Objectives: Data are limited regarding the clinical significance of nontuberculous mycobacteria pulmonary infections among lung transplant recipients. We investigated the incidence and characteristics of pulmonary nontuberculous mycobacteria infection in our lung transplant patient population.
Materials and Methods: We obtained data of the patients who underwent lung transplant in our center from January 1997 to March 2019.
Results: Of 690 patients, nontuberculous mycobacteria were identified in 58 patients (8.4%) over a median follow-up of 3 years. Types of species were as follows: Mycobacterium simiae (n = 24), avium complex (n = 12), abscessus (n = 9), fortuitum (n = 6), chelonae (n = 2), szulgai (n = 1), kansasii (n = 1), lentiflavum (n = 1), and undefined mycobacteria (n = 2). When we compared infections in the early versus late period posttransplant (before and after 6 months), infections with Mycobacterium simiae (16 vs 8 incidents) and Mycobacterium fortuitum (5 vs 1 incident) were more often observed within the early period, whereas most Mycobacterium abscessus (7 vs 1 incident) and Mycobacterium avium complex (9 vs 3 incidents) were observed in the later period. The median forced expiratory volume in 1 second over time did not differ significantly between patients with and without nontuberculous mycobacteria infection (P = .29). Nontuberculous mycobacteria acquisition was significantly associated with decreased survival (relative risk of 2.41, 95% CI, 1.70-3.43; P < .001).
Conclusions: The nontuberculous mycobacteria species isolated varied according to the time elapsed since transplant. Among lung transplant recipients, nontuberculous mycobacteria infection was associated with increased mortality but not with lung dysfunction.
Key words : Nontuberculous mycobacteria, Prognosis, Pulmonary function
Nontuberculous mycobacteria (NTM) are ubiquitous in the environment; more than 190 species have
been identified.1 Over the past few years, trends of increasing prevalence of NTM pulmonary infection have been reported in the general population.2-4 Solid-organ transplant recipients have an increased risk of infection, including NTM pulmonary infection, due to suppressed cell-mediated immunity.5-7 Although these infections are less common than other infections in the transplant recipient population, NTM is a source of significant morbidity and mortality. This is partly because of delayed diagnosis, which frequently results from difficulties in disease recognition.5-7
Among solid-organ transplant recipients, lung transplant is associated with the highest risk of NTM pulmonary infections.6,7 Nonetheless, published data regarding clinical and prognostic implications of NTM pulmonary infection occurring after lung transplant are scarce.8-13 We therefore investigated the occurrence and species of NTM pulmonary infections following lung transplant and assessed the associations between NTM infection and pulmonary function and long-term survival.
Materials and Methods
Study population and design
This retrospective study was conducted at the Rabin Medical Center, the sole center for lung transplantation in Israel. Figure 1 presents the study design. From January 1997 to March 2019, 713 lung transplantations were performed. We identified 699 patients according to the following eligibility criteria: age ?18 years and regular follow-up. Of eligible patients, NTM pulmonary infections were diagnosed in 67 patients. We excluded 9 patients due to the development of NTM before transplant (n = 7) or infection with Mycobacterium gordonae (n = 1) or Mycobacterium tuberculosis (n = 1). Of the 690 patients included in the cohort, 58 (8.4%) developed NTM pulmonary infections after lung transplant.
The study was carried out in accordance with the Declaration of Helsinki and was approved by our Institutional Ethics Committee.
Lung transplant recipients are routinely evaluated in the ambulatory clinic of our institution at 2 and 4 weeks posttransplant and then every 2 months, on average, thereafter. More frequent visits are scheduled when a clinical need arises. Follow-up includes a detailed medical interview, physical examination, chest radiograph, and pulmonary function test. At our center, all pulmonary function test measurements are performed on the ZAN 530 system (Zan Messgeräte GmbH). The measurement technique and reference values are calculated according to European clinical practice guidelines.14,15 Chest computed tomography (CT) scans are routinely performed at 6 and 12 months posttransplant and then annually.
All bronchoscopic examinations included in this study were performed at our pulmonary institute. Three scheduled bronchoscopies with bronchoalveolar lavage (BAL) are performed routinely at 1 and 2 weeks and at 1 month posttransplant. Additional bronchoscopic examinations are performed according to clinical need and in patients with clinical deterioration (ie, worsening dyspnea and pulmonary function tests), abnormal findings on chest CT, unresolved pneumonia, lobar atelectasis, suspected lung rejection, or bronchial stenosis.
Bronchoalveolar lavage procedure
To prevent contamination by upper airway flora, the BAL trap used to collect the specimen is connected to the suction channel of the bronchoscope only after the bronchoscope traverses the vocal cords. The bronchoscope is wedged into a subsegmental bronchus (usually toward the place of infiltrate, when present), and 3 aliquots of sterile saline (50 mL each) are instilled and aspirated.
Bronchoalveolar lavage samples are plated on blood, Chocolate, and MacConkey agars. Specimens are analyzed for mycobacteria using Ziehl-Neelsen stain and cultured on Lowenstein medium and in Mycobacterium growth indicator tubes (Bactec MGIT 960, Becton Dickinson). Mycobacterium growth indicator tubes and Lowenstein-Jensen cultures are discarded after 6 to 8 weeks. We use the GenoType Mycobacterium DNA strip assay (Hain Lifescience GmbH) to detect and identify Mycobacterium species obtained from positive liquid and solid mycobacterial cultures. Quantitative NTM cultures are not performed in our center.
Definition of nontuberculous mycobacteria pulmonary infection and disease
Nontuberculous mycobacteria pulmonary infection is diagnosed based on 1 positive culture from a BAL sample or 2 positive sputum cultures.3,14 During the study period, NTM pulmonary disease was defined using the following criteria: (1) presence of clinical pulmonary symptoms, (2) evidence of nodular or cavitary opacities on chest radiograph or multifocal bronchiectasis with multiple small nodules on CT, and (3) microbiologic confirmation of NTM pulmonary infection.3,16
Nontuberculous mycobacteria treatment
In general, we do not treat NTM pulmonary infections; however, patients are closely observed for development of NTM pulmonary disease. Treatment of NTM pulmonary disease is performed according to published guidelines.3,16 Treatment consists of multiple antibiotic medications, selected according to NTM species, sensitivity, expected toxicities, and interactions with immunosuppressive agents and other medications. The duration of treatment depends on the clinical course of the NTM pulmonary disease and usually lasts at least 1 year following repeat negative NTM cultures.
Data were obtained from electronic medical record database systems that integrate medical information from all hospitals in Israel. These data included the following variables: age, sex, single or double lung transplant, diagnosis that led to transplant, the type of Mycobacterium species, and the forced expiratory volume in 1 second (FEV1) over the duration of the study period. At the end of the follow-up period, vital status or date of death were ascertained from hospital records and the registry of the Israeli Ministry of Internal Affairs.
Descriptive data are expressed as means and SD or numbers (percentages) of presented cases. We used the chi-square test for categorical variables and the t test for continuous variables. P < .05 was considered statistically significant. We compared FEV1 values between patients with and without NTM pulmonary infection using a linear mixed model with random effects. A Cox proportional hazards model with time-dependent covariates was used for analysis of the association between NTM pulmonary infection and survival. Statistical analysis was performed using SAS software, version 9.2 (SAS Institute Inc).
Table 1 presents the baseline characteristics of the study population (n = 690). Mean age of the study population was 53.9 ± 13.2 years; 63.1% were males. Pulmonary fibrosis and emphysema were the most common etiologies for lung transplant. Nontuberculous mycobacteria isolates were identified on BAL cultures in 58 patients (8.4%). Demographic characteristics, transplant types, and the etiologies for the lung transplantation were comparable between the patients with and without NTM pulmonary infections.
Spectrum of nontuberculous mycobacteria pulmonary infections
During a median follow-up period of 3 years, the following NTM species were identified among 58 patients: M. simiae (n = 24), M. avium complex (n = 12), M. abscessus (n = 9), M. fortuitum (n = 6), unidentified mycobacteria (n = 2), M. chelonae (n = 2), M. szulgai (n = 1), M. kansasii (n = 1), and M. lentiflavum (n = 1). Figure 2 illustrates the distributions of NTM species in the early period versus the late period after transplant (before and after a 6-month median point). In the early period posttransplant, cultures were more often positive for M. simiae (16 vs 8 patients) and M. fortuitum (5 vs 1 patient). In the late period posttransplant (later than 6 months), M. abscessus (8 vs 1 patient) and M. avium complex (9 vs 3) were more commonly identified.
Of the 58 patients with positive NTM cultures, 51 had positive BAL cultures for NTM species that did not meet diagnostic criteria for NTM pulmonary disease. The remaining 7 patients met the diagnostic criteria for NTM pulmonary disease. Causes of NTM disease were by M. abscessus in 5 patients and M. avium complex in 2 patients.
Pulmonary lung function
During the follow-up period, mean FEV1 did not differ significantly between patients with and without NTM isolates (P = .29; Figure 3).
During the study period, 393 of the lung transplant patients died (56.9%). The mortality rates were higher among those with NTM pulmonary infection, that is, in 34/51 (67%) with NTM versus in 357/632 (57%) without NTM. Of the 7 patients with NTM pulmonary disease, 5 survived and 2 died. On multivariate analysis, NTM acquisition (infection or disease) after lung transplant, as a time-dependent variable, was significantly associated with increased mortality (relative risk of 2.41, 95% CI, 1.70-3.43; P < .001).
This study reported the isolation of culture-positive NTM in 8.4% of lung transplant recipients. This is within the range of incidence of NTM isolates after lung transplant reported in other studies of 3.3% to 22.4%.8-12 Discrepancies between studies in the prevalence of NTM isolates may be explained by differences in the median follow-up periods, which ranged from 97 to 1205 days.8-12 The variance in incidence of NTM isolates among lung transplant recipients may also be attributed to the varied prevalence of pulmonary NTM infection across geographic locations.3,13 Even within Israel, a broad spectrum of prevalence of NTM infections has been reported, with higher rates in humid coastal cities and lower rates in the dry mountainous area.17
Among our study patients, half the NTM pulmonary infections were identified during the first 6 months posttransplant. This is within the range of 3 to 9 months as the median time for the development of NTM pulmonary infection posttransplant reported by previous studies.8-10 Several reasons may explain the early occurrence of NTM pulmonary infection posttransplant. First, chronic pulmonary NTM colonization before lung transplant could be underrecognized. Second, NTM pulmonary infection might be vertically transferred from the lung donor. Third, a nosocomial source of NTM infection is possible.6,18 Finally, lung transplant recipients are more heavily immunosuppressed in the first than in the subsequent months following transplant, and thus patients can be presumably more vulnerable to NTM pulmonary infections.6,7 Of note, Huang and colleagues8 reported that single lung transplants were associated with increased incidence of posttransplant NTM infection. They proposed that the native abnormal lung may harbor NTM at the time of transplant and facilitate NTM infection posttransplant.8 However, in our cohort, we did not find a significant difference between patients with unilateral and bilateral lung transplant procedures with regard to occurrence of NTM infections within the first 6 months posttransplant.
The most common NTM species isolated in our study were M. simiae (41.4%), which is generally considered nonpathogenic, and M. avium complex (20.7%), which is generally considered pathogenic. Diversity in the spectrum of NTM species among lung transplant recipients has been previously reported.8-11 Our results concur with other studies that identified M. avium complex as one of the common NTM species among lung transplant recipients.8-11 In contrast, M. abscessus was identified as the most prevalent isolate in 2 studies9,11 and M. simiae8 and M. fortuitum10 were the most prevalent in 1 study each. Our finding of M. simiae prominence corroborates other studies conducted in Israel that identified this as the most common NTM species among patients with cystic fibrosis17 and bronchiectasis.19
We reported different distributions of NTM species isolated within 6 months and at more than 6 months posttransplant. Specifically, isolates of M. simiae and M. fortuitum were more often identified early, within 6 months of transplant, whereas M. abscessus and M. avium complex were more often isolated at a later date. Moreover, M. simiae and M. fortuitum are considered less virulent and generally colonizers,3,16 whereas M. abscessus and M. avium complex are generally associated with NTM pulmonary disease. With a longer time elapsed since transplant, the cumulative effect of the immunosuppressive drug regimen more likely increased the risk of pulmonary infection with more virulent NTM species. The clinical significance of the prevalence of various NTM species at different lapses of time following lung transplant should be investigated in larger patient populations.
Interestingly, among lung transplant recipients with NTM pulmonary acquisition, the decline in FEV1 over the study period was not significantly greater than among patients without NTM infection. We did not find studies that investigated an association of NTM infection with lung function in lung transplant recipients. In their study of non-lung transplant patients, Park and colleagues20 reported a significant decline in lung function over time among those with NTM pulmonary disease. The decline in lung function was greater among patients who did not respond to treatment for NTM pulmonary infection than among those who were successfully treated. Notably, most of the patients in that study had NTM pulmonary disease, whereas most of our patients with NTM colonization did not develop NTM pulmonary disease. Thus, it appears likely that the structural damage from NTM colonization, if any, does not substantially impair lung function.
Another important finding of the current study is the association of NTM pulmonary acquisition with poor long-term survival. Three studies did not find a significant association of NTM pulmonary infection with mortality in similar patient populations.9-11 However, as in the present study, Huang and colleagues8 and Friedman and colleagues13 reported an association of posttransplant NTM pulmonary infection with a higher risk of mortality. Several explanations are possible for the discrepancy between our findings and others. First, in the previous reports, the number of patients with NTM pulmonary infections was relatively small, ranging from 33 to 53,9-11 which may have impacted the statistical comparison. Second, the possibility of bias arises due to the time-dependent development of NTM pulmonary infection among lung transplant recipients. Thus, those who survived in the first months posttransplant were more likely to be infected with NTM over time. To mitigate this possible bias, we analyzed the association of NTM infection with long-term survival using a Cox proportional hazards model with time-dependent covariates. The underlying mechanisms for the association between posttransplant NTM pulmonary infection and decreased survival are not clear. For some lung transplant recipients, the development of NTM pulmonary infection might be related to severe immunosuppression, which may increase the mortality risk from non-NTM infections.8 In addition, NTM pulmonary infection may be a marker of more severe lung damage, which could lead to poor outcome. Associations have been reported of NTM pulmonary infections with pulmonary damage,3,16 chronic lung rejection,11 and bronchial posttransplant complications.8 Nonetheless, we did not find a significant association between NTM pulmonary acquisition and impaired lung function.
Limitations of the present study include its retrospective single-center design, which represents 1 geographical region. Additionally, the number of patients with NTM pulmonary infections was relatively small and may have affected statistical power for comparisons of some relevant data. Notwithstanding, our study represents one of the largest investigations that have been conducted to date on lung transplant recipients with NTM pulmonary infection.
Nontuberculous mycobacteria pulmonary infections are not uncommon following lung transplant. Although most species identified do not cause NTM pulmonary disease, especially in the first 6 months posttransplant, the risk for NTM disease increases with longer time elapsed since transplant. Although NTM pulmonary acquisition was not found to be significantly associated with decreased pulmonary function, it was associated with increased mortality.
Volume : 19
Issue : 10
Pages : 1076 - 1081
DOI : 10.6002/ect.2021.0177
From the 1Pulmonary Institute, Rabin Medical Center, Petah Tikva; the 2Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv; and the 3Department of Internal Medicine F, Yitzhak Shamir (Assaf Harofeh) Medical Center, Zerifin, Israel
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Shimon Izhakian, Pulmonary Institute, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski St., Petach Tikva 49100, Israel
Phone: +972 3 9377221
Figure 1. Flowchart Presenting the Study Design
Table 1. Baseline Characteristics of Lung Transplant Recipients With and Without Nontuberculous Mycobacteria
Figure 2. Spectrum of Nontuberculous Mycobacteria Species in the Early and Late Posttransplant Periods According to 6-Month Median Cut-off
Figure 3. Mean Values of Forced Expiratory Volume in 1 Second in Lung Transplant Recipients With and Without Nontuberculous Mycobacteria Pulmonary Infections (P = .29)