique de mercure assure une meilleure protection que les autres conservateurs disponibles. Il s’agit d’éthyl-mercure, à métabolisation et élimination rapide (T ½ : moins d’une semaine), à ne pas confondre avec le méthyl-mercure, qui s’accumule lui longtemps dans l’organisme. Il est actuellement encore présent dans de nombreux vaccins multidoses à raison de 25 à 50 µg/dose, le Pandemrix en renfermant 5 µg/dose. L’emploi de vaccins contenant du thiomersal n’a jamais été lié épidémiologiquement avec une embryo ou foetotoxicité, ni avec des troubles neuropsychiatriques. Diverses instances, dont la FAO, considèrent que l’ingestion de 96-100 µg/semaine (dont 80% sont absorbés au niveau intestinal) ne présente pas de risque, y compris pour la femme enceinte. L’allergie de contact au thiomersal (présente chez 10-12% des gens) ne contre-indique en rien l’administration d’un vaccin le contenant

Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines. Verstraeten T, Vaccine 2008• Vaccine. 2008 Dec 2;26(51):6630-8.• GlaxoSmithKline Biologicals, Rixensart, Belgium. thomas.verstraeten@gskbio.com• Newly licensed vaccines against human papillomavirus (HPV) and hepatitis B (HBV), and several

vaccines in development, including a vaccine against genital herpes simplex virus (HSV), contain a novel Adjuvant System, AS04, composed of 3-O-desacyl-4' monophosphoryl lipid A and aluminium salts. Given the background incidence of autoimmune disorders in some of the groups targeted for immunisation with these vaccines, it is likely that autoimmune events will be reported in temporal association with vaccination, even in the absence of a causal relationship. The objective of this integrated analysis was to assess safety of AS04 adjuvanted vaccines with regard to adverse events (AEs) of potential autoimmune aetiology, particularly in adolescents and young adults. All randomised, controlled trials of HPV-16/18, HSV and HBV vaccines were analysed in an integrated analysis of individual data (N = 68,512). A separate analysis of the HPV-16/18 vaccine trials alone was also undertaken (N = 39,160). All data were collected prospectively during the vaccine development programmes (mean follow-up of 21.4 months), and included in the analysis up to a pre-defined data lock point. Reporting rates of overall autoimmune events were around 0.5% and did not differ between the AS04 and control groups. The relative risk (AS04/control) of experiencing any autoimmune event was 0.98 (95% confidence intervals 0.80, 1.21) in the integrated analysis and 0.92 (0.70, 1.22) in the HPV-16/18 vaccine analysis. Relative risks calculated overall, for disease category or for individual events were close to 1, and all confidence intervals around the relative risk included 1, indicating no statistically significant difference in event rates between the AS04 and control groups. This integrated analysis of over 68,000 participants who received AS04 adjuvanted vaccines or controls demonstrated a low rate of autoimmune disorders, without evidence of an increase in relative risk associated with AS04 adjuvanted vaccines