Transcript 1-4-Morrisx
Tuberculosis in Transplant Recipients 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 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 TB in 2015 • Mycobacterium tuberculosis identified 130 years ago • Currently 2nd 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) 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 http://gamapserver.who.int/mapLibrary/Files/Maps/Global_TBincidence_2013.png 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. 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. Data from Taiwan’s National Health Insurance Research Database Chen C-Y. Am J Transpl 2015;15:2180-2187. Immunosuppressant Drug Choice & Risk for TB Univariate Analysis Drug HR (95% CI) P-value Azathioprine 2.00 (0.49-8.22) 0.338 Cyclosporine 0.78 (0.33-1.84) 0.567 Mycophenolate 0.66 (0.33-1.34) 0.253 Steroids 0.80 (0.38-1.71) 0.567 Tacrolimus 0.73 (0.36-1.47) 0.371 mTORs 3.40 (1.85-6.27) <0.001 Multivariate Analysis HR (95% CI) P-value 3.09 (1.68-5.69) <0.001 Chen C-Y. Am J Transpl 2015;15:2180-2187. 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 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 Getahun H, Matteelli A, Chaisson RE, Raviglione M. New Engl J Med 2015;372;2127-35. 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. Quantiferon-TB Gold Test Performance in Transplant Candidates Transplant Type Total Positive Test Result Indeterminate Test Result Negative Test Result Liver alone 310 60 (19.4%) 126 (40.6%) 124 (40%) Kidney alone 541 175 (32.3%) 57 (10.5%) 309 (57.1%) Liver-Kidney 20 2 (10%) 8 (40%) 10 (50%) KidneyPancreas 31 3 (9.7%) 4 (12.9%) 24 (77.4%) Heart alone 12 3 (25%) 3 (25%) 5 (50%) Other 27 2 (7.4%) 8 (29.6%) 17 (63%) Theodoropoulos N, Lanternier F, Rassiwala J. Transpl Inf Dis 2011. 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. TB Post Liver Transplant Seen in almost half of patients Holty J-EC, Gould MK, Meinke L. Liver Transpl 2009. TB in Transplant Benito N. Clin Microbiology Infect 2015;21(7):651-658. 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 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 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 Ethambutol Voriconazole Coumadin Tacrolimus PZA Rifampin INH MMF Hepatic Metabolism Meds listed in bold are associated with major interactions Prednisone 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 Recurrence High TB Resistance Rates No Difference in Post-TB Rejection Rate No 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 – 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. 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? [email protected]