Mycobacterium tuberculosis in transplantation: Immunity sufficient to perpetuate disease?

Studies of screening and chemoprophylaxis for tuberculosis in transplantation are essential, notably in endemic regions, and should include the impact of immunomodulatory therapies on the risk of disease reactivation. See the article from Viana et al on page 1421. Studies of screening and chemoprophylaxis for tuberculosis in transplantation are essential, notably in endemic regions, and should include the impact of immunomodulatory therapies on the risk of disease reactivation. See the article from Viana et al on page 1421. Tuberculosis (TB) remains a major infectious challenge worldwide, notably in immunocompromised hosts. Guidelines for management exist.1Bumbacea D Arend SM Eyuboglu F et al.The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement.Eur Respir J. 2012; 40: 990-1013Crossref PubMed Scopus (171) Google Scholar, 2Lewinsohn DM Leonard MK LoBue PA et al.Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention clinical practice guidelines: diagnosis of tuberculosis in adults and children.Clin Infect Dis. 2017; 64: 111-115Crossref PubMed Scopus (390) Google Scholar, 3Aguado JM Torre-Cisneros J Fortun J et al.Tuberculosis in solid-organ transplant recipients: consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology.Clin Infect Dis. 2009; 48: 1276-1284Crossref PubMed Scopus (200) Google Scholar In areas with low TB endemicity, the prevalence among transplant recipients is 0.5%-6.4%, rising to 15.2% in highly endemic areas.4Singh N Paterson DL Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management.Clin Infect Dis. 1998; 27: 1266-1277Crossref PubMed Scopus (495) Google Scholar,5Munoz P Rodriguez C Bouza E Mycobacterium tuberculosis infection in recipients of solid organ transplants.Clin Infect Dis. 2005; 40: 581-587Crossref PubMed Scopus (259) Google Scholar 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.3Aguado JM Torre-Cisneros J Fortun J et al.Tuberculosis in solid-organ transplant recipients: consensus statement of the Group for the Study of Infection in Transplant Recipients (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology.Clin Infect Dis. 2009; 48: 1276-1284Crossref PubMed Scopus (200) Google Scholar,4Singh N Paterson DL Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management.Clin Infect Dis. 1998; 27: 1266-1277Crossref PubMed Scopus (495) Google Scholar Most transplant patients present with pulmonary TB (51%), while 16% have extrapulmonary disease and 33% have disseminated TB. Only 64% of recipients with localized disease present with fever. Atypical radiographic presentations are common. In normal hosts, the risk of active TB is ~5% in the first 5-7 years after infection and ~0.1% per year thereafter. After transplant, most cases occur in the first 6 months except in renal recipients, where onset is typically later as observed by Viana et al (median 18.8 months, IQR 7.2-60).4Singh N Paterson DL Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management.Clin Infect Dis. 1998; 27: 1266-1277Crossref PubMed Scopus (495) Google Scholar,6Torre-Cisneros J Doblas A Aguado JM et al.Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort.Clin Infect Dis. 2009; 48: 1657-1665Crossref PubMed Scopus (199) Google Scholar,7Viana L, Cristelli M, Santos DW, et al. Influence of epidemiology, immunosuppression, clinical presentation and treatment on kidney transplant outcomes of patients diagnosed with tuberculosis: a retrospective cohort analysis [published online ahead of print 2018]. Am J Transplant. https://doi.org/10.1111/ajt.15220.Google Scholar Late TB might be anticipated if primary infection occurred after transplant due to local exposure. In TB-infected recipients, graft loss approaches 33%, attributed to reductions in immunosuppression with graft rejection, interactions of immunosuppressive drugs with antituberculous medications resulting in reduced exposure to calcineurin inhibitors, as well as mortality associated with progressive TB. In this series, the absence of “immune reconstitution” following reduced immunosuppression may reflect continuation of prednisone8Meintjes G Stek C Blumenthal L et al.Prednisone for the prevention of paradoxical tuberculosis-associated IRIS.N Engl J Med. 2018; 379: 1915-1925Crossref PubMed Scopus (80) Google Scholar; still, 25.6% of patients had graft loss, half with rejection. Mortality of 57%-83% is largely attributable to TB and is increased by delayed clinical recognition and therapy.4Singh N Paterson DL Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management.Clin Infect Dis. 1998; 27: 1266-1277Crossref PubMed Scopus (495) Google Scholar,7Viana L, Cristelli M, Santos DW, et al. Influence of epidemiology, immunosuppression, clinical presentation and treatment on kidney transplant outcomes of patients diagnosed with tuberculosis: a retrospective cohort analysis [published online ahead of print 2018]. Am J Transplant. https://doi.org/10.1111/ajt.15220.Google Scholar Antibiotic susceptibility testing is a cornerstone of management for TB; resistance is a major factor in management in endemic regions but was not identified as a major factor in this series. Pretransplant screening is based on the presence of TB-specific immunity, classic radiographs, or exposure history. As in this series, chest radiographs are often negative in patients who ultimately develop TB posttransplant. Multiple challenges exist to universal screening: cost, coordination of skin testing or interferon (INF)γ release assay assays, spurious results of screening (eg, skin test anergy), and compliance and toxicity of therapy for latent TB infection. In endemic regions, preventive chemotherapy without immunodiagnostic testing may be considered for transplant recipients. Childhood bacillus Calmette-Guérin vaccination does not appear to affect the development of TB in adults. Consensus does not exist regarding the optimal approach to chemoprophylaxis among individuals with negative screening assays but with risk factors (eg, domiciliary exposures). Immune control of Mycobacterium tuberculosis is incompletely understood. An effective immune response requires collaboration between various cells of innate and adaptive immunity. Granulomas, a defining histologic feature of TB, are carefully orchestrated aggregates of immune cells. In zebrafish larvae lacking adaptive immunity, Mycobacterium marinum infection produces fully formed granulomas with typical epithelioid macrophages and granuloma-associated gene expression patterns. Traditionally, these macrophages have been thought to protect the host by “walling off” replicating mycobacteria using microbicidal activity limiting replication of intracellular and extracellular organisms. Host macrophages both block and facilitate persistent infection; pathogenic mycobacteria accelerate macrophage apoptosis while accelerating accumulation of uninfected macrophages, which provides a “safe harbor” for further replication and spread. In higher species, once bacilli are engulfed by phagocytes, the spread of bacilli occurs unless a specific Th1-type immune response develops, including IFNγ-producing CD4 and CD8 T cells. Polyfunctional memory CD4 T cells producing IFNγ, tumor necrosis factor-α, and interleukin-2 appear to prevent disease reactivation. Surprisingly, overexuberant T cell responses or excess tumor necrosis factor causes granulomata to undergo necrosis with increased extracellular spread. Interestingly, in this series, the rate of TB was greatest (14.7%) in the small population receiving belatacept/mycophenolate mofetil (hazard ratio 13.1). Assessment of the impact of costimulatory blockade in larger populations is needed. In mycobacterial infection in normal hosts, cytotoxic T-lymphocyte–associated antigen 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.9Sharpe AH Mechanisms of costimulation.Immunol Rev. 2009; 229: 5-11Crossref PubMed Scopus (241) Google Scholar 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.10Rostaing L Vincenti F Grinyó J et al.Long-term belatacept exposure maintains efficacy and safety at 5 years: results from the long-term extension of the BENEFIT study.Am J Transplant. 2013; 13: 2875-2883Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar It is unclear whether the mechanisms underlying the 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. The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.