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Rapid-growing nontuberculous mycobacteria (NTM) were strongly associated with death or re-transplantation in adult lung transplant patients, based on data from a new study of approximately 1000 individuals.

NTM are ubiquitous environmental organisms, but the clinical significance of isolating NTM posttransplant remains poorly defined, and previous studies have been mainly small and single center, said lead author Gabrielle Mezochow, MD, a pulmonology and critical care fellow at the University of Pennsylvania in Philadelphia.

“This is important because treatment is particularly challenging in lung transplant recipients, requiring prolonged multidrug regimens that can be toxic and interact with immunosuppression,” Mezochow said. “We conducted this study to better understand how often NTM is isolated after lung transplant, and whether isolation is associated with important outcomes such as chronic lung allograft dysfunction (CLAD) and death or re-transplantation in a large multicenter cohort,” she said.

In the study, presented at the annual meeting of the International Society for Heart and Lung Transplantation (ISHLT), Mezochow and colleagues reviewed data from 1044 adult lung transplant recipients in the Lung Transplant Outcomes Group cohort who underwent transplant between 2007 and 2022 at three centers.

The researchers evaluated the time from transplantation to graft failure (defined as death or re-transplantation) and CLAD (as defined by the ISHLT). They used a proportional hazards model adjusted for age, diagnosis, BMI, primary graft dysfunction, postoperative extracorporeal membrane oxygenation, and transplant type.

A total of 136 patients (13%) had pulmonary growth of NTM within a year of their transplants; the most common types were Mycobacterium avium (88 patients) and Mycobacterium abscessus (16 patients).

Overall, the association between early growth of any NTM and the risk for graft failure did not reach statistical significance (adjusted hazard ratio [HR], 1.27). However, patients who had early growth of rapid-growing NTM (including M abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium immunogenum, Mycobacterium mageritense, and Mycobacterium mucogenicum) had an increased risk for graft failure compared to those with early growth of slow-growing NTM such as M avium (unadjusted HR, 2.36; adjusted HR, 2.49). The associations were consistent when patients with cystic fibrosis were excluded, and no significant association was observed between early NTM growth by slow or rapid types and increased risk for CLAD (adjusted HR, 1.09).

“One of the most interesting findings was that associations differed by NTM species,” Mezochow said. “Rapid-growing NTM were most strongly associated with death or re-transplantation, whereas slow-growing NTM appeared to have a stronger association with CLAD,” she said. “We were also intrigued by the stronger associations with negative outcomes observed among recipients with ILD [interstitial lung disease], particularly those undergoing single lung transplantation,” Mezochow noted. “This raises the possibility that characteristics of the native lung or underlying lung disease may influence susceptibility and outcomes,” she said.

“Importantly, our study evaluated NTM isolation rather than NTM pulmonary disease, which is often difficult to define in lung transplant recipients,” said Mezochow. The results suggest that NTM isolation should not be dismissed as a benign microbiologic finding and could serve as an early marker of lung transplant recipients at increased risk for poor outcomes, even before disease can be definitively established, she noted. “Certain subgroups of recipients, including those with specific NTM species or underlying diagnoses, may be at a particularly elevated risk for poor outcomes, while not all patients with NTM isolation are likely to require treatment,” she added.

Limitations and Next Steps

The findings were limited by several factors including the observational design and lack of detailed patient-level medication data including longitudinal immunosuppression, antibiotic exposures, and azithromycin use for bronchiolitis obliterans syndrome prevention, any of which could influence both NTM isolation and downstream outcomes, Mezochow said.

The researchers also were unable to adjudicate NTM pulmonary disease according to current guideline-based definitions because of the lack of longitudinal radiographic and symptom data, she added. “That said, these diagnostic criteria were developed outside the transplant setting and have not been validated in lung transplant recipients, so their applicability here is uncertain,” she added. “Although we focused on the first posttransplant year, when surveillance bronchoscopy is relatively routine, some residual ascertainment bias is still likely,” she noted.

“Future research should focus on identifying which recipients with NTM isolation are most likely to progress to CLAD or death, understanding the biologic mechanisms linking NTM and allograft injury, and determining whether treatment strategies or immunosuppression modifications can improve outcomes,” said Mezochow. “Ultimately, the goal is to develop a framework that helps clinicians distinguish who may benefit from treatment from those who can be safely observed,” she said.

Added Value for Patient Assessment

The current study addresses major questions in lung transplantation, namely, whether isolation of NTM species in the first year after a lung transplant is a marker of airway vulnerability, structural airway defects, patient frailty, or a true contributor to allograft function and failure, said Jacqueline Burnell, MD, an associate professor of clinical medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, and a specialist in infections in transplant and immunocompromised patients. “This study separated rapidly growing NTM from slow growers to attempt to identify species associated with poor outcomes and provide prognostication,” said Burnell, who was not involved in the study. The association of rapidly growing NTM and poorer outcomes was not surprising, she noted. “Mycobacterium abscessus species, which accounted for the majority of rapidly growing isolates, are thought to be more aggressive and are certainly more challenging to treat,” she said. “The absence of association with CLAD is interesting, as this has been found in other studies looking at NTM infections post-lung transplant,” she added.

The results suggest that rapidly growing NTM should be risk-stratified separately from slow-growing NTM, said Burnell. “Early growth of rapid-growing NTM should prompt careful evaluation and assessment in a multidisciplinary fashion and not be deemed colonization without thorough evaluation,” she said. Routine posttransplant cultures also may have prognostic value in graft failure, she noted.

However, additional research with more granular detail regarding patient characteristics would be useful for risk stratification, said Burnell. “For example, information about pretransplant colonization, type of transplant (single vs double), immunosuppressive regimens, co-infections, and other factors would be useful,” she said. The current study did not address delineation between colonization, transient isolation, and infection, and data on treatment regimens and timing were lacking; therefore, collaborative studies are needed to assess these factors and their relationship to patient outcomes, Burnell noted.

The study was funded by institutional grants from the National Heart, Lung, and Blood Institute. Mezochow and Burnell had no financial conflicts to disclose.