Challenges in Management: Solid Organ Transplantation & Tuberculosis
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1 Challenges in Management: Solid Organ Transplantation & Tuberculosis Michele I Morris, M.D., FACP, FIDSA Director, Immunocompromised Host Section Associate Professor of Clinical Medicine Division of Infectious Diseases University of Miami Miller School of Medicine Miami, FL, USA
2 The Nightmare Scenario 45 year old female nurse mother of 2 develops active pulmonary TB after work related exposure Treated with RIPE, develops hepatic failure 12 weeks into therapy Is she a candidate for liver transplant? If so, how do you manage her TB posttransplant?
3 Expert Clinical Opinion
4 TB in Solid Organ Transplant Epidemiology (SOT) Interventions to prevent TB post-transplant Screening deceased & living donors Screening transplant candidates Management of Latent TB in SOT Worse Case Scenario Treating TB posttransplant How TB providers can help
5 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 Morris MI. Amer J Transpl 2012;12:
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 (anti-t cell antibody therapy)
7 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 Transplant experts with little TB experience TB experts with little transplant experience
8 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
9 TST & IGRA Performance in Transplant Candidates Only 20-25% of post-transplant TB patients had +TST pre-transplant End stage organ failure TST anergy/igra indeterminate results No gold standard to diagnose LTBI Sensitivity of IGRAs may be better than TST Both tests specific, any + should be considered as evidence of TB infection Neither TST nor IGRA can distinguish latent from active TB
10 QuantiFERON-TB Assay in Hemodialysis Patients High rate of indeterminates but none with active TB Inoue T, Nakamura T, Katsuma A. Nephrol Dial Transplant 2009.
11 Predictive Value of T-SPOT TB Test in Kidney Transplant Candidates Rate difference 3.3/100 + vs -/indeterminate P<0.001 Kim S-H, Lee S-O, Park JB. Amer J Transpl 2011.
12 Quantiferon-TB Gold Test Performance in Transplant Candidates Transplant Type Total Positive Test Result Indeterminate Test Result Negative Test Result Liver alone (19.4%) 126 (40.6%) 124 (40%) Kidney alone (32.3%) 57 (10.5%) 309 (57.1%) Liver-Kidney 20 2 (10%) 8 (40%) 10 (50%) Kidney- Pancreas 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.
13 Quantiferon-TB Assay in Liver Candidates TST and QFT diagnose latent TB infection at similar rates pre-liver transplant consider IGRA followed by TST, esp in high risk Candidates with advanced liver disease Indeterminate results more likely QFT performs better than TST Approach to indeterminate QFT Repeat when patient healthier Alternative test T-SPOT TB or TST Manuel O, Humar A, Preiksaitis J. Amer J Transpl Casas S, Munoz L, Moure R. Liver Transpl Theodoropoulos N, Lanternier F, Rassiwala J. Transpl Inf Dis 2011.
14 Pre-transplant Latent TB Evaluation: CT vs. CXR 2549 liver transplant recipients in South Korea 36 developed TB Matched 4:1 with controls without post-transplant TB Lyu J, Lee S-G, Hwang S. Liver Transpl 2011.
15 TB Screening Algorithm for Transplant Candidates Aguado JM, Torre-Cisneros J. Clin Infect Dis 2009.
16 Testing Post-Transplant: TST vs. IGRA 205 Swiss renal transplant recipients Comparison of 2 IGRAs with TST All show poor sensitivity T-SPOT TB most sensitive Hadaya K, Bridevaux P-O, Roux-Lombard P. Transplantation 2013.
17 TB Screening of Deceased Donors Detailed History is Key, but Complex End Stage Organ Failure +/- ICU Care Required Screening for Multiple Infectious Diseases Reliance on Diagnostic Tests with Variable Sensitivity
18 Donor Management Brain death Eval Consent 6-48 hours Aortic cross-clamp Referral pt. on ventilator Meds, Stabilize, Labs, Echo, Bronch Place organs Surgical organ recovery Slide provided by Susan Ganz, M.D.
19 TB Screening of Deceased Donors TST not feasible IGRAs often indeterminant Head injury patients known to have cellular immunity Screening cattle for M. bovis pre/post mortem demonstrated ~50% decrease in gamma interferon after slaughter IGRA evaluated in 105 deceased donors Quantiferon TB Gold - 56/105 (53%) indeterminant FACS (research assay) - 13/104 (12.5%) indeterminant ELISPOT 0/97 - (0%) indeterminant Schmidt T, Schub D, Wolf M. Amer J Transpl 2014.
20 TB Screening of Deceased Donors History Imaging Micro Obtained from relatives, sometimes distant or uninformed, often inaccurate CXR often obscured by trauma, pulmonary edema. Unspecified lung nodules/granulomas may not be identifiable as TB pre-transplant Standard AFB smear and culture results not ready prior to transplant. Rapid molecular methods not universally available at all centers
21 Managing Transplant Candidates after LTBI screening If positive Screen for active TB Baseline labs and detailed medication review Clarify likely timing of transplant If negative Rescreen annually esp. if awaiting renal transplant TREAT pre transplant History of inadequately treated active or latent TB Recent exposure to active TB
22 Treatment Options Pre-SOT Subramainian AK, Morris MI. Amer J Transpl 2013;13:68-76.
23 LTBI Treatment of SOT candidates INH/Rif 12 week regimen - 17 patients presot 83% dose compliance, 76% completion rate No transaminase elevations > 2x baseline, 4x ULN Lopez de Castilla D, Rakita RM, Spitters CE. Transplantation 2014.
24 Timing of Isoniazid Jafri S-M, Singal AG, Kaul D. Liver Transpl 2011.
25 INH vs. Rifampin for LTBI Retrospective cohort study of 2255 patients in MD treated for LTBI Page KR. Arch Int Med 2006.
26 Risks of Latent TB Treatment Drug related hepatotoxicity HBV, HCV coinfections Liver transplant candidates with ESLD Multiple drug-drug interactions Heart transplant candidates on coumadin, amiodarone Renal transplant candidates with oral hypoglycemics, antihypertensives
27 Transplant Candidates with History of Latent or Active TB No need for repeat TST or IGRA Need reliable documentation of adequate therapy or repeat treatment pre/post SOT RE-EVALUATE Assess for signs/symptoms of active TB CXR with consideration for other imaging/testing Microbiology prn Culture slow if smear negative Nucleic acid amplification rapid, automated may be false negative with few mycobacteria present
28 TB 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 Lopez de Castilla D, Schluger NW. Transpl Infect Dis 2010.
29 TB Post Liver Transplant Seen in almost half of patients Holty J-EC, Gould MK, Meinke L. Liver Transpl 2009.
30 Active TB & SOT 2009 Unrecognized active TB at time of SOT Liver transplant in patients with hepatic failure due to TB treatment (our nightmare scenario) Aguado JM, Torre-Cisneros J. Clin Infect Dis 2009.
31 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.
32 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.
33 Treatment of TB post-sot Do NOT treat alone need transplant team clinician involvement Complex drug-drug interactions Potential loss of organ allograft Do NOT use standard 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
34 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.
35 Take Home Messages Transplant recipients are at high risk for TB related morbidity and mortality Available diagnostics do not work optimally in deceased donors & critically ill transplant candidates Diagnose & treat LTBI pre-transplant if possible Post-transplant TB treatment requires close teamwork
36 Questions?
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