Not TB But Not To Be Underestimated: The Challenges of Nontuberculous Mycobacteria Infection in Solid Organ Transplant Recipients

Nontuberculous mycobacteria (NTM) are a group of ubiquitous organisms with a propensity for affecting patients with chronic lung disease and suppressed immunity. These conditions often coexist among solid organ transplant recipients, with an incidence of NTM infection as high as 4.5% among lung transplant recipients.1,2 Despite being relatively uncommon, several factors have been associated with NTM disease, including lung transplantation, pretransplant NTM infection, lymphocyte-specific antibody therapy, and older age.3-5 NTM disease offers unique challenges for transplant recipients. First, diagnostic criteria are primarily validated in immunocompetent patients (namely those with structural lung disease).6 Second, treatment strategies are likewise extrapolated from nontransplant populations. Typical antibiotic regimens commonly have drug-drug interactions with usual maintenance immunosuppression and carry many potential adverse effects. Third, transplant recipients are at risk for concurrent pathogens, which can complicate NTM diagnosis and lead to compounding toxicity from multiple treatment regimens. While NTM disease has been associated with increased mortality and allograft dysfunction among transplant recipients,4,7 data are lacking and urgently needed regarding optimal management and outcomes of NTM disease in transplant recipients. In this issue of Transplantation, López-Medrano et al8 added much-needed data to this conversation. They used data from a previously reported matched case-control study,3 analyzing management strategies and outcomes of solid organ transplant recipients with NTM disease. Case patients were diagnosed with NTM between January 1, 2008, and December 31, 2018. Eighty-five patients from transplant centers in Europe, North America, and South America were matched in a 1:2 ratio to uninfected controls based on the type of transplant, institution, transplant date, and survival at least to a similar index date as their matched case patient. NTM disease was diagnosed at a median of 1.8 y after transplant. Most patients had a pulmonary infection, although a considerable number had localized extrapulmonary (25.9%) or disseminated (16.5%) infection. Most infections were with Mycobacterium avium complex (32%), followed by M abscessus (21%), M fortuitum (11%), M kansasii (9%), and M chelonae (9%). Patients were recipients of kidney (37.6%), lung (34.1%), liver (10.6%), heart (10.6%), and pancreas (1.2%) allografts. Only 57% of patients underwent antibiotic susceptibility testing, and 91% received NTM therapy for any duration (median 225 d). Treatment regimens were similar among those with slow-growing mycobacteria but extremely variable for rapid-growing isolates. Medication toxicity requiring a change in NTM treatment was common (40%), although only 1 patient required complete cessation of treatment because of adverse effects. Overall, 20% of those with NTM infection died within 1 y, significantly >3% of uninfected control patients. However, only 5 of 17 infected patients' deaths (29%) were directly attributed to NTM infection. Factors associated with 1-y mortality included receipt of a lung transplant, dyspnea as a presenting symptom, and lack of NTM treatment. Overall, results of this study are striking for several reasons: The rate of antibiotic susceptibility testing was low, with only 57% of these results available. Although not statistically significant (likely due to low numbers), patients who were alive at 1 y had higher rates of susceptibility testing for rapid-growing (72% versus 40%) and slow-growing isolates (49% versus 25%). Tolerability of NTM therapy is clearly problematic. Forty percent required a change in treatment because of toxicity, and the overall rate of side effects, including those not requiring a change in therapy, was not reported but likely even higher. Drug-drug interactions were not specifically examined in this study, although it stands to reason interactions may have either increased the risk of toxicity, introduced variability to immunosuppression drug concentrations or led to the use of a less effective or more toxic alternative agent. There is an overlap between factors associated with NTM disease and subsequent mortality. Lung transplant recipients are at particularly elevated risk for both outcomes, along with multiple measures of heightened immunosuppression and medical complexity, such as acute rejection and longer duration of immediate posttransplant intensive care unit admission.3,5,8 How does this study apply to today's patients? First, the disparity in mycobacterial susceptibility testing highlights the necessity of important diagnostics and other specialized resources, as recommended by current NTM guidelines.6,9 Improved access to mycobacterial susceptibility testing or centers with expertise in managing complex NTM infections is needed. Second, while NTM disease contributed directly to some of the reported deaths (with treatment difficulties playing a role), NTM disease likely also influences mortality by leading to allograft dysfunction.4 It is also notable that NTM-infected patients commonly underwent immunosuppression reduction. Reductions in immunosuppression were more common among those who died, possibly by causing rejection or otherwise impacting allograft function. Although not specifically examined for NTM, other infections such as cytomegalovirus have been associated with subsequent acute rejection and are postulated to be related to reductions in immunosuppression.10 This highlights the fine balance in managing complex infections in the transplant population, which should be considered in treatment decisions. Finally, patients at risk for NTM disease may also be at inherently higher risk for mortality independent of NTM because of underlying comorbidities and complications that predispose them to NTM disease (Figure 1). Mitigating these earlier complications may prevent both NTM disease and early mortality.FIGURE 1.: Directed acyclic graph of proposed associations between clinical factors, NTM disease, and outcomes after solid organ transplantation. NTM, nontuberculous mycobacteria.Although large relative to past studies, this work was limited by sample size. Other limitations included multiple comparisons and the inclusion of variable NTM species and sites of infection. Ideally, future studies would be able to investigate differential effects on mortality and allograft outcomes by species, treatment agent, and site of infection. Despite these limitations, the authors should be applauded for shedding light on outcomes and next steps to advance care for transplant recipients with NTM disease. Ultimately, transplant recipients need better strategies to prevent NTM disease, more tolerable treatment regimens, and approaches that minimize effects of NTM on mortality and allograft function. This study is a much-needed step forward and one the transplantation community can build on to tackle the challenges of NTM disease.