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Who, When, With What and For How Long? Management of Nontuberculous Mycobacteria in Lung Transplantation

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Eileen K Maziarz, MD
Duke University Medical Center
Department of Medicine, Division of Infectious Diseases and International Health
Durham, North Carolina, USA

A 68 year-old patient with pulmonary fibrosis, who underwent single lung transplant, is found to have MycobacteriuM abscessus isolated (smear negative) from the 1-month surveillance bronchoscopy. Post-transplant course has been without notable complications. He has no symptoms and pulmonary function tests continue to improve. Exam reveals stable dry crackles on examination of native lung, clear examination on the allograft side and a well-healed thoracotomy incision. The remaining pre- and post-transplant respiratory cultures are otherwise negative. No rejection was identified on transbronchial biopsies coincident with M abscessus isolation (AFB special stains were negative) and explant histopathology was consistent with usual interstitial pneumonia (UIP) without evidence of granulomatous inflammation involving the lung or explanted lymph nodes. A chest CT without contrast reveals a small effusion, slightly decreased from prior post-operative films, and a calcified upper lobe nodule on the allograft side; review of the native lung reveals stable diffuse reticular opacities and honeycombing consistent with known UIP.

How would you characterize this patient and how do you proceed? Treat? Monitor closely? Does NTM positivity without symptoms post-transplant merit considerations of treatment earlier than in other scenarios? Does the particular species matter?

Infection remains a leading cause of both early and late morbidity among lung transplant recipients. While bacterial, viral and fungal infections have established associations with allograft dysfunction, the impact of mycobacteria on lung allograft function is less well understood. Nontuberculous mycobacteria (NTM) are ubiquitous environmental organisms with variable potential to cause human infection, ranging from asymptomatic colonization to invasive clinical disease. Clinically significant NTM pulmonary disease is mediated by complex interactions between the host and pathogen, including recognized risk factors of structural lung disease and immune dysfunction (both systemic and local). For this reason, lung transplant recipients represent a population at unique risk for NTM infections and complications compared to other solid organ transplant recipients.

There are conflicting data on the outcome of NTM infections among lung transplant recipients, which have important implications for candidate selection and management.

NTMs have been isolated with increased frequency among lung transplant candidates and recipients over recent years, likely reflecting both increased prevalence and improved diagnostic and surveillance techniques [3, 11]. Single center estimates of pre-transplant NTM prevalence vary but have been reported to be around 3% [7,8], without distinction between colonization and disease. Within certain cohorts, however, NTM prevalence is higher, with up to 19.7% of CF patients awaiting transplantation affected [1,12]. Mycobacterium avium complex (MAC) and MycobacteriuM abscessus are the most commonly isolated species in the US, with other species including M chelonae, M fortuitum, and M kansasii accounting for other clinically significant isolates [1,3,11]. Compared to MAC, M abscessus is more likely to be repeatedly isolated and associated with pulmonary function decline [3].

Among lung transplant recipients, post-transplant NTM infection can be acquired in several ways: contamination at the time of transplantation; reactivation of disease from colonized proximal airways or retained lymphatic reservoirs; donor-derived infection; and late-onset environmental acquisition. NTM prevalence following lung transplantation is highly center-dependent, ranging from 1.4%-22.4% [1,6,7,8]. This variation is likely explained by lack of a clear distinction between colonization and disease, geographic distribution of centers and center-specific surveillance protocols. Estimates of post-transplant NTM disease, however, are considerably lower, ranging from 2.5%-4.4% [1,6,8]. Pre-transplant NTM isolation increases the risk of post-transplant NTM isolation [1,12], but only among patients with M abscessus has NTM isolation prior to transplantation been associated with development of post-transplant disease [1,6]. M abscessus accounts for a disproportionate amount of post-transplant NTM disease and has a unique predilection for pleural space and soft-tissue infection that is frequently disseminated and extremely challenging to treat [4,6,8,13]; identification of this pathogen post-transplant warrants heightened attention. On average, post-transplant NTM disease is late in onset (~ 9.5 months post-transplant) and is often preceded by a period of asymptomatic colonization [2,6,8,9]. Several centers have reported that episodic isolation of NTMs is common following lung transplantation and is not associated with clinical deterioration or meaningful impact on allograft function or survival [1,7,8,9,12]. In contrast, both NTM colonization and disease were found to be associated with (though not causative of) increased risk of death even after controlling for single lung transplant status and bronchiolitis obliterans syndrome (BOS) in at least one analysis [6]. This group observed a non-significant trend toward increased risk of BOS among the NTM group [6].

A few certainties exist in the murky waters of NTM infection following lung transplantation. While the ATS/IDSA guidelines provide a framework for management, there are unique aspects to consider in this population [5]. First, the required treatment involves multiple agents for a prolonged duration (i.e 6-9 months), with well-recognized drug interactions with immunosuppressive agents, and issues of tolerance and long-term toxicities of therapy must be balanced with anticipated benefits [4,9]. In the case of rapid growers such as M abscessus and M chelonae, in vitro susceptibility should be performed to guide therapy. Second, careful surveillance of patients both prior to and following transplant can help identify at-risk patients and allow for close monitoring and aggressive up-front therapy in high-risk patients, when warranted. Management decisions for patients colonized with NTMs prior to transplant require close collaboration between experts in pulmonary, surgery and infectious diseases to optimize approach and timing/decision for treatment. Not every patient with NTMs isolated following lung transplantation requires treatment and careful surveillance can allow for unnecessary antibiotic exposure without untoward effects [8,9]. Finally, treatment of concomitant pathogens is important given the recognition of non-NTM infection as a frequent cause of death in these patients [6].

A number of unanswered questions remain, however. There is no consensus on the optimal management of patients colonized with NTMs prior to transplant and many experts consider a course of therapy prior to and through transplantation in most cases, particularly for MAC and M abscessus. Whether or not to treat the asymptomatic patient with repeated isolation of the same NTM species following lung transplant is an area of uncertainty as well. Isolation of M abscessus and other rapid growers should prompt a directed evaluation inclusive of high-resolution chest CT and evaluation for skin and soft-tissue infection when deciding on an optimal management strategy. Finally, management of the colonized patient undergoing augmented immune suppression for treatment of rejection has not been rigorously evaluated. Ultimately a multicenter approach to understanding the impact of and optimal approach to NTM infections in lung transplantation can best answer these very important questions.

The patient's M abscessus isolate was sent for in vitro susceptibility testing and plans were made for repeat bronchoscopy and bronchoalveolar lavage (BAL) from both native lung and allograft to assess for repeated growth. Course was complicated by Klebsiella pneumoniae surgical site infection requiring operative debridement (AFB cultures negative). Repeat imaging revealed increase in the size of pleural effusion and basilar tree-in-bud opacities on allograft side. A chest tube was placed and the patient was placed on therapy with inhaled Amikacin, Azithromycin, Imipenem, and Tigecycline based on results of susceptibility testing, pending results of pleural fluid and repeat BAL studies, which again demonstrated growth of M abscessus, as did AFB blood cultures. Following drainage of pleural effusion and initiation of directed therapy, blood and BAL cultures remain negative at 16 months follow up. The patient completed a 6-month course of mycobacterial therapy and has had no further infectious complications.

Disclosure Statement: The author has no conflicts of interest to report.


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