Risk Factors for Nontuberculous Mycobacterial Pulmonary Disease

BackgroundNontuberculous pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at increased risk of developing the disease. Understanding patients at risk is essential to allow for prompt testing and diagnosis and appropriate management to prevent disease progression.Research QuestionWhat are the risk factors for NTM-PD that should prompt a physician to consider NTM testing and diagnosis?Study Design and MethodsElectronic searches of PubMed and EMBASE were conducted in July 2021 for the period 2011-2021. Inclusion criteria were studies of patients with NTM-PD with associated risk factors. Data were extracted and assessed using the Newcastle–Ottawa Scale. Data analysis was conducted using the R-based “meta” package. Only studies that reported association outcomes for cases with NTM-PD compared with control subjects (healthy populations or subjects without NTM-PD) were considered for the meta-analysis.ResultsOf the 9,530 searched publications, 99 met the criteria for the study. Of these, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population and were included in the meta-analysis. Comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD (bronchiectasis [OR, 21.43; 95% CI, 5.90-77.82], history of TB [OR, 12.69; 95% CI, 2.39-67.26], interstitial lung disease [OR, 6.39; 95% CI, 2.65-15.37], COPD [OR, 6.63; 95% CI, 4.57-9.63], and asthma [OR, 4.15; 95% CI, 2.81-6.14]). Other factors noted to be associated with an increased risk of NTM-PD were the use of inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), solid tumors (OR, 4.66; 95% CI, 1.04-20.94) and the presence of pneumonia (OR, 5.54; 95% CI, 2.72-11.26).InterpretationThe greatest risk for NTM-PD is conferred by comorbid respiratory diseases such as bronchiectasis. These findings could help with identification of patient populations at risk for NTM-PD, to drive prompt testing and appropriate initiation of therapy. Nontuberculous pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at increased risk of developing the disease. Understanding patients at risk is essential to allow for prompt testing and diagnosis and appropriate management to prevent disease progression. What are the risk factors for NTM-PD that should prompt a physician to consider NTM testing and diagnosis? Electronic searches of PubMed and EMBASE were conducted in July 2021 for the period 2011-2021. Inclusion criteria were studies of patients with NTM-PD with associated risk factors. Data were extracted and assessed using the Newcastle–Ottawa Scale. Data analysis was conducted using the R-based “meta” package. Only studies that reported association outcomes for cases with NTM-PD compared with control subjects (healthy populations or subjects without NTM-PD) were considered for the meta-analysis. Of the 9,530 searched publications, 99 met the criteria for the study. Of these, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population and were included in the meta-analysis. Comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD (bronchiectasis [OR, 21.43; 95% CI, 5.90-77.82], history of TB [OR, 12.69; 95% CI, 2.39-67.26], interstitial lung disease [OR, 6.39; 95% CI, 2.65-15.37], COPD [OR, 6.63; 95% CI, 4.57-9.63], and asthma [OR, 4.15; 95% CI, 2.81-6.14]). Other factors noted to be associated with an increased risk of NTM-PD were the use of inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), solid tumors (OR, 4.66; 95% CI, 1.04-20.94) and the presence of pneumonia (OR, 5.54; 95% CI, 2.72-11.26). The greatest risk for NTM-PD is conferred by comorbid respiratory diseases such as bronchiectasis. These findings could help with identification of patient populations at risk for NTM-PD, to drive prompt testing and appropriate initiation of therapy. Take-home PointsStudy Question: What are the risk factors for developing NTM-PD?Results: Comorbid respiratory disease, including bronchiectasis, COPD, and history of tuberculosis, was associated with the highest risk for NTM-PD; the use of inhaled corticosteroids, solid tumors, and the presence of pneumonia were also important factors.Interpretation: This is the first study to provide an overview of risk for NTM-PD for a comprehensive set of potential factors. Study Question: What are the risk factors for developing NTM-PD? Results: Comorbid respiratory disease, including bronchiectasis, COPD, and history of tuberculosis, was associated with the highest risk for NTM-PD; the use of inhaled corticosteroids, solid tumors, and the presence of pneumonia were also important factors. Interpretation: This is the first study to provide an overview of risk for NTM-PD for a comprehensive set of potential factors. Nontuberculous mycobacteria (NTM) are ubiquitous in the environment1Hoefsloot W. van Ingen J. Andrejak C. et al.The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study.Eur Respir J. 2013; 42: 1604-1613Crossref PubMed Scopus (570) Google Scholar,2Zweijpfenning S.M.H. Ingen J.V. Hoefsloot W. Geographic distribution of nontuberculous mycobacteria isolated from clinical specimens: a systematic review.Semin Respir Crit Care Med. 2018; 39: 336-342Crossref PubMed Scopus (45) Google Scholar and encompass more than 200 species, which differ in their propensity to cause pulmonary disease (NTM-PD).2Zweijpfenning S.M.H. Ingen J.V. Hoefsloot W. Geographic distribution of nontuberculous mycobacteria isolated from clinical specimens: a systematic review.Semin Respir Crit Care Med. 2018; 39: 336-342Crossref PubMed Scopus (45) Google Scholar NTM-PD is a serious, chronic, rare infectious disease that often presents in people with underlying lung conditions such as bronchiectasis, cystic fibrosis (CF), and COPD.3Cowman S. van Ingen J. Griffith D.E. Loebinger M.R. Non-tuberculous mycobacterial pulmonary disease.Eur Respir J. 2019; 541900250Crossref PubMed Scopus (121) Google Scholar NTM-PD can be a substantial burden for patients, contributing to lung function decline and reduced health-related quality of life, and is associated with significant morbidity and mortality.4Asakura T. Ishii M. Ishii K. et al.Health-related QOL of elderly patients with pulmonary M. avium complex disease in a university hospital.Int J Tuberc Lung Dis. 2018; 22: 695-703Crossref PubMed Scopus (14) Google Scholar, 5Mehta M. Marras T.K. Impaired health-related quality of life in pulmonary nontuberculous mycobacterial disease.Respir Med. 2011; 105: 1718-1725Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 6Park HY, Jeong BH, Chon HR, et al. Lung function decline according to clinical course in nontuberculous mycobacterial lung disease. Chest.;150(6):1222-1232.Google Scholar, 7Diel R. Lipman M. Hoefsloot W. High mortality in patients with Mycobacterium avium complex lung disease: a systematic review.BMC Infect Dis. 2018; 18: 206Crossref PubMed Scopus (84) Google Scholar Incidence rates of NTM-PD are rising, but the disease remains challenging to diagnose and treat.8van Ingen J. Obradovic M. Hassan M. et al.Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex: disease burden, unmet needs, and advances in treatment developments.Expert Rev Respir Med. 2021; 15: 1387-1401Crossref PubMed Scopus (12) Google Scholar Clinical symptoms of NTM-PD are nonspecific and often overlap with those of other underlying respiratory conditions, leading to a high proportion of patients with NTM-PD remaining undiagnosed.9Doyle O.M. van der Laan R. Obradovic M. et al.Identification of potentially undiagnosed patients with nontuberculous mycobacterial lung disease using machine learning applied to primary care data in the UK.Eur Respir J. 2020; 562000045Crossref PubMed Scopus (11) Google Scholar, 10Ringshausen F.C. Ewen R. Multmeier J. et al.Predictive modeling of nontuberculous mycobacterial pulmonary disease epidemiology using German health claims data.Int J Infect Dis. 2021; 104: 398-406Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar, 11Griffith D.E. Aksamit T. Brown-Elliott B.A. et al.An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.Am J Respir Crit Care Med. 2007; 175 (Feb 15): 367-416Crossref PubMed Scopus (4512) Google Scholar Testing for NTM-PD is important to allow for prompt diagnosis and, after this, appropriate management—which should be individualized and may include guideline-based therapy or nonpharmacological treatment such as airway clearance—can be initiated to prevent disease progression.12Wagner D. van Ingen J. Adjemian J. et al.Annual prevalence and treatment estimates of nontuberculous mycobacterial pulmonary disease in Europe: a NTM-NET collaborative study.Eur Respir J. 2014; 44: P1067Google Scholar, 13Park T.Y. Chong S. Jung J.W. et al.Natural course of the nodular bronchiectatic form of Mycobacterium avium complex lung disease: long-term radiologic change without treatment.PLoS One. 2017; 12e0185774Crossref Scopus (15) Google Scholar, 14Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.Eur Respir J. 2020; 562000535Crossref PubMed Scopus (245) Google Scholar Previous data have highlighted that particular groups of patients are at risk of NTM-PD.15Andréjak C. Nielsen R. Thomsen V. et al.Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis.Thorax. 2013; 68: 256-362Crossref PubMed Scopus (252) Google Scholar Testing for NTM-PD is recommended by some societal guidelines when risk factors, clinical symptoms, or suspicious radiological findings are found14Daley C.L. Iaccarino J.M. Lange C. et al.Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.Eur Respir J. 2020; 562000535Crossref PubMed Scopus (245) Google Scholar,16Haworth C.S. Banks J. Capstick T. et al.British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).Thorax. 2017; 72: ii1-ii64Crossref PubMed Scopus (426) Google Scholar; however, no study has provided a comprehensive insight into risk factors for NTM-PD, including underlying comorbidities and patient characteristics. The aim of this current study is to identify risk factors for NTM-PD that can be used to determine which patients are at risk of infection so that prompt and appropriate diagnoses can be made. The systematic literature review has been registered in the International Prospective Register of Systematic Reviews (www.crd.york.ac.uk/prospero; record ID: 347379) and has been conducted in line with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) guidelines.17Moher D. Shamseer L. Clarke M. et al.Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.Syst Rev. 2015; 4: 1Crossref PubMed Scopus (13947) Google Scholar Institutional Review Board approval was not required. All authors determined a search strategy that included both free-text words and medical subject headings. The search string can be found in e-Table 1 and was used to perform searches in PubMed and were in July Inclusion and criteria for are in e-Table were to in between and was used to the of between and the and of the criteria authors C. and the of and and was a of to determine which met criteria for review and by the All authors potentially studies to determine their and the of the were the studies study study study and study groups, and patient disease NTM and patient NTM-PD association with comorbidities respiratory disease, disease, and and NTM-PD association with risk factors and and were into a data was determined of the data M. J. J. R. R. and assessed the quality of study using the a recommended by the D. et al.The for the quality of studies in J. J. et for Systematic Reviews of Scholar The review the criteria of the Of Systematic J. et to risk of in systematic was Full Text Full Text PDF PubMed Scopus Google Scholar Data analysis was conducted by C. and using the R-based “meta” package. was that included of study population risk factors, or association 95% CI, of and association Only studies that reported association outcomes for cases with NTM-PD compared with control subjects (healthy populations or subjects without NTM-PD) were considered for the meta-analysis. that not include a without NTM-PD or not 95% for the risk estimates were not for the meta-analysis. The data or risk were used but data were used when data were not data was using can be as to not be to may to may substantial to All the studies an study and a was a was used in the meta-analysis. The meta-analysis was with the analysis as population and data (OR, HR, or an of 9,530 publications, which after to the of 99 studies e-Table Of the 99 were and were included primary studies and overview of included studies is in e-Table studies reported a analysis of association (OR, HR, or between risk factors and of NTM-PD, of the studies reporting an association for or risk factors, studies data for and risk factors, e-Table the association between use of particular clinical patient and The comorbidities with a association with NTM-PD were COPD history of TB and and were also reporting an association in more than Other clinical and factors an association with NTM-PD included bronchiectasis, (healthy and radiological infection with or and analysis an increased risk of NTM-PD with of the in at Of the publications, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population without NTM or control subjects without NTM-PD) and were included in the meta-analysis C. Nielsen R. Thomsen V. et al.Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis.Thorax. 2013; 68: 256-362Crossref PubMed Scopus (252) Google et al.Nontuberculous mycobacterial pulmonary disease and associated risk factors in 2021; Full Text Full Text PDF PubMed Scopus Google Scholar, factors and care in a primary care population with non-tuberculous mycobacterial disease in the UK.Eur J Infect Dis. 2019; PubMed Scopus (14) Google Scholar, J. of pulmonary nontuberculous mycobacterial in patients with cystic fibrosis in the 2018; 15: PubMed Scopus Google Scholar, Adjemian J. of nontuberculous mycobacterial and associated use with cystic J Respir Crit Care Med. 2013; PubMed Scopus Google Scholar, R. et risk of mycobacterial associated with 2015; PubMed Scopus Google Scholar, R. et of non-tuberculous with cystic 2017; Full Text Full Text PDF PubMed Scopus (12) Google Scholar, L. et between non-tuberculous and mycobacteria in Respir J. 2015; Scholar, D. C. et in the and mycobacterial Infect Dis. 2020; PubMed Scopus Google Scholar, factors and outcomes of nontuberculous mycobacterial disease a study in a Scholar, et of with nontuberculous mycobacterial infection in patients with 2021; Scopus Google Scholar, et between inhaled use and pulmonary nontuberculous mycobacterial 2018; 15: PubMed Scopus Google Scholar, C. et factors for nontuberculous mycobacterial in solid a Infect Dis. 2014; PubMed Scopus Google Scholar, D. W. of nontuberculous mycobacterial lung disease in 2017; Full Text Full Text PDF Google Scholar, M. W. D. Non-tuberculous mycobacterial disease is in patients with fibrosis J Infect Dis. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, L. et of pulmonary non-tuberculous mycobacterial after lung Infect Dis. 18: PubMed Scopus Google Scholar, K. of of nontuberculous mycobacterial pulmonary disease.Eur Respir J. 2021; Scopus Google Scholar, S. T. K. et associated with nontuberculous mycobacterial disease in Med. 2020; PubMed Scopus (12) Google Scholar, T. et are to Mycobacterium avium complex lung disease: Infect Dis. 2019; PubMed Scopus Google Scholar, L. C.S. of nontuberculous mycobacteria (NTM) with cystic fibrosis 15: Full Text Full Text PDF PubMed Scopus Google Scholar, Marras T.K. et potentially undiagnosed nontuberculous mycobacterial lung disease patients with pulmonary disease: of a using claims J Respir Crit Care Med. 2021; Scholar, J. J. et in nontuberculous mycobacteria isolated in from a One. 2014; Scopus Google Scholar, J. S. W. and risk factors of pulmonary nontuberculous mycobacterial in the of 2019; PubMed Scopus Google Scholar, et al.The risk of mycobacterial associated with inhaled Respir J. 2017; PubMed Scopus Google Scholar Of 24 reported HR, reported and the reported or of studies reporting possible risk factors associated with NTM-PD were from the analysis for the meta-analysis that comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD, with from to the association (OR, 21.43; 95% CI, by a history of TB (OR, 12.69; 95% CI, interstitial lung disease (OR, 6.39; 95% CI, COPD (OR, 6.63; 95% CI, and asthma (OR, 4.15; 95% CI, Other factors noted to be associated with an increased risk of NTM-PD were including inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), corticosteroids (OR CI, and other such as or (OR 95% CI, as as treatment for (OR, 95% CI, solid tumors (OR, 4.66; 95% CI, the presence of pneumonia (OR, 5.54; 95% CI, disease (OR, 95% CI, and (OR, 95% CI, e-Table (OR, 95% CI, or high (OR, 95% CI, were associated with factors, and long-term use of for underlying disease, not was as against NTM-PD (OR, 95% CI, e-Table was a risk for with an OR of CI, risk factors for All data are as OR risk risk cystic of interstitial lung treatment risk factors for All data are as OR risk risk cystic of interstitial lung treatment Other or with NTM-PD were for lung function (OR, 95% CI, (OR, 95% CI, disease (OR, 95% CI, (OR, 95% CI, (OR, 95% CI, and infection with (OR, 95% CI, or (OR, 95% CI, The systematic literature review and meta-analysis to identify potential risk factors associated with NTM-PD reported in the literature and to The study data into a and of the of risk factors with The reported risk factors were use of COPD and history of or TB which is considered the risk for was assessed in for the meta-analysis that comorbid respiratory disease is associated with a significant increase in the risk of NTM-PD, with the association for bronchiectasis. 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K. et associated with nontuberculous mycobacterial disease in Med. 2020; PubMed Scopus (12) Google L. C.S. of nontuberculous mycobacteria (NTM) with cystic fibrosis 15: Full Text Full Text PDF PubMed Scopus Google Marras T.K. et potentially undiagnosed nontuberculous mycobacterial lung disease patients with pulmonary disease: of a using claims J Respir Crit Care Med. 2021; Scholar The studies used for the pneumonia analysis also not include data pneumonia and in those in which data were from patients with data to disease were studies in the the of a solid the risk of D. 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