1. Michele I Morris, M.D., FACP, FIDSA, FAST Director, Immunocompromised Host Section Associate Professor of Clinical Medicine Division of Infectious Diseases University of Miami Miller School of Medicine Miami, FL, USA Tuberculosis in Transplant Recipients

2. TB in Solid Organ Transplant (SOT) Epidemiology & Outcomes Latent TB Diagnosis in Transplant Candidates Latent TB treatment Active TB Diagnosis Post-Transplant Active TB Treatment Post-Transplant

3. Mycobacterium tuberculosis identified 130 years ago Currently 2 nd leading infectious cause of death after HIV 2013 worldwide data: – 9 million people newly infected with TB – 1.5 million people died of TB 1/3 of the world population is infected (~2 billion people), most with latent TB (LTBI) TB in 2015 http://www.who.int/tb/publications/factsheet_global.pdf?ua=1 WHO Global TB Report 2014. Accessed 7/13/15 at http://apps.who.int/iris/bitstream/10665/137094/1/9789241564809_eng.pdf?ua=1

4. http://gamapserver.who.int/mapLibrary/Files/Maps/Global_TBincidence_2013.png

5. TB Epidemiology in SOT SOT recipients 36-74 fold higher risk for TB than general population TB incidence 1.2-6.4%, up to 15% in highly endemic countries Risk factors for TB in SOT – Country of origin – Older age – Lung transplant – Social – homeless, alcohol, incarceration – Medical – DM, low BMI, H/O untreated TB, Radiographic evidence of prior TB Morris MI. Amer J Transpl 2012;12:2288-2300.

6. TB Mortality in SOT Mortality of TB in SOT 10-30% TB-attributable mortality 9-20% Predictors of TB mortality – Disseminated infection – Prior rejection – Increased immunosuppression mTOR inhibitors Chen C-Y. Am J Transpl 2015;15:2180-2187.

7. Data from Taiwan’s National Health Insurance Research Database

8. Immunosuppressant Drug Choice & Risk for TB DrugHR (95% CI)P-valueHR (95% CI)P-value Azathioprine2.00 (0.49-8.22)0.338 Cyclosporine0.78 (0.33-1.84)0.567 Mycophenolate0.66 (0.33-1.34)0.253 Steroids0.80 (0.38-1.71)0.567 Tacrolimus0.73 (0.36-1.47)0.371 mTORs3.40 (1.85-6.27)<0.0013.09 (1.68-5.69)<0.001 Univariate Analysis Multivariate Analysis Chen C-Y. Am J Transpl 2015;15:2180-2187.

9. TB in SOT: Reasons for Increased Mortality Delayed Diagnosis – Immunocompromised with multiple infection risks – Unusual clinical presentations Drug-drug interactions with transplant immunosuppressants  allograft rejection  organ loss

10. Sources of TB in Transplant Recipients Reactivation in recipients with untreated or unrecognized latent or active TB Post-transplant exposure – Likely more common in high TB incidence countries – Nosocomial outbreaks – Travel Donor-derived – transmitted through organ allograft – ~4% post-transplant TB – Likely more common in lung recipients Relapse – history of previously treated active TB with persistent viable bacilli despite clinical cure – 3.5% relapse rate at 2 years with 4 drug/6 month TB therapy

11. Getahun H, Matteelli A, Chaisson RE, Raviglione M. New Engl J Med 2015;372;2127-35.

12. IGRA+ Pre-Transplant Patients with no clinical risk factors for TB randomized to Isoniazid vs no Isoniazid (INH) Kim S-H. J Antimicrob Chemother 2015;70:1567-72.

13. Quantiferon-TB Gold Test Performance in Transplant Candidates Transplant Type TotalPositive Test Result Indeterminate Test Result Negative Test Result Liver alone31060 (19.4%)126 (40.6%)124 (40%) Kidney alone541175 (32.3%)57 (10.5%)309 (57.1%) Liver-Kidney202 (10%)8 (40%)10 (50%) Kidney- Pancreas 313 (9.7%)4 (12.9%)24 (77.4%) Heart alone123 (25%) 5 (50%) Other272 (7.4%)8 (29.6%)17 (63%) Theodoropoulos N, Lanternier F, Rassiwala J. Transpl Inf Dis 2011.

14. TB Diagnosis Post Transplant Clinical presentations atypical – FUO – Allograft dysfunction – Uncommon sites of involvement – GI tract, Kidney, Bone, Skin 33-50% of post-transplant disease is disseminated or extrapulmonary – 15% in normal hosts Symptom onset within 1 year of transplant – median 11.2 months Muñoz P, Rodriguez C, Bouza E. Clin Infect Dis 2005. Lopez de Castilla D, Schluger NW. Transpl Infect Dis 2010.

15. TB Post Liver Transplant Holty J-EC, Gould MK, Meinke L. Liver Transpl 2009. Seen in almost half of patients

16. TB in Transplant Benito N. Clin Microbiology Infect 2015;21(7):651-658.

17. Post-Transplant TB Case: Nothing in Life is Simple 56 y/o male receives living donor kidney from his healthy sister, CMV D+/R- – ESRD due to hypertension – Hypercoagulable state with recurrent bilateral DVTs prior to transplant Below the Knee Amputation due to clot Pancreatitis – Discharged on Tacrolimus, Mycophenolic acid, Prednisone, Valganciclovir, Trimethoprim/Sulfa

18. Unusual Presentation of Post Transplant TB Admitted to outside hospital 3 months post transplant with 3 days of fever, weakness, diarrhea – Pleural effusion noted on CXR  transferred to MTI CT thorax reveals multiple opacities BAL  M. TB PCR +, aspergillus galactomannan + (> 3.5) Sputum x 3 AFB smear and culture + M. tuberculosis

19. 3 Months Post-Transplant

20. Diagnostic Challenges Recipient – Born in NYC, lives in central Florida – No foreign travel – No TB risk factors – TST & Quantiferon TB assay negative pre-transplant – No post transplant exposures (wife, contacts all negative) Donor – Healthy 50 y/o female – Lifelong resident of New York City – School teacher tested frequently – No TB risk factors – TST & Quantiferon TB assay negative

21. Treatment Challenges Drug-drug interactions – RIPE – Isoniazid/Rifabutin vs Rifampin/Pyrazinamide/Ethambutol/Pyridoxine – Voriconazole – Coumadin vs Heparin – Tacrolimus/Mycophenolic acid/Prednisone Elevated liver enzymes at the time of TB diagnosis

22. Drug-Drug Interactions Hepatic Metabolism INHRifampin PZAEthambutol VoriconazoleCoumadinTacrolimus MMFPrednisone Meds listed in bold are associated with major interactions

23. Treatment Modifications Rifampin  Rifabutin Voriconazole  Micafungin Coumadin  Heparin Tacrolimus/Prednisone/Mycophenolic acid  Tacrolimus

24. After 2.5 Months of Treatment

25. Outcome Increased lung nodules on CT thorax done 6 weeks into therapy – BAL  negative smears, cultures, TB PCR, aspergillus galactomannan Aspergillus treatment 3-4 months TB treatment 6 months Clinically well & infection free 4 years later with excellent graft function

26. Active TB & SOT 2009 Aguado JM, Torre-Cisneros J. Clin Infect Dis 2009.

27. Rifampin Sparing Regimens Increased Risk of TB RecurrenceHigh TB Resistance RatesNo Difference in Post-TB Rejection RateNo Difference in Mortality Meije Y, Piersimoni C, Torre-Cisneros J. Clin Microbiol Infect 2014.

28. Transplant TB Treatment Tips 2015 Rifampin-containing regimens may be preferred – Increase immunosuppressants 3-5 fold, esp. tacrolimus, cyclosporine, sirolimus, everolimus – Increase corticosteroids – Closely monitor immunosuppressant levels Dose adjustments often needed in renal transplant recipients – INH, Ethambutol, Streptomycin ? Treat longer – 2004 - Better outcomes with treatment duration >12 months even rifampin-free – 1997 - Treatment < 9 months associated with  mortality Meije Y, Piersimoni C, Torre-Cisneros J. Clin Microbiol Infect 2014. Aguado JM, Herrera JA, Gavalda J. Transplantation 1997. Park YS, Choi JY, Cho CH. Yonsei Med J 2004.

29. Treatment of TB post-SOT Do NOT treat without transplant team involvement – Complex drug-drug interactions – Potential loss of organ allograft Do NOT use intermittent directly observed therapy (DOT) – Daily dosing strongly preferred due to impact on other medications (and medication levels) Do NOT give up on the organ allograft or the patient – Frequent visits with both transplant clinician managing TB and TB provider essential for successful outcome

30. Immune Reconstitution Syndrome (IRS) in Post-SOT TB Increased inflammatory response seen in HIV patients Occurs in 14% of TB post-transplant Risk Factors – Liver transplant – Cytomegalovirus (CMV) infection – Rifampin therapy Complicates monitoring of clinical response to treatment – Need to distinguish from progressive infection – Median onset 47 days after starting anti-TB therapy Increased 1 year Mortality (33% IRIS vs 17% no IRIS) Sun HY. Prog Transplant 2014;24:37-43.

31. Take Home Messages Transplant recipients are at high risk for TB related morbidity and mortality IGRAs still not perfect in the diagnosis of latent TB in transplant candidates Post-transplant TB diagnosis can be challenging Successful post-transplant TB treatment requires: – Planning of regimen with attention to drug-drug interactions – Close monitoring for side effects and response to therapy – Excellent teamwork

32. Questions? mmorris2@miami.edu