|Year : 2020 | Volume
| Issue : 1 | Page : 48-52
Outcomes of pulmonary Mycobacterium abscessus infection
William G Flight1, Natasha E Hough1, Stephen J Chapman2
1 Oxford Adult Cystic Fibrosis Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
2 Oxford Adult Cystic Fibrosis Centre, Oxford University Hospitals NHS Foundation Trust; University of Oxford, Oxford, UK
|Date of Submission||01-Apr-2020|
|Date of Acceptance||01-Aug-2020|
|Date of Web Publication||6-Mar-2020|
William G Flight
Oxford Universoty Hospitals NHS Foundation Trust, Oxford, OX3 9DU
Source of Support: None, Conflict of Interest: None
Background: Treatment of Mycobacterium abscessus pulmonary disease (PD) is challenging with frequent side effects and uncertain rates of success. Methods: We performed a retrospective review of all patients at our center with at least one respiratory sample positive for M. abscessus between 2014 and 2019. Electronic health records were reviewed to determine factors associated with M. abscessus infection and clinical outcomes. Results: Thirty-seven patients were identified including 24 with cystic fibrosis (CF), 10 with bronchiectasis, two with chronic obstructive PD (COPD), and one with asthma. American Thoracic Society/Infectious Diseases Society of America criteria for nontuberculous mycobacteria PD were met in 21/37 (56.8%) of cases. Evidence of Aspergillus lung disease was noted in 18 (75.0%) CF patients compared with 3 (23.1%) non-CF patients (P = 0.005). Induction therapy for M. abscessus was given to 22/37 (59.5%) patients (18/24 [75%] with CF and 4/13 [30.8%] without CF). Median duration of induction therapy was 6 weeks (range 3–12). Maintenance antibiotic therapy was prescribed to 17/22 (77.3%) of treated patients. Culture conversion was seen in 15/24 (62.5%) of CF patients compared with 3/13 (23.1%) in the non-CF group (P = 0.034). Culture conversion occurred in 10/22 (45.5%) of treated patients compared with 8/15 (53.3%) untreated patients. Three patients (8.1%) died during follow-up: one with CF and two with COPD. Conclusions: Culture conversion following isolation of M. abscessus from respiratory samples not only is more common in CF than in patients without CF but also frequently occurs spontaneously in both groups. Targeted treatment for M. abscessus did not clearly impact rates of culture conversion.
Keywords: Bronchiectasis, cystic fibrosis, Mycobacterium abscessus, nontuberculous Mycobacterium
|How to cite this article:|
Flight WG, Hough NE, Chapman SJ. Outcomes of pulmonary Mycobacterium abscessus infection. Int J Mycobacteriol 2020;9:48-52
| Introduction|| |
Numerous studies have reported that the prevalence of pulmonary infection with nontuberculous mycobacteria (NTM) has been increasing over recent decades, and is associated with significant risk of mortality.Mycobacterium abscessus complex is a group of rapidly-growing species of NTM with extensive, intrinsic resistance to antimicrobial therapy. M. abscessus accounts for up to 16% of cases in epidemiological studies of NTM-pulmonary disease (NTM-PD) although the prevalence varies according to the geographical location and the particular characteristics of the cohorts studied. M. abscessus accounts for a much greater proportion of cases of pulmonary NTM infection among people with cystic fibrosis (CF), for example, with 39% of cases reported in the US CF Foundation Patient Registry found to be due to M. abscessus.
Treatment of M. abscessus PD is extremely challenging with high rates of treatment failure and relapse.,, Although national and international guidelines have been published on the diagnosis and management of NTM-PD,,, there have been no randomized controlled trials to date of therapy for M. abscessus infection. As a result, the recommendations contained in the current guidelines are based on single-center case series and expert opinion. Treatment of M. abscessus typically involves an induction phase which includes a combination of intravenous antibiotics followed by a prolonged maintenance phase of multiple oral and nebulized antibiotics. Such treatment regimens are associated with considerable side effects and risk serious complications, such as ototoxicity and renal impairment. A further significant challenge is that it is difficult to identify accurately whether a given patient isolating M. abscessus has active NTM-PD requiring therapy or alternatively has simple colonization which does not require treatment.
We reviewed cases of pulmonary infection with M. abscessus among patients attending our center to identify factors associated with successful culture conversion and clearance of M. abscessus. Some data from this study have previously been presented in the abstract form at a scientific conference.
| Methods|| |
We performed a retrospective cohort study to determine outcomes following M. abscessus pulmonary infection. Patients attending our center were included if they provided at least one respiratory sample which was culture positive for M. abscessus between January 2014 and July 2019. Demographic, clinical, and microbiological data were obtained from patients' electronic health records.
Culture conversion was defined according to the British Thoracic Society NTM Guidelines (i.e., three consecutive negative mycobacterial sputum cultures collected over a minimum of 3 months, with the time of conversion being the date of the first of the three negative mycobacterial cultures). Clearance of M. abscessus was defined as ≥6 negative sputum samples over a period of ≥12 months off treatment, or ≥1 negative bronchoalveolar lavage (BAL) sample after at least 12 months off treatment.
The study was registered with the Clinical Governance Department at our institution. Formal research ethics committee approval was not sought as the project was deemed primarily to be a service evaluation to inform future patient care.
Data are presented as mean (standard deviation) or median (range) as appropriate. Categorical variables were compared using Fisher's exact test while continuous variables were analyzed using the Mann–Whitney U-test. Statistical analysis was conducted using GraphPad Prism v. 8 (GraphPad Software, San Diego, USA).
| Results|| |
Thirty-seven patients were identified. All patients had a history of underlying lung disease with 24 (64.9%) having CF, 10 (27.0%) bronchiectasis, 2 (5.4%) chronic obstructive PD (COPD), and 1 (2.7%) asthma. Within the CF group, one patient first isolated M. abscessus following lung transplantation. Baseline demographics of the cohort separated into patients with and without CF are shown in [Table 1].
American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) criteria for NTM-PD were met in 21/37 (56.8%) of cases. Twenty-nine patients (78.4%) had a thoracic computed tomography scan at baseline, and a summary of the reported radiological features in the cohort is shown in [Table 2]. Six patients (16.2%) had a single isolate of M. abscessus only. Initial isolates were smear-positive in 21/37 cases (56.8%) including 13/24 (54.2%) CF patients and 8/13 (61.5%) in the non-CF group. Thirty patients (81.1%) had positive sputum samples only, 3 (8.1%) had both positive sputum and BAL samples, while 4 (10.8%) had positive BAL samples only. Coinfection with other NTM species was common with 13/37 (35.1%) of patients isolating ≥ 1 NTM other than M. abscessus during the study period (Mycobacterium avium complex, n = 10; Mycobacterium fortuitum, n = 2; Mycobacterium gordonae, n = 2; and Mycobacterium triplex, n = 1). A history of isolating NTM other than M. abscessus was more common in patients with CF, affecting 11/24 (45.8%) compared with 2/13 (15.4%) in the non-CF cohort.
|Table 2: Radiological features on baseline thoracic computed tomography scans|
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In vitro antimicrobial susceptibility testing of initial isolates revealed that amikacin had the lowest rates of resistance of the agents tested with 58.6% sensitive, 27.6% intermediately sensitive, and 13.8% resistant. Equivalent values for clarithromycin were 20.0%, 10.0%, and 70.0%. Sensitivity rates for the full panel of antibiotics tested are shown in [Figure 1].
|Figure 1: In vitro antimicrobial sensitivity test results for initial isolates of Mycobacterium abscessus|
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Twenty-two patients (59.5%) received treatment for M. abscessus infection including 18 patients with CF and four patients with other diagnoses. Of the treated patients overall, 19/22 (86.4%) met the ATS/IDSA criteria for NTM-PD. Treated patients received initial induction therapy with a median of two (range 2–3) intravenous antibiotics for a median duration of 6 weeks (range 3–12). Details of induction intravenous antibiotic therapy are given in [Table 3]. An oral macrolide was included alongside intravenous antibiotics in 14/22 cases (azithromycin in 10 and clarithromycin in 4 patients). Maintenance therapy was prescribed in 17/22 (77.3%) of the patients who received induction treatment. Nebulized amikacin as part of maintenance therapy was poorly tolerated and was continued in only 8/22 (36.4%) patients.
|Table 3: Frequency of use of various antibiotic agents in initial induction therapy regimens|
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Overall, 18/37 (48.6%) of the patients achieved culture conversion with a median of 15 (range 4–54) negative respiratory samples. Culture conversion was seen in 15/24 (62.5%) CF patients compared with 3/13 (23.1%) in the non-CF group (P = 0.034). Confirmed clearance of M. abscessus was seen in 9/24 (37.5%) in the CF group and 3/13 (23.1%) of non-CF patients (P = 0.48). Culture conversion and confirmed clearance were seen in 10/22 (45.5%) and 6/22 (27.3%) of the patients who received treatment for M. abscessus compared with 8/15 (53.3%) and 6/15 (40%) among untreated patients. There was no significant difference in time from first M. abscessus isolate to initiation of treatment among those with culture conversion compared with those patients failing to convert (median of 88.5 days [range 14–946] versus 69 days [49–979], respectively; P = 0.60).
During the follow-up period, three (8.1%) patients died at a median of 29 months (range 11–41) following first isolation of M. abscessus. Of the patients that died, one had CF and two had COPD.
| Discussion|| |
M. abscessus infection continues to pose a considerable challenge in the management of CF, bronchiectasis, and other chronic lung diseases. Our data add to the currently very limited literature and further highlight the difficulty in making informed treatment decisions when faced with new M. abscessus infection. We have identified significant differences in the demographics and outcomes between patients with CF and M. abscessus infection compared to those with bronchiectasis or obstructive airway disease. As with a number of other case series, we found that spontaneous clearance of M. abscessus was common which raises important questions as to when combination therapy is needed.,
In our cohort, patients with CF were significantly more likely to have coexisting Aspergillus lung disease than patients without CF. A link between NTM infection and Aspergillus lung disease including allergic bronchopulmonary aspergillosis (ABPA) has been noted in previous studies although the pathophysiology of this connection is poorly understood.,,, Whether the risk of Aspergillus-NTM coinfection is truly increased in CF compared to non-CF bronchiectasis, a group also at risk of ABPA, requires further investigation. Similarly, the tendency we have observed for patients with CF and M. abscessus infection to have cultured other species of NTM is not currently explained. This finding suggests that there is a particular phenotype of CF that predisposes to mycobacterial infection. Potential factors contributing to this may include non-CFTR modifier genes, environmental exposures, and maintenance therapies for CF. Additional work in larger cohorts is required to unravel these associations.
A further important finding from our study is the high rates of spontaneous culture conversion and subsequent clearance of M. abscessus infection. There was no significant difference in the proportion of patients clearing M. abscessus or reaching culture conversion among those receiving antibiotic treatment compared with the untreated patients. This mirrors findings from other cohorts of M. abscessus infection, for instance, the work of Tippett et al. which found that over two-thirds of cases cleared M. abscessus spontaneously. Jhun et al. also found that the initiation of antimicrobial therapy in NTM-PD had no significant impact on prognosis. A novel finding in our study is that culture conversion was significantly more likely among patients with CF than in the non-CF group. It is also of interest that of the four non-CF patients in our cohort who received treatment, none reached culture conversion despite aggressive therapy. One possible explanation for this observation is a degree of selection bias with only those patients with more severe disease or rapid progression offered active treatment and therefore having a lower chance of clearance of M. abscessus.
Although the international guidelines have been published on the management of NTM-PD,,, there have been no randomized controlled trials of initial antibiotic treatment for M. abscessus infection. Recommendations from the CF Foundation and European CF Society for the treatment of M. abscessus in CF are largely drawn from single-center case series in Asia and the United States in non-CF cohorts.,, It is unclear how applicable these studies truly are to the CF population specifically and more generally to people with M. abscessus infection in a UK or European setting. The use of population-based registries, already well developed in the field of CF and more recently introduced in non-CF bronchiectasis, represents a promising means of enriching the quality of the NTM-PD literature with regard to outcomes.
In addition to considering the likelihood of successful treatment, the current NTM-PD guidelines recommend that the decision on whether and when to initiate treatment should take into account of a variety of additional factors. Important considerations include patient-specific factors such as severity and rate of disease progression as well as the presence of any significant comorbidities. Additional factors of importance include the radiological appearances as well as microbiological factors, such as the frequency of positive cultures and smear positivity. An additional important consideration, especially in the context CF, is the likelihood of future lung transplantation. Although recent guidelines are at pains to state that a history of NTM-PD should not preclude assessment for lung transplantation,, a considerable number of studies have reported adverse outcomes following transplantation in patients with preexisting M. abscessus infection.,,, As a result, our practice has been to adopt a lower threshold for starting M. abscessus treatment in people with CF in whom lung transplantation is likely to be an option in future in the hope of early eradication of the infection. This is likely to explain why not all patients receiving targeted treatment for M. abscessus in our cohort fully met the ATS-IDSA criteria for NTM-PD. Whether such a strategy is justified given the high rate of spontaneous clearance of M. abscessus we have observed remains unclear, particularly as two recent small case series from the USA have reported equivalent posttransplant outcomes in patients with M. abscessus infection to those without.,
Our study is subject to all the usual limitations of retrospective analyses. Although it is larger than many case series of M. abscessus infection, our cohort remains small and is drawn from a single center which may limit its applicability to other settings. In addition, the study covered a period in which our clinical service was in transition from paper-based medical notes to an electronic health record. As a result, the data available electronically were incomplete, particularly with regard to lung function and height, so it was not possible to include reliable data on forced expiratory volume in 1 s percentage-predicted or body mass index. Despite these limitations, our study adds important data to a field with a paucity of clinical information to guide treatment decisions.
| Conclusion|| |
We have shown that in patients with M. abscessus infection, there are important differences between patients with and without CF. We have shown that spontaneous culture conversion is common and that targeted antibiotic treatment of M. abscessus at our center was not clearly associated with improved outcomes. There is a pressing need for future large-scale randomized controlled trials and registry studies to determine the true efficacy and costs of M. abscessus therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]