ESCMID Online Lecture Library. by author

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1 Therapies or diseases predisposing to infection Congenital immunodeficiences Acquired conditions Common variable immunedeficiency particular diseases (e.g. HIV, cancer,leukemia, lymphoma, diabetes, cystic fibrosis, etc) particular medical procedures Chemotherapy and immunosuppression with/out biological response modifiers for cancer (leukemia, lymphoma, solid tumors) Immunosuppression with /out biological response modifiers for autoinflammatory diseases (e.g. reumathoid arthritis, bowel inflammatory diseases, SLE) Immunosuppression with/out biological response modifiers for diseases with a newly understood pathogenesis (multiple sclerosis, Paroxysmal Nocturnal Hemoglobinuria) ESCMID Online Lecture Library Bone marrow or solid organ transplant, including the use of biological response modifiers Splenectomy Intensive care procedures

2 ANTI-TNF-α Aberrant activity of TNF-α has been implicated in RA, JRA, inflammatory bowel disease, psoriasis, GVHD, ankylosing spondylitis, uveitis and vasculitis. Drugs that block the effects of TNF-α have been developed for the treatment of these inflammatory and granulomatous conditions. Increased risk of developing certain types of infections Attributable excess risk for infection difficult to elucidate: Patients with granulomatous and autoimmune disorders already have impaired immune responses to infection Many also receive other immunosuppressive agents ESCMID Online Lecture Library

3 Etanercept (ENBREL) Anti-TNF alfa Infliximab (REMICADE) Anakinra (KINERET) Adalimumab (HUMIRA) Class stnf-r TNF-a mab IL-1 Ra TNF-a mab Structure Recomb. Chimeric Recomb. Human T 1/ d 8-10 d 4-6 h d Ligands TNF-a/LT-a TNF-a IL-1R type I TNF-a ESCMID Online Lecture Library

4 Is the use of anti TNF alfa blockers associated with an increased overall risk of infection? ESCMID Online Lecture Library

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9 Serious infections during anti-tnfα treatment in RA patients Frequency of serious infections by infection site and responsible micro-organism ESCMID Online Lecture Library LORHEN registry 1114 patients Favalli EG et al, Autoimmunity Reviews 2009

10 Serious infections during anti-tnfα treatment in RA patients Univariable and multivariable predictors of serious infections ESCMID Online Lecture Library a HR: hazard ratio. b 95% CI: 95% confidence interval. c AHR: adjusted hazard ratio. Favalli EG et al, Autoimmunity Reviews 2009

11 Effect of anti-tnf Therapy on Occurrence of one or more Serious Infections ESCMID Online Lecture Library Bongartz T et al JAMA 2006; 255: 2275

12 Tumor Necrosis Factor and Granulomas TNF plays a central role in formation and maintenance of granulama TNF blockade results in granulomas breakdown and dissemination of microrganisms entrapped in granulomas ESCMID Online Lecture Library Ehlers S CID 2005; 41 (suppl 3)

13 Tuberculosis Infection in Patients With Rheumatoid Arthritis and the Effect of Infliximab Therapy Prior to the widespread use of infliximab, the rate of TB in 10,782 RA patients followed up prospectively was 6.2 (95% CI ) per 100,000 patients during 16,173 patient-years of observation. Patients who received infliximab had a TB incidence rate of 52.5 (95% CI ) per 100,000 patient-years of exposure. All cases occurred in persons without complete screening for TB and without prophylaxis. ESCMID Online Lecture Library Wolfe F et. al ARTHRITIS & RHEUMATISM 2004; 50:

14 TNF-α Antagonist Therapy and TB Atypical clinical presentation 50% extrapulmonary 15% 20% disseminated Median time to onset Infliximab (INF) = 12 weeks (range, 1 52 weeks) 1 Etanercept (ETN) = 11.5 months (range, 1 20 months) 2 ESCMID Online Lecture Library 1. Keane J et al. N Engl J Med. 2001;345: Mohan AK et al. Clin Infect Dis. 2004;39:

15 Winthrop KL Intl J Rheum 2010

16 Other Bacterial Infections Legionella pneumophila (Beigel F et al, Inflamm Bowel Dis. 2009) Listeriosis. Incidence of (95% CI: ), greater than the incidence observed in the general population from Europe and in the EMECAR (Peña- Sagredo JL et al, Clin Exp Rheumatol. 2008) Salmonella (Bassetti M et al, Clin Microbiol Infect. 2009; Garcia-Vidal C et al, Eur J Clin Microbiol Infect Dis ) ESCMID Online Lecture Library

17 Toxoplasmosis. 4 cases (Lassoued S et al, Semin Arthritis Rheum 2007) Visceral leishmaniasis and anti-tnf-alpha therapy. 6 cases so far reported. (De Leonardis F et al, Clin Exp Rheumatol. 2009; Garcia-Vidal C et al, Eur J Clin Microbiol Infect Dis. 2009, Bassetti, Rheumatology, 2006 ) West nile virus meningoencephalitis and acute flaccid paralysis after infliximab treatment (Chan- Tack KM et al, J Rheumatol. 2006). ESCMID Online Lecture Library

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19 Fungal Infections Complicating Tumor Necrosis Factor [alpha] Blockade Therapy ESCMID Online Lecture Library Pneumocystis jiroveci pneumonia during infliximab therapy (Josephson ME et al, Ugeskr Laeger. 2008) Tsiodras S et al, Mayo Clin Proc 2008

20 Tsiodras S et al, Mayo Clin Proc 2008

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22 TC POLMONARE GEN 09 ESCMID Online Lecture Library

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24 What is that? ESCMID Online Lecture Library

25 Suggested Screening before Initiation of anti-tnf Therapy ESCMID Online Lecture Library

26 So, what should we do? Use a lot of common sense, to protect patients without scaring them to death ESCMID Online Lecture Library Stay tuned with CDC and other similar alert reports (Hantavirus example)

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36 Immunization ESCMID Online Lecture Library

37 Vaccines: general principles No live vaccines (e.g. yellow fever) Use as in normal host Hepatitis A and B Japanese encephalitis Meningococcus Polio Salk Rabies Typhoid fever Specifically recommended Pneumococus ESCMID Online Lecture Library Tetanus/diphteria/pertussis H. influenzae Influenza

38 Eculizumab, as expecteg since it blocks CD5 of the complement, has been associated with cases (how many??) due to meningococcal meningitis. Officially no death!!! Vaccination recommended, but no vaccine for group B

39 Recurrent and life-threatening meningococcal infection is the principle complication of the inherited deficiencies of terminal complement, including deficiency of the fifth complement component, C5. (Figueroa et al., 1993) Vaccination against N. meningitidis with meningococcal tetravalent polysaccharide vaccine in terminal complement deficiency has been shown to reduce but not eliminate the risk of infection. (Fijen et al., 1998; Platonov et al., 2003) Risk estimated to range between 0.5 and 1 case every 100 patients on eculizumab therapy No vaccine for group B There is emerging evidence that re-vaccination with tetravalent polysaccharide vaccines leads to tolerization and a reduced efficacy with time. ESCMID Online Lecture Library However, new vaccines are coming

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