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 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 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 WHO Global TB Report Accessed 7/13/15 at TB Epidemiology in SOT SOT recipients fold higher risk for TB than general population TB incidence %, 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: 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: Data from Taiwans National Health Insurance Research Database Immunosuppressant Drug Choice & Risk for TB DrugHR (95% CI)P-valueHR (95% CI)P-value Azathioprine2.00 ( )0.338 Cyclosporine0.78 ( )0.567 Mycophenolate0.66 ( )0.253 Steroids0.80 ( )0.567 Tacrolimus0.73 ( )0.371 mTORs3.40 ( )< ( ) 3.5) Sputum x 3 AFB smear and culture + M. tuberculosis 3 Months Post-Transplant 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 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 Drug-Drug Interactions Hepatic Metabolism INHRifampin PZAEthambutol VoriconazoleCoumadinTacrolimus MMFPrednisone Meds listed in bold are associated with major interactions Treatment Modifications Rifampin Rifabutin Voriconazole Micafungin Coumadin Heparin Tacrolimus/Prednisone/Mycophenolic acid Tacrolimus After 2.5 Months of Treatment 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 Active TB & SOT 2009 Aguado JM, Torre-Cisneros J. Clin Infect Dis 2009. 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. 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 Better outcomes with treatment duration >12 months even rifampin-free Treatment < 9 months associated with mortality Meije Y, Piersimoni C, Torre-Cisneros J. Clin Microbiol Infect Aguado JM, Herrera JA, Gavalda J. Transplantation Park YS, Choi JY, Cho CH. Yonsei Med J 2004. 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 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. 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 Questions?