1. I ABTO MEETING ON TRANSPLANT INFECTIOUS DISEASES I IBEROAMERICAN MEETING ON TRANSPLANT INFECTIOUS DISEASES I ABTO MEETING ON TRANSPLANT INFECTIOUS DISEASES I IBEROAMERICAN MEETING ON TRANSPLANT INFECTIOUS DISEASES Sao Paulo, Brazil- 23-24 November, 2012 José María Aguado Hospital Universitario 12 de Octubre, Madrid, Spain Instituto de Investigación 12 + i The New Frontiers in Epidemiology and Surveillance Tuberculosis in Solid Organ Transplantation

2. Tuberculosis is really a surprise or not so much?

3. X20-74 Singh N. CID 1998 ;Aguado JM. GESITRA. Transplantation 1997. Muñoz P. Clinical Infectious Diseases 2005 Prevalence of TB according to world region

4. Type of transplant Frequency Incidence/10 5 IC90% Odds ratio Heart 1/404 (0.25) 255 (6.5-1421) 13.7 (1.9-97.3) Kidney 7/2052 (0.34) 358 (144-728) 19.0 (9.0-39.7) Liver 8/1507 (0.53) 541 (269-1065) 29.5 (14.8-58.9) Kidney- pancreas 1/122 (0.82) 1204 (30.5-6710) 45.5 (6.5-320.4) Lung 4/303 (1.32) 2072 (565-5306) 73.3 (27.7-194.1) Total 21/4388 (0.49) 512 (317-783) 26.6 (17.4-40.8) Clinical Infectious Diseases 2009; 48:1657–65 Incidence of TBC in SOT RESITRA Network (2003-2005)

5. Reactivation, reinfection or donor transmission?

6. Pathogenesis Reactivation New infection Donor * New infection Donor * 91.5% 8.5% 47 TB in Kidney Tx (*) Donor with history or TBC or + PPD with a negative Recipient Lichtenstein IH Rev Infect Dis 1983;5:216 (*) Donor with history or TBC or + PPD with a negative Recipient Lichtenstein IH Rev Infect Dis 1983;5:216

7. How important is the type of immunosuppression?

8. Immunosuppressive treatment Mean doses of immunosuppressive drugs in cases and controls were not significantly different 1 Mean doses of immunosuppressive drugs in cases and controls were not significantly different 1 Rejection (56% vs. 32%, P=0.004; OR=2.7, CI(95%): 1.3-5.6) 1 Rejection (56% vs. 32%, P=0.004; OR=2.7, CI(95%): 1.3-5.6) 1 OKT3 or Anti-T cell antibodies (79% vs 64%, p=0.19) 2 OKT3 or Anti-T cell antibodies (79% vs 64%, p=0.19) 2 Cyclosporine vs azathioprine first year (OR 2.5) 3 Cyclosporine vs azathioprine first year (OR 2.5) 3 Use of mycophenolate (4.5% vs 6.1%, p=NS) 4. Use of mycophenolate (4.5% vs 6.1%, p=NS) 4. Mean doses of immunosuppressive drugs in cases and controls were not significantly different 1 Mean doses of immunosuppressive drugs in cases and controls were not significantly different 1 Rejection (56% vs. 32%, P=0.004; OR=2.7, CI(95%): 1.3-5.6) 1 Rejection (56% vs. 32%, P=0.004; OR=2.7, CI(95%): 1.3-5.6) 1 OKT3 or Anti-T cell antibodies (79% vs 64%, p=0.19) 2 OKT3 or Anti-T cell antibodies (79% vs 64%, p=0.19) 2 Cyclosporine vs azathioprine first year (OR 2.5) 3 Cyclosporine vs azathioprine first year (OR 2.5) 3 Use of mycophenolate (4.5% vs 6.1%, p=NS) 4. Use of mycophenolate (4.5% vs 6.1%, p=NS) 4. 1 23 4 1 Basiri A. Transplant Proc 2008; Singh N. Clin.Microb.Rev. 2005; 2 ; 3 John GT. Kidney Int 2001; 4 Atasever A. Nephrol Dial Transplant. 2005

9. Reduce immunosuppression? Controversial. Consider in severe cases in kidney Tx Controversial. Consider in severe cases in kidney Tx Change immunosuppressive drugs? (imTOR) Change immunosuppressive drugs? (imTOR) Controversial. Consider in severe cases in kidney Tx Controversial. Consider in severe cases in kidney Tx Change immunosuppressive drugs? (imTOR) Change immunosuppressive drugs? (imTOR)

10. What are the risk factors for tuberculosis in SOT?

11. Risk factors Previous data of TBC Previous data of TBC Underlying disease Underlying disease Hemodialysis. Longer pre-transplant HD? X2 Hemodialysis. Longer pre-transplant HD? X2 Diabetes mellitus (X2-4) Diabetes mellitus (X2-4) Older age Older age Coexisting infection: CMV, PCP, HCV X1.6-2.3 Coexisting infection: CMV, PCP, HCV X1.6-2.3 Previous data of TBC Previous data of TBC Underlying disease Underlying disease Hemodialysis. Longer pre-transplant HD? X2 Hemodialysis. Longer pre-transplant HD? X2 Diabetes mellitus (X2-4) Diabetes mellitus (X2-4) Older age Older age Coexisting infection: CMV, PCP, HCV X1.6-2.3 Coexisting infection: CMV, PCP, HCV X1.6-2.3 Klote MM. Am J Transplant 2004; John GT. Kidney Int 2001; Basiri A. Transplant Proc 2005. Basiri A. Tranpl Infect Dis 2007; Torres J. Transpl Int. 2008. Klote MM. Am J Transplant 2004; John GT. Kidney Int 2001; Basiri A. Transplant Proc 2005. Basiri A. Tranpl Infect Dis 2007; Torres J. Transpl Int. 2008. Aguado JM. Clin Infect Dis 2009; 48:1657–65

12. Some clinical peculiarities Some clinical peculiarities?

13. <01 2-3 4-5 6-7 8-9 9-12 13-24 >24 Months after Tx 0 0 2 2 4 4 6 6 8 8 10 12 14 16 Number of patients Onset of Symptoms Median 9 months (60%) >24m: 40% Median 9 months (60%) >24m: 40% AguadoJM. Transplantation.97

14. Clinical Characteristics (RESITRA cohort, 2002-2005) Early TB (< 3 mo.) Late TB (> 3 mo.) Time of onset 20 days (5-50 days) 12 months (3-30 m) Frequency10%90% Source Risk factors TB in transplant candidate. Donor transmission. Latent TB (Chest XR, PPD). Reactivation.Nosocomial. Primary infection. Clinical manifestations Pulmonary, extrapulmonar, disseminated, FUO. Pulmonary Crude mortality 40%15-20% Related mortality 2-3%1%

15. LUNG 50-65% EXTRAPULMONARY 12-16% DISSEMINATED 25-35% Singh N. Clin.Microb.Rev. 2005; Aguado JM. GESITRA. Transplantation. 1997 Sites of infection

16. Clinical manifestations Fever of unknown origin 11-26% Fever of unknown origin 11-26% Constitutional symptoms Constitutional symptoms Cough Cough Other sites Other sites Skin and soft tissues 4%, osteoarticular 1% Skin and soft tissues 4%, osteoarticular 1% Genitourinary 0.6% Genitourinary 0.6% Liver, pancreas, larynx, adrenal glands, thyroid, eye Liver, pancreas, larynx, adrenal glands, thyroid, eye Fever of unknown origin 11-26% Fever of unknown origin 11-26% Constitutional symptoms Constitutional symptoms Cough Cough Other sites Other sites Skin and soft tissues 4%, osteoarticular 1% Skin and soft tissues 4%, osteoarticular 1% Genitourinary 0.6% Genitourinary 0.6% Liver, pancreas, larynx, adrenal glands, thyroid, eye Liver, pancreas, larynx, adrenal glands, thyroid, eye John GT. 2001

17. Diagnostic difficulties?

18. Diagnosis Delayed diagnosis > mortality Delayed diagnosis > mortality association with other infections association with other infections aggressive diagnostic techniques: FB, BX... aggressive diagnostic techniques: FB, BX... PPD testing PPD testing Low efficacy (only 20-25% of patients are PPD+) Low efficacy (only 20-25% of patients are PPD+) Anergy skin testing??? Anergy skin testing??? IGRAs: Quantiferon-TB Gold, T-SPOT. TB IGRAs: Quantiferon-TB Gold, T-SPOT. TB IFN-  from sensitized L IFN-  from sensitized L Delayed diagnosis > mortality Delayed diagnosis > mortality association with other infections association with other infections aggressive diagnostic techniques: FB, BX... aggressive diagnostic techniques: FB, BX... PPD testing PPD testing Low efficacy (only 20-25% of patients are PPD+) Low efficacy (only 20-25% of patients are PPD+) Anergy skin testing??? Anergy skin testing??? IGRAs: Quantiferon-TB Gold, T-SPOT. TB IGRAs: Quantiferon-TB Gold, T-SPOT. TB IFN-  from sensitized L IFN-  from sensitized L

19. Casas S et al. Liver Transpl 2011;17:1205-1211 Quantiferon-TB vs TST

20. Kim S-H et al. Am J Transplant 2011;11:1927 * * TST (>10 mm) was performed immediately before or after of surgery. No booster.

21. European Survey TB (ESGICH) (16 European countries, 50 transplant programs) Methods for screening  TST alone 41%  IGRAs alone 32%  TST and IGRAs simultaneously 22%  TST followed by IGRAs if TST positive 5% Methods for screening  TST alone 41%  IGRAs alone 32%  TST and IGRAs simultaneously 22%  TST followed by IGRAs if TST positive 5% Boillat-Blanco N, Aguado JM, Manuel O et al. ECCMID London 2012

22. Any therapeutic difficulties?

23. Interactions with Antituberculous drugs Isoniazid Rifampin Rifabutin Pirazinamide Etambutol Moxifloxacin Cicloserin Isoniazid Rifampin Rifabutin Pirazinamide Etambutol Moxifloxacin Cicloserin CyA -  - * FK -  - MMF -  - SRL -  - * Increase the levels of antituberculous drugs

24. Impact of rifampin based anti-tuberculosis regimens on outcomes in SOT recipients 63 SOT recipients with TB: RIF 26, non-RIF 37 63 SOT recipients with TB: RIF 26, non-RIF 37 Rejection rate and death at 1 year were similar in both groups. Rejection rate and death at 1 year were similar in both groups. Immune Reconstitution Syndrome (IRS) more frequent in RIF than in non-RIF (27% vs 5,4%, p=.04) Immune Reconstitution Syndrome (IRS) more frequent in RIF than in non-RIF (27% vs 5,4%, p=.04) Mortality at 1 y: 33% with IRS, 14% without IRS (p = 0.15) Mortality at 1 y: 33% with IRS, 14% without IRS (p = 0.15) 63 SOT recipients with TB: RIF 26, non-RIF 37 63 SOT recipients with TB: RIF 26, non-RIF 37 Rejection rate and death at 1 year were similar in both groups. Rejection rate and death at 1 year were similar in both groups. Immune Reconstitution Syndrome (IRS) more frequent in RIF than in non-RIF (27% vs 5,4%, p=.04) Immune Reconstitution Syndrome (IRS) more frequent in RIF than in non-RIF (27% vs 5,4%, p=.04) Mortality at 1 y: 33% with IRS, 14% without IRS (p = 0.15) Mortality at 1 y: 33% with IRS, 14% without IRS (p = 0.15) Sun HY et al. ICAAC 2012. Singh N et al. ICAAC 2011

25. Aguado JM et al. Clinical Infectious Diseases 2009; 48:1276–84 Guidelines. RESITRA-Spanish Society of Infectious Diseases

26. European Survey TB (ESGICH) (16 European countries, 50 transplant programs) Treatment with rifamycins in TB Treatment with rifamycins in TB  Non-severe TB 61%  Severe disseminated TB 95% Treatment with rifamycins in TB Treatment with rifamycins in TB  Non-severe TB 61%  Severe disseminated TB 95% Boillat-Blanco N, Aguado JM, Manuel O et al. ECCMID London 2012

27. Crude mortality 19%. Attributable mortality 9.5% Crude mortality 19%. Attributable mortality 9.5% RESITRA Network data Clinical Infectious Diseases 2009; 48:1657–65 Tuberculosis in SOT: current situation in Spain

28. Poor prognostic factors Factors that increase mortality Factors that increase mortality Rejection Rejection  Interference RFM-CsA  Antilymphocyte antibody treatment Concomitant opportunistic infection Concomitant opportunistic infection Treatment less than 9 months Treatment less than 9 months In kidney Tx: diabetes and chronic liver disease In kidney Tx: diabetes and chronic liver disease Immune Reconstitution Syndrome Immune Reconstitution Syndrome Factors that increase mortality Factors that increase mortality Rejection Rejection  Interference RFM-CsA  Antilymphocyte antibody treatment Concomitant opportunistic infection Concomitant opportunistic infection Treatment less than 9 months Treatment less than 9 months In kidney Tx: diabetes and chronic liver disease In kidney Tx: diabetes and chronic liver disease Immune Reconstitution Syndrome Immune Reconstitution Syndrome Aguado JM. GESITRA. Transplantation. 1997; 63: 1278-86. Singh N Clin Infect Dis 1998; John GT. Kidney Int 2001 Aguado JM. GESITRA. Transplantation. 1997; 63: 1278-86. Singh N Clin Infect Dis 1998; John GT. Kidney Int 2001

29. Prophylaxis: who, what, when, how long?

30. Exclude active infection and give prophylaxis if the recipient: TST >5mm (initial of after “booster”) TST >5mm (initial of after “booster”) TST negative and TST negative and Compatible lung residual lesions (RR 1.05-3.4) Compatible lung residual lesions (RR 1.05-3.4) History of untreated TB (RR 1.2-48) or TB contact History of untreated TB (RR 1.2-48) or TB contact Donor with possible TB Donor with possible TB TST >5mm (initial of after “booster”) TST >5mm (initial of after “booster”) TST negative and TST negative and Compatible lung residual lesions (RR 1.05-3.4) Compatible lung residual lesions (RR 1.05-3.4) History of untreated TB (RR 1.2-48) or TB contact History of untreated TB (RR 1.2-48) or TB contact Donor with possible TB Donor with possible TB GESITRA. Consensus Document. Clinical Infectious Diseases 2009; 48:1276–84

31. …or if the donor Live kidney donor TST+ : 3 months of INH beforeTx Live kidney donor TST+ : 3 months of INH beforeTx Death donor consider prophylaxis if Death donor consider prophylaxis if History of tuberculosis History of tuberculosis PPD (+) with normal Chest-X ray PPD (+) with normal Chest-X ray Residual lung lesions (contraindication for lung Tx) Residual lung lesions (contraindication for lung Tx) Lymph nodes found during surgery Lymph nodes found during surgery Live kidney donor TST+ : 3 months of INH beforeTx Live kidney donor TST+ : 3 months of INH beforeTx Death donor consider prophylaxis if Death donor consider prophylaxis if History of tuberculosis History of tuberculosis PPD (+) with normal Chest-X ray PPD (+) with normal Chest-X ray Residual lung lesions (contraindication for lung Tx) Residual lung lesions (contraindication for lung Tx) Lymph nodes found during surgery Lymph nodes found during surgery GESITRA. Consensus Document. Clinical Infectious Diseases 2009; 48:1276–84

32. Clinical Infectious Diseases 2009; 48:1657–65 Limitations for the Control of TBC RESITRA Network

33. European Survey TB (ESGICH) (16 European countries, 50 transplant programs) Screening of TB in SOT candidates Screening of TB in SOT candidates  systematically 61%  only in patients with risk factors 30%  no screening 9% Treatment of latent TB (Prophylaxis) Treatment of latent TB (Prophylaxis)  prior to liver TX 41%  no prophylaxis at all 5%-17% (depending on the organ)  considered a temporary contraindication for TX 32% Screening of TB in SOT candidates Screening of TB in SOT candidates  systematically 61%  only in patients with risk factors 30%  no screening 9% Treatment of latent TB (Prophylaxis) Treatment of latent TB (Prophylaxis)  prior to liver TX 41%  no prophylaxis at all 5%-17% (depending on the organ)  considered a temporary contraindication for TX 32% Boillat-Blanco N, Aguado JM, Manuel O et al. ECCMID London 2012

34. Toxicity of prophylaxis Toxicity: 2.7% KT, 4% HTx, 2-20% LT Individualize in liver recipients Individualize in liver recipients If stable consider prophylaxis before Tx If stable consider prophylaxis before Tx If not, wait till transplantation has been done If not, wait till transplantation has been done Toxicity: 2.7% KT, 4% HTx, 2-20% LT Individualize in liver recipients Individualize in liver recipients If stable consider prophylaxis before Tx If stable consider prophylaxis before Tx If not, wait till transplantation has been done If not, wait till transplantation has been done GESITRA. Consensus Document. Clinical Infectious Diseases 2009; 48:1276–84

35. Efficacy and Safety of Levofloxacin vs. Isoniazid for the Treatment of Latent Tuberculosis Infection in Liver Transplant Recipients Phase III stuy, multicentric, prospective, randomized, and open Candidates for liver transplantation. FLISH Study. Phase III stuy, multicentric, prospective, randomized, and open Candidates for liver transplantation. FLISH Study. Group A (usual practice): isoniazid 300 mg / day for 9 months beginning after the transplant, when the "liver function is stable" and not before 3 months and after 6 months. Group B (experimental): levofloxacin 500 mg daily for 9 months (commencing on the waiting list). Primary endpoint: difference in the incidence of TBC in both groups at 18 months of follow-up after transplantation. Sample size: n = 870 patients. 16 centers in Spain

36. Conclusions........ - Incidence > general population - Reactivation - Mortality > 30% - Clinical presentation: atypical and diverse - Treatment requires control of interactions - Prophylaxis is complicated because of: - Difficulty in identifying pts at risk - Toxicity of therapy. - Incidence > general population - Reactivation - Mortality > 30% - Clinical presentation: atypical and diverse - Treatment requires control of interactions - Prophylaxis is complicated because of: - Difficulty in identifying pts at risk - Toxicity of therapy.

37. Thanks God, he finished jaguadog@medynet.com