Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms and are opportunistic pathogens seen mostly in patients with impaired systemic immunity or in immunocompetent patients with chronic airway disease such as chronic obstructive pulmonary disease or cystic fibrosis (CF). The recognition of NTM as lung pathogens in immunocompetent hosts is often underappreciated as they cause insidious, subtle, and non-specific symptoms.¹ This is especially true in CF patients with severe bronchiectasis whose airways are chronically infected with co-existing bacteria that inhibit the in vitro growth of NTM.^2–,⁴ A recent large prospective multicentre study that applied vigilant screening and the use of appropriate NTM culture techniques showed that NTM are commonly isolated from the airway secretions of CF patients with an overall prevalence of 13%.⁵ Patients with CF develop NTM diseases restricted to the lung,^5–,⁷ whereas patients with advanced AIDS develop disseminated NTM disease rarely involving the lung.^8,9 This suggests complementary roles for host local lung defence and systemic immune defence against NTM disease.

NTM infections have increasingly been recognised after thoracic organ transplantation^10–,¹⁸ with a prevalence of 1.4–6.5%. Cystic fibrosis is the leading indication for bilateral lung transplantations, comprising 31.5% and 44% of all adult and paediatric bilateral lung transplantations worldwide, respectively.¹⁹ A cohort of patients with end stage CF serves as a unique homogeneous group of high risk lung transplant candidates in which to study the pre-transplant risk factors for the development of post-transplant NTM infection/disease. At the time of transplant surgery the severe bronchiectatic airways harbouring NTM are removed while systemic immunosuppressants are introduced. In addition, CF patients universally receive bilateral lung transplants which reduces the possibility of seeding NTM from native tissues.²⁰ CF lung transplant recipients undergo the abrupt transition from a population with local risk factors for NTM disease to a population with a combination of risk factors including altered systemic immune status and inherent changes in the thorax after surgery.

We have assessed the impact of pre-transplant NTM infection on the development of post-transplant NTM disease in a retrospective study.

METHODS

RESULTS

NTM in end stage CF patients

Twenty nine NTM isolates were cultured from the respiratory specimens of 26 CF lung transplant candidates before transplantation (prevalence rate 19.7%; fig 1⇓ and table 2⇓). The characteristics of these 26 NTM positive patients are compared with those of the 106 NTM negative patients in table 1⇑. There were no differences in age, sex, forced vital capacity (%FVC), forced expiratory volume in 1 second (%FEV₁), body mass index (BMI), or the coexistence of common bacterial pathogens in the CF airway (Pseudomonas aeruginosa, Burkholderia cepacia complex, or Staphylococcus aureus) between the two groups (p>0.2 for all).

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Table 2

 Clinical and microbiological features of patients from whom NTM were isolated before (n = 26) and/or after (n = 20) transplantation

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Figure 1

 Flow diagram showing the patients with CF included in the study based on the presence of absence of NTM isolation before and after transplantation.

The most common NTM species isolated was M avium complex (n = 13, 45%), closely followed by M abscessus (n = 12, 41%; table 2⇑). Other species recovered included M gordonae (n = 2, 7%), M fortuitum (n = 1, 3%), and one isolate was unidentifiable (n = 1, 3%).

Six patients had pre-transplant NTM disease which was restricted to the lungs (patients 1, 2, 3, 8, 9, and 25 in table 2⇑). All except one was due to M abscessus. Two patients were successfully treated, three failed to improve after treatment (patients 1, 3, and 9), and one was unable to tolerate the side effects of treatment (patient 2). The symptoms resolved quickly after treatment, but one of the patients needed long term treatment due to recrudescence of infection when antibiotics were withdrawn.

DISCUSSION

NTM were isolated from patients with end stage CF who were lung transplant candidates and, to a lesser extent, from CF lung transplant recipients, with prevalence rates of 19.7% and 13.7%, respectively. While post-transplant NTM disease caused significant morbidity in a small number of patients (prevalence 3.4%), these patients were successfully treated and the survival of patients with post-transplant NTM (isolation or disease) was not different from those without NTM.

The true prevalence of NTM among end stage CF patients has not previously been determined; in this study we found NTM in approximately one in five patients with end stage CF awaiting lung transplantation. Thus, NTM isolates are more prevalent among end stage CF patients than among a more heterogeneous CF population (n = 986) evaluated in a prospective multicentre study by Olivier et al⁵ (prevalence ∼13%). In both studies the two most common species isolated from CF airways were M avium complex and M abscessus.

Following lung transplantation there have been only four previous case reports of NTM species isolated from the airways of CF recipients in the setting of progressive graft dysfunction. Here we report 20 additional CF lung recipients with post-transplant pulmonary NTM isolates and confirm the broad array of clinical settings in which the isolation of NTM can occur. Moreover, the 13.7% prevalence rate of NTM isolates among our CF patients after transplant is 2–3 times higher than in the general (CF and non-CF) lung transplant population,^15,16 indicating that CF patients are particularly prone to post-transplant NTM infection. We found that the only pre-transplant predictor for post-transplant NTM isolation or disease was pre-transplant NTM isolation, with pre-transplant NTM positive patients five times more likely to culture NTM species and six times more likely to develop NTM disease after lung transplantation than pre-transplant NTM negative patients. The similarity of the NTM species recovered before and after transplantation and the lack of their recovery from donor lungs in our study suggests that recurrence of NTM after transplantation was due to colonisation of the native CF airway above the surgical anastomoses (main stem bronchi, trachea or sinuses). The two patients with M abscessus in their explanted (whole) hilar lymph nodes indicates that other reservoirs of NTM exist beyond the respiratory tract in patients with CF, and these may be potential sources of post-transplant infection if intraoperative contamination occurs.

Pulmonary^{10–13,15,16,18} and extrapulmonary^15–,¹⁷ diseases caused by NTM have increasingly been recognised following thoracic organ transplantation. Without a consensus, the diagnosis of pulmonary NTM disease and its differentiation from colonisation in immunocompromised lung transplant patients represents a significant challenge. Transplant pulmonologists often treat isolates even if there is uncertainty of invasive disease. In this study, with a mean follow up of 4 years after recovery of the first isolate, only five of 146 CF lung recipients (3.4%) developed definite NTM disease, all of which involved the thorax. However, four of the patients from whom NTM had been isolated before transplantation developed NTM disease after surgery (three of whom were infected with M abscessus). Only one patient (<1%) developed disseminated disease. Thus, NTM isolation after transplantation in individuals with CF is common, but rates of invasive disease are low.

Four cases of M abscessus disease have been reported in general lung transplant recipients manifesting as empyema with (n = 1) or without (n = 2)^15,18 mycobacteraemia or graft dysfunction (n = 1),¹³ resulting in death due to ventilatory failure.^18,26 We extended these findings by confirming the particular virulence of M abscessus and its ability to recur after transplantation. Pre-transplant M abscessus culture positive CF patients, regardless of AFB smear positivity, were more likely to develop post-transplant disease than pre-transplant M abscessus culture negative patients. Thus, a recurrent isolation of M abscessus from a CF lung transplant recipient should increase the suspicion of the development of disease until proved otherwise. In addition, we observed two distinct presentations by M abscessus after lung transplantation: early infections that caused empyema or mediastinitis, and late infection in the setting of severe lung graft dysfunction (BOS stage 3) that caused lung abscess. In contrast to a previous report, we did not find that M avium complex was a common cause of post-transplant NTM disease.¹⁵ In the only case of disease associated with M avium complex in our study, co-infection with M szulgai, a known human pathogen,²⁷ may have been exclusively responsible for her deterioration.

These data suggest that the high rate of NTM isolation in CF patients before transplantation results in higher rates of NTM isolation after transplantation but, with the exception of M abscessus, does not increase the rate of NTM disease. While treatment can be challenging, all three cases of M abscessus disease and the one case of M kansasii disease were successfully treated. As a result, the survival of patients with post-transplant NTM isolation or disease was not different from those without. Proactive pre-transplant surveillance for NTM is advocated; the possible benefits from additional intraoperative NTM specific antiseptic practices for these recipients remain unsettled.

This study has potential shortcomings. Retrospective studies can be limited by ascertainment bias, despite our best efforts to review all available paper and electronic records. In addition, we relied on microbiology results over a long time period, so protocols for specimen processing, culture, and identification of NTM may have varied leading us to underestimate the number of cases of isolation and disease. Thirdly, considerable controversy exists over the definitions of isolation, colonisation, infection, and disease which makes it difficult to extrapolate from the non-CF literature and might confound our prevalence statistics. Nonetheless, this is the largest study of NTM in CF patients referred for and following lung transplantation, and our lengthy follow up without the development of disease in cases we defined as “NTM isolation” strengthened our conclusions. Fourthly, as this was a single centre study it was limited by a relatively small number of NTM disease cases and changes in practice over time may have affected the overall results. Lastly, we did not perform molecular genotyping studies to confirm that the cases of M abscessus that occurred early after transplantation were true recurrences rather than new acquisitions. Further study of NTM in patients with CF will be required before treatment recommendations can be made to address NTM positive patients before referral for lung transplantation. In addition, comprehensive studies to assess potential post-transplant risk factors for NTM in both CF and non-CF patients are needed.

In conclusion, NTM are very commonly isolated from the airways of end stage CF lung transplant candidates. CF recipients are at increased risk for NTM isolation and NTM disease after lung transplantation. However, the overall rates of invasive disease are low and the increased risk for post-transplant NTM disease is restricted largely to those with pre-transplant M abscessus isolates. Medical treatment effectively controls NTM disease after lung transplantation, resulting in no attributable mortality. The isolation of M abscessus before transplantation was associated with post-transplant disease and morbidity but did not affect survival. We recommend proactive transplant surveillance for patients with M abscessus isolates, and we await an outcomes analysis from other centres to confirm our findings and help us to understand better the full impact of M abscessus on post-transplant survival. Our findings support the view that isolation of M abscessus from the sputum should be considered a relative but not an absolute contraindication for transplantation.