PPT Grossi "Tuberculosis and transplants"

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PPT Grossi "Tuberculosis and transplants", Symposium on TB, 15 October, V Session (Physicians & surgeons), Monza, Italy.

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PPT Grossi "Tuberculosis and transplants"

  1. 1. Clinica delle Malattie Infettive e Tropicali Università degli Studi dell’Insubria – Ospedale di Circolo e Fondazione Macchi, Varese “Second Opinion” Infettivologica Centro Nazionale Trapianti, ISS, Roma Tubercolosi e trapianti Paolo GrossiTUBERCOLOSI: UNA MALATTIA COMPLESSA Monza 14-15 Ottobre, 2011
  2. 2. Post-transplant tuberculosis 20-70 times higher incidence Prevalence mimics endemic prevalence (0.35-15%) High morbidity and mortality (13-40%) TB contributes to graft dysfunction High incidence of extrapulmonary involvement and atypical presentation Complex management/drug-interactions Importance of preventive measures Singh&Paterson Clin Infect Dis (1998) 27: 1266; Munoz et al Clin Infect Dis (2005) 40: 581
  3. 3. M. tuberculosis Infection in Recipients of Solid Organ Transplants CLINICAL MANIFESTATIONS 511 transplant patients with tuberculosis Singh N, Paterson DL. Clin Infect Dis 1998; 27:1266–77. 33 lung involvementdisseminated 51% 16extrapulmonary OVERALL MORTALITY RATE 29% Major predictors of mortality - disseminated infection (P = .0003), - prior rejection (P = .006), - receipt of OKT3 or anti-T cell antibodies (P = .0013) Università degli Studi di Udine – Clinica di Malattie Infettive
  4. 4. M. tuberculosis Infection in Recipients of Solid Organ Transplants EPIDEMIOLOGY Munoz P, Rodriguez C, Bouza E, Clin Infect Dis 2005; 40:581–7% 15 6,5 2,3 2,5 2 1 1,5 0,7 0,5 0,23 0,79 adult liver pediatric liver kidney heart lung bone marrow min max Università degli Studi di Udine – Clinica di Malattie Infettive
  5. 5. Frequency of Tuberculosis in solid-organ transplant recipients Transplanted OrganPrevalence, % Overall Lung Kidney Liver Heart Kidney- pancreasLiterature 1.2-15 2-6.5 0.5-15 0.7-2.3 1-1.5 …GESITRA 0.45 1.15 0.35 0.47 0.26 0.85(Spain, from2008)Incidence 512 2012 358 541 255 1204 Higher risk of TB among SOT recipients when(Cases per 105 (317-783) (565- (144-728) (269- (6.5- compared (30.5-6710)popul/year; 5306) 1065) 1421)GESITRA) with the general population Aguado JM et al, CID 2009; 48:1276-84
  6. 6. Risk factors for tuberculosis after transplantation Aguado JM, et al. Clinical Infectious Diseases 2009; 48:1276–84
  7. 7. Screening pre-trapiantoEsame Se positivo Se negativoIntradermoreazione alla Escludere malattiatubercolina (PPD) tubercolare in attoTest IGRA Valutazione malattia tubercolare Anamnesi e esame Esami di laboratorio Esami strumentali clinico (in tutti i candidati)Storia di TBC Ricerca micobatteri Rx torace (protocolloFattori di rischio e (diretto, PCR e colturale) su standard)contatti espettorato, urine e sangue Ecografia addome (almeno 3 campioni) completoEventuali terapie Eventuale ricerca su altri Eventuale TC Toracepregresse campioniAdeguatezza delleterapieValutazione clinica Altro
  8. 8. Immunodiagnosis of latent M. tuberculosis infection antigens/ peptides APC IGRA IFN- release assayPPDESAT-6/CFP-10/TB7.7 T cell activation/ cytokine cytokine cytokine cytokine induction induction induction induction Skin test ELISA ELISPOT assay Flow-cytometry activation marker QuantiFERON TB gold T-SPOT.TB cytokine
  9. 9. Test characteristics Skin-test ELISA ELISPOT Sensitivity 77 % 78 % 90 % Specificity 59-97 % 96 % 93 %Low risk controls Pai et al Ann Intern Med (2008) 149: 177
  10. 10. Treatment for Latent TB Infection• Treating LTBI reduces the risk that M. tuberculosis infection will develop into TB disease• Certain groups have higher risk for developing TB disease after infection; should be treated• Before beginning treatment for LTBI – Exclude diagnosis of TB – Ensure patient has no history of adverse reactions resulting from prior LTBI treatment
  11. 11. Treatment Regiments for LTBI Months of Minimum Drugs Interval Duration Doses Daily 270 INH 9* 2x wkly 76 Daily 180 INH 6 2x wkly 52 RIF 4 Daily 120*PreferredINH=isoniazid; RIF=rifampin
  12. 12. Diagnosis of active tuberculosisPatient historyChest X-rayCultureAcid-fast bacilli stainingNucleic acid amplification testing
  13. 13. Poor specificity for distinction of active and latent infection Skin-test ELISA ELISPOT Sensitivity 77 % / 65 % 78 % / 80 % 90 % / 81 % Specificity 59-97 % 96 % 93 % Low risk controls Specificity 75 % 79 % 59 % TB suspectsSester et al Eur Respir J (2011) 37: 100 Pai et al Ann Intern Med (2008) 149: 177
  14. 14. IFN-γ and IL-2 cytokine profiles of antigen-specific T cells measured by flow-cytometry ex vivo might correlate with TB disease activity in vivo. Receiver operator characteristics (ROC) analysis revealed that frequencies of PPD specific IFN- γ /IL-2 dual-positive T cells below 56% were an accurate marker for active TB (specificity 100%, sensitivity 70%) enabling effective discrimination from non-active states. In conclusion, a frequency lower than 56% IFN- γ /IL-2 dual positive PPD-specific circulating CD4 T-cells is strongly indicative of active TB.Sester M, et al. PLoS ONE 2011;6:
  15. 15. Case – donor-derived tuberculosis Deceased donor •CNS disease not recognized as having active TB •CSF was AFB negative•48 years, male •29 years, male •30 years, male•TB 8 weeks post-Tx •TB 3 months post-Tx •ATG treatment•BAL/Bone marrow AFB+ •Hepatic abscess AFB+ •TB 3 weeks post-Tx•Patient survived •Patient survived •Bone marrow AFB+ •Patient died Edathodu et al Int J Tuberc Lung Dis (2010) 14: 1493
  16. 16. Donor‘s Risk factors for TB transmission Active TB History of untreated/improperly treated TB Positive TST/IGRA, in particular recent conversion Abnormal chest X-ray Recent close contact to TB case Birth/residence in a high prevalence country TB disease Highest risk donors Latency Live bacilli? Latency Bacterium extinguished? Singh&Paterson Clin Infect Dis (1998) 27: 1266 Munoz et al Clin Infect Dis (2005) 40: 581
  17. 17. Management – Donor screening Grouped by living or deceased donor Categorized • Active TB vs latent infection • Active TB - History of active disease or currently active - Treated adequately > 2 years ago or not - Same site of organ being transplanted or distant site (except lung) • Microbiologic or pathologic diagnosis Donor-Derived Consensus Conference TB – Morris et al in preparation
  18. 18. Problems with diagnostics in deceased donorsResults often only obtained aftertransplantationClinical history often not reliableSkin testing not feasibleIGRAs not validated
  19. 19. Summary Donor risk assessmentNeed for increased awarenessIdentification of who may have greatest risk fortransmission or reactivation of M. tuberculosisApplication of recommendations likely to vary fromcountry to country and even region to regionConsult infectious disease specialistCommunication among transplant centers
  20. 20. Major areas for future studiesUse of IGRAs in deceased donorsEvaluation of nucleic acid based testing onbody fluids of high risk donorsProspective evaluation and outcomes ofrecipients receiving organs from donors withhigh risk for latent infection Donor-Derived Consensus Conference TB – Morris et al in preparation
  21. 21. Dati anamnestici CS, maschio, 44 in 60^ giornata post-tx co-infezione Dimesso aa, ex-tossicodipendente, HIV-HCVdimissione: Esami alla Terapia immunosoppressiva: DM tipo 1, IRC da nefropatia diabeticamg/sett - creatinina= 1,1mg/dL - Tacrolimus 0,5 in emodialisi dal 2000 - glicemia= 80mg/dL - Micofenolato mofetile Valutazione pre-tx: Anamnesi per TB e PPD negative - Metilprednisolone (sospeso a 3 Nell’aprile 2007 trapianto mesi dal tx) di combinato di rene-pancreas Terapia antiretrovirale: Ottima ripresa della Lamivudina/Abacavir - funzionalità dei graft ComplicanzeFosamprenavir/ritonavir - chirurgiche: 1°gg sanguinamento dal corpo del pancreas e dall’anastomosi arteria renale. 26°gg deiscenza della ferita con eviscerazione, colecistite gangrenosa e ascesso pelvico; colecistectomia e toilette chirurgica
  22. 22. .... 36 mesi post-txComparsa sintomi aspecifici: astenia, febbricola, sudorazioni notturne Lieve incremento degli indici di flogosi (VES=45, PCR=27) Funzionalità renale e pancreatica nella norma HIV-RNA undetectable; Linfociti T CD4= 307/mmc Tra i vari esami effettuati: Intradermoreazione alla tubercolina: positiva QuantiFERON-TB Gold: positivo BAL: •Esame microscopico pos per micobatteri • Esame molecolare (PCR) pos per Mycobacterium tuberculosis • Esame colturale + antibiogramma: Mycobacterium tuberculosis sensibile a streptomicina, isoniazide, rifampicina, etambutolo, pirazinamide
  23. 23. Terapia NO Rifampicina Isoniazide 300 mg/die Livelli FK, CyA, Etambutolo 1600 mg/die Rapamicina, Inibitori Moxifloxacina 400 mg/die Protesi Pirazinamide 1500 mg/die (sospesa dopo 2 mesi) Vit B 6 Lieve aumento delle transaminasi (2vv) Aumento dell’uricemia DispepsiaTacrolimusAcido micofenolicoAbacavir/lamivudinaFosamprenavirRitonavirAllopurinoloAcido acetilsalicilico
  24. 24. TB treatment options in solid organ transplant recipients (GESITRA)Aguado JM. Clinical Infectious Diseases 2009; 48:1276–84
  25. 25. Quali sono le problematiche correlate alla terapia della tubercolosi nel paziente immunocompromesso per trapianto?  Interazione tra i farmaci  Maggior Tossicità  Compliance  Durata della terapia
  26. 26. Drug Interactions• Relatively few drug interactions substantially change concentrations of antituberculosis drugs• Antituberculosis drugs sometimes change concentrations of other drugs – Rifamycins can decrease serum concentrations of many drugs, (e.g., most of immunosuppressive drugs, the HIV-1 protease inhibitors and many others), to subtherapeutic levels – Isoniazid increases concentrations of some drugs (e.g., phenytoin) to toxic levels
  27. 27. Conclusioni• La Tubercolosi rappresenta una grave complicanza nel post- tx dovuta nella maggior parte dei casi a riattivazione di TB latente, raramente da trasmissione dal donatore, ma anche come infezione primaria comunitaria• E’ fondamentale un’approfondita valutazione pre-tx (anamnesi, clinica, PPD o Test IGRA) non solo per diagnosticare un’eventuale TB latente, ma anche per acquisire un dato di negatività che può rivelarsi utile nel post-tx• Le indagini colturali vanno sempre eseguite anche alla luce dell’emergenza di MDR• Il trattamento deve possibilmente escludere l’utilizzo di rifamicine, potenti induttori del CYP450; se utilizzate, stretto monitoraggio dei livelli degli immunosoppressori• La durata della terapia deve proseguire per almeno 12-18 mesi

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