Mycobacterium tuberculosis in transplantation: Immunity sufficient to perpetuate disease?

Abstract

Tuberculosis (TB) remains a major infectious challenge worldwide, notably in immunocompromised hosts. Guidelines for management exist. 1-3 In areas with low TB endemicity, the prevalence among transplant recipients is 0.5%-6.4%, rising to 15.2% in highly endemic areas. 4,5 Factors affecting TB incidence after transplant include T cell-depleting therapies, treatment of graft rejection, renal insufficiency, chronic liver disease, diabetes mellitus, hepatitis C virus infection, and increased recipient age. 3,4 Most transplant patients present with pulmonary TB (51%), while 16% have extrapulmonary disease and 33% have disseminated TB. Only 64% of recipients withtigen 4 (CTLA-4), programmed cell death 1, and programmed cell death 1 ligand exert inhibitory functions on T cell activation by antigen; CTLA-4 and programmed cell death 1 deficiencies or inhibition enhance M. tuberculosis-specific T cell expansion (immune reconstitution) with tissue necrosis and development of more numerous pulmonary lesions and increased mortality. 9 The mechanisms underlying this effect are uncertain. Belatacept blocks both CTLA-4 (T cell inhibitory) and CD28 (T cell activating). Thus, costimulatory blockade might disrupt the maintenance of latency via disparate mechanisms: suppression of Th1 responses and recruitment of naïve T cells; induced unresponsiveness (anergy or regulatory T cells) to tuberculous antigens in the presence of latent (low-level replication) infection or distant childhood BCG vaccinations; or, conversely, by stimulating immune reconstitution with necrosis of granulomata and bacillary spread. In follow-up studies of belatacept, cases of TB (in endemic regions) as well as Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder were noted. 10 It is unclear whether the mechanisms underlying the | 1263 EDITORIAL impact of belatacept on EBV and posttransplant lymphoproliferative disorder risk might be related to the effect on TB risk. In belatacept-treated patients, most lymphomas occur in EBV-negative recipients of EBV-positive kidneys, presumably new antigen exposure. Regardless of the mechanism, screening and chemoprophylaxis for TB might be emphasized in patients who will be receiving belatacept, notably in regions endemic for TB. Given the public health importance of TB, understanding of the complex immune responses to M. tuberculosis may facilitate clinical management and impact vaccine development.

Mycobacterium tuberculosis DNA in living donor transplanted livers and donor‐related tuberculosis in recipients: A retrospective longitudinal cohort study

“…When these livers were transplanted and recipients were given significant immune suppression to prevent rejection, only one patient out of the 25 recipients whose donors were positive for M tuberculosis DNA developed tuberculosis. Infection was most likely related to post‐transplant exposure given that it developed 15 months after transplantation . We were unable to sequence M tuberculosis from the donor liver to compare it with the cultured strain from the recipient.…”

“…Infection was most likely related to post-transplant exposure given that it developed 15 months after transplantation. 23 We were unable to sequence M tuberculosis from the donor liver to compare it with the cultured strain from the recipient. Thus, we believe that all the donors have cleared the M tuberculosis infection, as none of the recipients developed early post-transplant tuberculosis that could be attributed to donor organs.…”

Bacterial and Viral Infection and Sepsis in Kidney Transplanted Patients

“…However, the disease distribution directly correlates with economic status, with endemic diffusion in low-income areas [72,73]. Most patients develop a latent infection, classified by WHO as a state of persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifested active TB disease [74], which may become active in case of reduced host defenses (i.e., for transplant immunosuppression) [73,75,76]. Not surprisingly, solid organ transplanted patients are an "at-risk" population with high incidence and adverse outcomes, including allograft impairment [73,[77][78][79].…”