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Research Article| Volume 161, 105847, January 2020

Predictors of radiographic progression for NTM–pulmonary disease diagnosed by bronchoscopy

  • Hung-Ling Huang
    Affiliations
    Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
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  • Meng-Rui Lee
    Affiliations
    Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan

    Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    College of Medicine, National Taiwan University, Taipei, Taiwan
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  • Chia-Jung Liu
    Affiliations
    Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan

    Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
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  • Meng-Hsuan Cheng
    Affiliations
    Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Departments of Respiratory Therapy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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  • Po-Liang Lu
    Affiliations
    Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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  • Author Footnotes
    1 The two authors contributed equally.
    Jann-Yuan Wang
    Correspondence
    Corresponding author. Department of Internal Medicine, National Taiwan University Hospital, #7, Zhongshan South Rd., Zhongzheng Dist., Taipei, 10002, Taiwan.
    Footnotes
    1 The two authors contributed equally.
    Affiliations
    Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

    College of Medicine, National Taiwan University, Taipei, Taiwan
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  • Author Footnotes
    1 The two authors contributed equally.
    Inn-Wen Chong
    Footnotes
    1 The two authors contributed equally.
    Affiliations
    Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

    Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Departments of Respiratory Therapy, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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  • Author Footnotes
    1 The two authors contributed equally.
Open ArchivePublished:November 23, 2019DOI:https://doi.org/10.1016/j.rmed.2019.105847

      Highlights

      • Risk of radiographic progression in 2 years was 28% in bronchoscopy-diagnosed NTM-PD.
      • Male sex, low BMI, ICS use and index sample AFS ≥2 + were poor prognostic factors.
      • Half with ongoing radiographic progression died within 2 years if left untreated.

      Abstract

      Objectives

      A single isolate of nontuberculous mycobacterium (NTM) from bronchoscopic samples satisfies the microbiological criterion for diagnosing NTM-pulmonary disease (PD). Studies investigating patients with NTM-PD and multiple culture-negative sputum samples but culture-positive bronchoscopic samples are lacking. We investigated the clinical characteristics, outcome, and predictors of radiographic progression in this special population.

      Methods

      Patients with negative NTM culture from ≥2 expectorated sputum samples within the 3 months prior to bronchoscopy diagnosis of NTM-PD between 2009 and 2017 were included. Patient characteristics and clinical course were described. Predictors for radiographic progression of NTM-PD within 2 years were analysed by using multivariate logistic regression.

      Results

      Among 66 patients with bronchoscopy-diagnosed NTM-PD, radiographic progression occurred within 2 years in 17 (26%). Of the 60 patients not initially treated, radiographic progression occurred in 17 (28%). Among them, 10 never received treatment, with 6 deteriorating and 3 dying. Of the 6 and 7 patients who received treatment immediately after NTM-PD diagnosis and after radiographic progression, respectively, none had further radiographic progression. The independent predictors of radiographic progression were male sex, body mass index <18.5 kg/m2, use of inhaled corticosteroids, and acid-fast smear grade ≥2 of index bronchoscopic samples.

      Conclusions

      Among patients with bronchoscopy-diagnosed NTM-PD, one fourth experienced radiographic progression within 2 years. The risk was even higher in those with the aforementioned predictors, immediate treatment or close monitoring is recommended. For others, conservative management by regular microbiological monitoring for sputum samples and image follow-up may be the optimal choice.

      Keywords

      1. Introduction

      The prevalence of pulmonary disease (PD) caused by nontuberculous mycobacteria (NTM) is increasing worldwide, and prompt diagnosis and timely intervention of NTM-PD should be considered when patients encounter clinical deterioration. According to the current statements of the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) published in 2007 [
      • Griffith D.E.
      • Aksamit T.
      • Brown-Elliott B.A.
      • Catanzaro A.
      • Daley C.
      • Gordin F.
      • Holland S.M.
      • Horsburgh R.
      • Huitt G.
      • Iademarco M.F.
      • Iseman M.
      • Olivier K.
      • Ruoss S.
      • von Reyn C.F.
      • Wallace Jr., R.J.
      • Winthrop K.
      An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.
      ] and the British Thoracic Society (BTS) guidelines published in 2017 [
      • Haworth C.S.
      • Banks J.
      • Capstick T.
      • Fisher A.J.
      • Gorsuch T.
      • Laurenson I.F.
      • Leitch A.
      • Loebinger M.R.
      • Milburn H.J.
      • Nightingale M.
      • Ormerod P.
      • Shingadia D.
      • Smith D.
      • Whitehead N.
      • Wilson R.
      • Floto R.A.
      British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).
      ], diagnosis of NTM-PD should be made on the basis of microbiological evidence from respiratory specimens in conjunction with appropriate clinical and radiographic findings. For patients with little or even no sputum and those with persistent culture-negative sputum, bronchoscopy can facilitate the diagnosis of NTM-PD [
      • Huang J.H.
      • Kao P.N.
      • Adi V.
      • Ruoss S.J.
      Mycobacterium avium-intracellulare pulmonary infection in HIV-negative patients without preexisting lung disease: diagnostic and management limitations.
      ,
      • Tanaka E.
      • Amitani R.
      • Niimi A.
      • Suzuki K.
      • Murayama T.
      • Kuze F.
      Yield of computed tomography and bronchoscopy for the diagnosis of Mycobacterium avium complex pulmonary disease.
      ,
      • Sugihara E.
      • Hirota N.
      • Niizeki T.
      • Tanaka R.
      • Nagafuchi M.
      • Koyanagi T.
      • Ono N.
      • Rikimaru T.
      • Aizawa H.
      Usefulness of bronchial lavage for the diagnosis of pulmonary disease caused by Mycobacterium avium-intracellulare complex (MAC) infection.
      ], and a single NTM isolate from bronchoscopic samples can satisfy the microbiological criterion required for a diagnosis.
      Data are limited regarding the prognosis of patients with culture-negative sputum samples and with NTM-PD that is diagnosed only after culture of bronchoscopic samples. A prospective study conducted by Kim et al. in South Korea demonstrated variations in the outcomes of patients with NTM-PD that was diagnosed through bronchoscopy [
      • Kim H.J.
      • Lee J.H.
      • Yoon S.H.
      • Kim S.A.
      • Kim M.S.
      • Choi S.M.
      • Lee J.
      • Lee C.H.
      • Han S.K.
      • Yim J.J.
      Nontuberculous mycobacterial pulmonary disease diagnosed by two methods: a prospective cohort study.
      ]. Those with little sputum (n = 47) tended to have a poorer outcome in terms of culture conversion and disease progression than did those with no sputum (n = 21). However, the size of each group was too small to clearly illustrate the clinical characteristics of the groups. Furthermore, the optimal time at which to initiate antimicrobial treatment for these patients remains uncertain. The decision to begin the lengthy and potentially toxic treatment for NTM-PD should be carefully made [
      • Huang J.H.
      • Kao P.N.
      • Adi V.
      • Ruoss S.J.
      Mycobacterium avium-intracellulare pulmonary infection in HIV-negative patients without preexisting lung disease: diagnostic and management limitations.
      ].
      We therefore conducted this multicentre, retrospective cohort study of patients with negative mycobacterial culture in at least 2 sputum samples and with NTM-PD diagnosed through bronchoscopic culture. The objectives of this study are to investigate the risk and predictors of radiographic progression.

      2. Material and methods

      2.1 Study design

      The present retrospective cohort study was conducted in 2 tertiary referral medical centres, namely National Taiwan University Hospital (NTUH) and Kaohsiung Medical University Hospital (KMUH), and their 4 branch hospitals. The study was approved by the medical centres’ institutional review boards (NTUH REC 201508017RIND and KMUH IRB-E −20150063), which waived the informed consent requirement because data used in this retrospective study had been deidentified.

      2.2 Patient selection

      For the period from June 2009 to June 2017, patients meeting the following criteria were identified from the mycobacteriology database: 1) ≥2 sputum samples provided within a 3-month period; 2) all sputum samples culture negative for NTM; 3) bronchoscopy within the 12 months following collection of the first sputum sample; and 4) NTM isolated from bronchoscopic samples. Among the patients, those with the following conditions were excluded: 1) any clinical samples yielding M. tuberculosis complex; 2) duration of follow-up being less than 2 years after bronchoscopy; and 3) clinical and radiographic findings incompatible with a diagnosis of NTM-PD [
      • Griffith D.E.
      • Aksamit T.
      • Brown-Elliott B.A.
      • Catanzaro A.
      • Daley C.
      • Gordin F.
      • Holland S.M.
      • Horsburgh R.
      • Huitt G.
      • Iademarco M.F.
      • Iseman M.
      • Olivier K.
      • Ruoss S.
      • von Reyn C.F.
      • Wallace Jr., R.J.
      • Winthrop K.
      An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.
      ,
      • Haworth C.S.
      • Banks J.
      • Capstick T.
      • Fisher A.J.
      • Gorsuch T.
      • Laurenson I.F.
      • Leitch A.
      • Loebinger M.R.
      • Milburn H.J.
      • Nightingale M.
      • Ormerod P.
      • Shingadia D.
      • Smith D.
      • Whitehead N.
      • Wilson R.
      • Floto R.A.
      British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).
      ].
      Acid-fast smear (AFS), mycobacterial cultures, and NTM species identification were performed as described in a previous study [
      • Huang H.L.
      • Cheng M.H.
      • Lu P.L.
      • Shu C.C.
      • Wang J.Y.
      • Wang J.T.
      • Chong I.W.
      • Lee L.N.
      Epidemiology and predictors of NTM pulmonary infection in Taiwan - a retrospective, Five-year multicenter study.
      ]. The patients were followed until radiographic progression of NTM-PD, death, or the censor date, which was 1 July 2019.

      2.3 Study outcome

      The primary outcome was radiographic progression of NTM-PD within 2 years, defined as an increase in the radiographic score and assessed through chest radiography and computed tomography (CT; preferred). The secondary outcome was treatment response and mortality due to NTM-PD within 2 years.

      2.4 Data collection and measurements

      Medical records, images, and mycobacteriology results were reviewed. We recorded clinical characteristics from medical records, including age, sex, body mass index (BMI), smoking status, pulmonary and systemic comorbidities, structural lung disease, image findings, results of AFS and mycobacterial culture, clinical course, and treatment. Structural lung disease included previous history of pulmonary tuberculosis, chronic obstructive pulmonary disease (COPD), and bronchiectasis.
      Two pulmonologists interpreted chest radiographs and CT scans. The patterns were categorised as fibrocavitary (FC), nodular bronchiectatic (NB), or other [
      • Hong S.J.
      • Kim T.J.
      • Lee J.H.
      • Park J.S.
      Nontuberculous mycobacterial pulmonary disease mimicking lung cancer: clinicoradiologic features and diagnostic implications.
      ]. The extent of pulmonary lesions was noted as either focal or multifocal. In addition, the radiographic score was used to assess the severity of pulmonary lesions [
      • Snider G.L.
      • Doctor L.
      • Demas T.A.
      • Shaw A.R.
      Obstructive airway disease in patients with treated pulmonary tuberculosis.
      ]. Briefly, each lung was divided into 3 areas. Each area was noted on a four-point scale of 0–3 for the extent of infiltration, with a maximum score of 18 for the most extensive involvement.

      2.5 Statistical analysis

      Numerical variables are presented as the mean ± standard deviation and were compared using independent-samples t tests. Categorical variables are expressed as number (percentage) and were compared using the chi-squared test or Fisher's exact test, as appropriate.
      Multivariate logistic regression was used to identify independent factors associated with radiographic progression of NTM-PD. Variables with a p value of less than 0.1 in the univariate analysis were entered into the multivariate analysis with forward stepwise regression. Adjusted odds ratios (aORs) with 95% confidence intervals and p values were calculated. Statistical significance was set at p < 0.05 (two-sided). All statistical analyses were performed using IBM SPSS version 20.0 (IBM, Armonk, NY, USA).

      3. Results

      3.1 Study population

      Fig. 1 presents a flowchart of patient selection and enrolment. From June 2009 to June 2017, there were 97,865 cases in the microbiological databases of 6 hospitals in which patients provided ≥2 expectorated sputum samples within a 3-month interval. After selection, a total of 66 cases of NTM-PD diagnosed through bronchoscopy were included for further analysis.
      Fig. 1
      Fig. 1Flowchart of case selection.
      Abbreviation: BS, bronchoscopic; MTB, Mycobacterium tuberculosis; NTM, nontuberculous mycobacteria.a 20 died within 6 months. The cause of death was bacterial sepsis complicated with acute respiratory failure in 9 (Pseudomonas aeruginosa: 4; Klebsiella pneumoniae: 2; Escherichia coli: 2; methicillin-resistant Staphylococcus aureus: 1), pneumonia in 7 (Acinetobacter baumannii: 4; Pseudomonas aeruginosa: 1; Enterobacteriaceae: 1; Streptococcus pneumoniae: 1), and 1 each for intra-abdominal infection without positive culture, neutropenic fever after chemotherapy for lung cancer, lung cancer progression, and acute myocardial infarction. Another 8 cases were excluded due to no microbiology or imaging follow-up.b In these 4 cases, bronchoscopy was performed under the suspicion of lung cancer.c Other patterns included consolidations in 8 cases and RLL atelectasis with pleural effusion in 1.

      3.2 Clinical characteristics

      The mean age of the enrolled patients was 63.4 ± 17.9 years, and 47% of the patients were men. The most common pulmonary and systemic comorbidity was bronchiectasis (47%) and diabetic mellitus (21%), respectively; 68% had structural lung disease. NB was the most common radiographic pattern (72%). The most common NTM species was MAC (55%), followed by M. kansasii (MK; 18%) and M. abscessus complex (17%). The FC radiographic pattern was more common in the male patients than in the female patients (23% [7 in 31] vs. 6% [2 in 35]; p = 0.046). Structural lung disease (77% [24 in 31] vs. 60% [21 in 35]; p = 0.133) and MK-PD (26% [8 in 31] vs. 11% [4 in 35]; p = 0.131) were more common, yet insignificantly, in the male patients. During the follow-up, radiographic progression occurred in 17 (26%) cases (Fig. 1 and Table 1). Compared with the patients without radiographic progression, those with radiographic progression were more likely to be male (71% vs. 39%; p = 0.024); to be malnourished (41% vs. 16%; p = 0.035); to have structural lung disease (88% vs. 61%; p = 0.035); and to be inhaled corticosteroid (ICS) users (29% vs. 4%; p = 0.010). Radiographically, multifocal involvement was more likely in the cases with radiographic progression (100% vs. 80%; p = 0.043; Table 2). The AFS grade of bronchoscopic samples was more likely to be ≥ 2 in cases with radiographic progression (29% vs. 8%; p = 0.025).
      Table 1Clinical characteristics of the 66 patients with bronchoscopy-diagnosed nontuberculous mycobacterial pulmonary disease, stratified by radiological progression.
      Progression (n = 17)No progression (n = 49)p-value
      Age (year)64.4 ± 16.363.1 ± 16.30.937
      Male sex12 (71%)19 (39%)0.024
      Body-mass index (kg/m2)18.9 ± 6.018.4 ± 6.90.424
       < 18.57 (41%)8 (16%)0.035
      Smoking status0.264
       Never smoker7 (41%)32 (65%)
       Ex-smoker7 (41%)10 (21%)
       Current smoker3 (18%)7 (14%)
      Pulmonary comorbidity16 (94%)36 (74%)0.073
       Structural lung disease
      Structural lung disease includes old pulmonary tuberculosis, bronchiectasis, and COPD.
      15 (88%)30 (61%)0.035
        Bronchiectasis10 (59%)21 (43%)0.256
        History of pulmonary tuberculosis4 (24%)8 (16%)0.507
        COPD3 (18%)6 (12%)0.576
       Asthma3 (18%)5 (10%)0.418
       Lung cancer4 (24%)5 (10%)0.168
      Systemic Comorbidity
       Diabetes mellitus5 (29%)9 (18%)0.337
       Extra-pulmonary cancer3
      1 had hepatocellular carcinoma, 1 lymphoma, and 1 gastric cancer.
      (18%)
      7
      3 had breast cancer, 2 nasopharyngeal carcinoma, 1 colon cancer, and 1 endometrial carcinoma.
      (14%)
      0.739
       Chronic kidney disease, stage 3–52 (12%)4 (8%)0.656
       Liver cirrhosis2 (12%)1 (2%)0.097
       Autoimmune disease03
      2 had Sicca syndrome, and 1 had rheumatic arthritis.
      (6%)
      0.563
       Old cerebrovascular accidence1 (6%)3 (6%)0.971
       Steroid user
      Steroid use was defined as consumption of steroids with an equivalent dose of prednisolone equal to or greater than 100 mg within the 6 months prior to index bronchoscopy.
      3 (18%)8 (16%)>0.999
       ICS user
      ICS use was defined as continuous use of ICSs for at least 1 year prior to index bronchoscopy. In the radiographic progression group, 3 received ICS due to COPD and 2 due to asthma. In the nonprogression group, 1 received ICS due to COPD-asthma overlap syndrome and 1 due to asthma.
      5 (29%)2 (4%)0.010
       Ventilator dependent1 (6%)2 (4%)>0.999
      Initial symptom
       Sputum12 (71%)39 (80%)0.445
       Cough13 (76%)35 (71%)0.688
       Hemoptysis8 (47%)14 (29%)0.164
       Dyspnea7 (41%)12 (25%)0.190
       Weight loss3 (18%)4 (8%)0.362
      Abbreviation: COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid.
      Data are the number (percentage) or mean ± standard deviation.
      a Structural lung disease includes old pulmonary tuberculosis, bronchiectasis, and COPD.
      b 1 had hepatocellular carcinoma, 1 lymphoma, and 1 gastric cancer.
      c 3 had breast cancer, 2 nasopharyngeal carcinoma, 1 colon cancer, and 1 endometrial carcinoma.
      d 2 had Sicca syndrome, and 1 had rheumatic arthritis.
      e Steroid use was defined as consumption of steroids with an equivalent dose of prednisolone equal to or greater than 100 mg within the 6 months prior to index bronchoscopy.
      f ICS use was defined as continuous use of ICSs for at least 1 year prior to index bronchoscopy. In the radiographic progression group, 3 received ICS due to COPD and 2 due to asthma. In the nonprogression group, 1 received ICS due to COPD-asthma overlap syndrome and 1 due to asthma.
      Table 2Initial radiographic findings and microbiological results of the 66 patients with bronchoscopy-diagnosed nontuberculous mycobacterial pulmonary disease, stratified by radiological progression.
      Progression (n = 17)No progression (n = 49)p-value
      Initial radiographic finding
       Predominant pattern
        Fibrocavitory4 (24%)5 (10%)0.220
        Nodular bronchiectasis12 (71%)36 (74%)0.818
        Others
      Other patterns included consolidations in 8 cases and atelectasis with pleural effusion at the right lung in 1.
      1 (6%)8 (16%)0.301
      Multifocal involvement17 (100%)39 (80%)0.043
      Radiographic score6.4 ± 2.55.5 ± 2.20.212
      Microbiology
      No. of sputum samples before bronchoscopy4.0 ± 1.43.0 ± 1.00.001
       Bronchoscopic sample AFS grade ≥25 (29%)4 (8%)0.025
       NTM species
        M. avium intracellular complex9 (53%)27 (55%)0.877
        M. kansasii5 (29%)7 (14%)0.164
        M. abscessus3 (18%)8 (16%)>0.999
        M. gordonae04 (8%)0.565
        M. fortuitum02 (4%)>0.999
       Unidentified species01 (2%)>0.999
      Abbreviation: AFS, acid-fast smear; NTM, nontuberculous mycobacteria.
      Data are number (percentage) or mean ± standard deviation.
      a Other patterns included consolidations in 8 cases and atelectasis with pleural effusion at the right lung in 1.

      3.3 Risk factors for radiographic progression

      The results of univariate logistical regression for predictors of radiographic progression are displayed in Table 3 (left panel). Multivariate analysis revealed 4 independent predictors of radiographic progression: male sex (aOR 4.60 [1.01–20.90]), BMI < 18.5 kg/m2 (aOR 6.15 [1.38–27.35]), ICS use (aOR 9.84 [1.47–65.98]), and initial bronchoscopic sample AFS grade ≥ 2 (aOR 6.86 [1.16–40.71]; Table 3, right panel).
      Table 3Univariate and multivariate logistical regression analysis for potential predictors of radiographic progression of bronchoscopy-diagnosed nontuberculous mycobacterial pulmonary disease.
      VariablesUnivariate analysisMultivariate analysis
      Variables with a p value of less than 0.1 in the univariate analysis were then entered into the multivariate logistic regression analysis with forward stepwise regression.
      Crude OR (95% CI)p valueAdjusted OR (95% CI)p value
      Age (years)1.05 (0.97–1.04)0.783
      Male sex3.79 (1.15–12.47)0.0284.60 (1.01–20.90)0.048
      BMI < 18.5 (kg/m2)3.59 (1.05–12.24)0.0416.15 (1.38–27.35)0.017
      Cough1.30 (0.36–4.68)0.688
      Sputum0.62 (0.18–2.15)0.448
      Dyspnea2.16 (0.67–6.92)0.195
      Hemoptysis2.22 (0.71–6.92)0.168
      Structural lung disease4.75 (0.98–23.14)0.054
      COPD1.54 (0.34–6.96)0.578
      History of pulmonary TB1.58 (0.41–6.10)0.509
      Bronchiectasis1.91 (0.62–5.83)0.259
      Lung cancer2.71 (0.63–11.58)0.179
      Diabetes mellitus1.85 (0.52–6.59)0.341
      CKD, stage 3–51.50 (0.25–9.03)0.658
      Inhaled corticosteroid user9.79 (1.69–56.81)0.0119.84 (1.47–65.98)0.019
      Systemic corticosteroid use1.00 (0.23–4.28)>0.999
      Initial radiographic score1.16 (0.92–1.48)0.213
      Nodular bronchiectatic pattern0.87 (0.26–2.94)0.818
      Fibrocavitary pattern2.71 (0.63–11.58)0.179
      Radiographic score1.16 (0.92–1.48)0.213
      Bronchoscopic sample AFS ≥24.69 (1.09–20.20)0.0386.86 (1.16–40.71)0.034
      MAC0.92 (0.30–2.77)0.877
      M. abscessus1.10 (0.26–4.72)0.900
      M. kansasii2.50 (0.67–9.31)0.172
      Abbreviation: AFS, acid-fast smear; BMI, body-mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; MAC, Mycobacterium avium complex; NTM, nontuberculous mycobacterium; TB, tuberculosis.
      a Variables with a p value of less than 0.1 in the univariate analysis were then entered into the multivariate logistic regression analysis with forward stepwise regression.

      3.4 Clinical course, treatment, and outcome

      Of the 17 (26% of 66) patients who experienced radiographic progression within the 2 years from the index date, the median time to progression was 10.9 months (Table 4); 11 (65%) cases of radiographic progression occurred within the first year. The radiographic progression rate was 29% (17 in 59) if excluding the seven patients with pulmonary disease caused by the two and unidentified NTM species.
      Table 4Clinical course and outcome of the 66 patients with bronchoscopy-diagnosed nontuberculous mycobacterial pulmonary disease, stratified by radiological progression.
      Progression (n = 17)No progression (n = 49)p-value
      Time to radiologic progression (months)10.8 [6.1–13.5]<0.001
      Final Radiographic score9.3 ± 4.35.1 ± 2.0<0.001
      Follow-up sputum study within 2 years
      Number of samples5.6 ± 4.92.9 ± 2.50.007
      Positive for same NTM species8 (47%)5 (10%)<0.001
      Presence of other NTM species2
      M. abscessus was obtained from 1 patient whose initial bronchoscopic sample was culture positive for M. kansasii. In the other patient whose initial bronchoscopic sample was culture positive for M. avium complex (MAC), a photochromogen was isolated during follow-up.
      (12%)
      2
      M. fortuitum was obtained from 1 patient whose initial bronchoscopic sample was culture positive for MAC. In the other patient whose initial bronchoscopic sample contained M. abscessus, MAC was isolated during follow-up.
      (4%)
      0.273
      Mortality within 2 years3
      One patient died of MAC-PD at 11 months after the index date. He did not receive anti-MAC treatment due to old age (78 years). Another patient received anti-M. kansasii treatment but this was discontinued 10 days later due to intolerance. She died of M. kansasii-PD at 13 months after the index date. The remaining patient died of lung cancer at 1 year after the index date.
      (18%)
      1
      This patient died of lung cancer at 17 months after the index date.
      (2%)
      0.050
      Abbreviation: NTM-PD, nontuberculous mycobacterial pulmonary disease.
      Data are the number (percentage) or median [Q1-Q3].
      a M. abscessus was obtained from 1 patient whose initial bronchoscopic sample was culture positive for M. kansasii. In the other patient whose initial bronchoscopic sample was culture positive for M. avium complex (MAC), a photochromogen was isolated during follow-up.
      b M. fortuitum was obtained from 1 patient whose initial bronchoscopic sample was culture positive for MAC. In the other patient whose initial bronchoscopic sample contained M. abscessus, MAC was isolated during follow-up.
      c One patient died of MAC-PD at 11 months after the index date. He did not receive anti-MAC treatment due to old age (78 years). Another patient received anti-M. kansasii treatment but this was discontinued 10 days later due to intolerance. She died of M. kansasii-PD at 13 months after the index date. The remaining patient died of lung cancer at 1 year after the index date.
      d This patient died of lung cancer at 17 months after the index date.
      Over the 2-year follow-up, the number of sputum samples obtained was significantly higher in cases with radiographic progression than those without (5.6 ± 4.9 vs 2.9 ± 2.5, p = 0.007; Table 3). NTM was isolated in follow-up sputum samples from 17 patients, with the same NTM species being discovered as that isolated from bronchoscopic samples in 13 cases and different NTM species being identified in 4 cases. Compare to those without same NTM species isolated from follow-up sputum, those with the same NTM species were more likely to have a BMI <18.5 (46% vs 17%, p = 0.024), more structural lung disease (92% vs. 62%, p = 0.037) and chronic kidney disease, stage 3–5 (23% vs 6%, p = 0.050). Fibrocavitory pattern (39% vs. 8%, p = 0.004) with more extensive involvement (77% vs. 45%, p = 0.041) at initial radiographic examination, AFS grade ≥2 (39% vs. 8%, p = 0.004) and isolation of M. kansassi (39% vs. 13%, p = 0.034) from initial bronchoscopic sample were also associated with isolation of same NTM species in follow-up sputum (Supplementary Table 1). In addition, isolation of the same NTM species from follow-up sputum was more common in the radiographic progression group than in the other group (47% vs. 10%, p < 0.001).
      Six patients received treatment for NTM-PD immediately after bronchoscopic samples indicated NTM (Fig. 2). Among them, 4 had improvement in pulmonary lesions and none experienced radiographic progression. Among the 60 cases in which treatment was not begun immediately after bronchoscopic samples yielded NTM, radiographic progression occurred in 17 (28%).
      Fig. 2
      Fig. 2Clinical course of the 66 patients with bronchoscopy-diagnosed nontuberculous mycobacterial pulmonary disease.
      Abbreviation: BS, bronchoscopic; NTM, nontuberculous mycobacteria.
      The mortality rate within 2 years was higher in the patients with radiographic progression than in those without (3 [18%] vs. 1 [2%], p = 0.050), and none received anti-NTM therapy (Table 4).

      4. Discussion

      This multicentre cohort study had 2 major findings. First, radiographic progression occurred within 2 years in one quarter of the patients with NTM-PD diagnosed through bronchoscopy. Second, risk factors for radiographic progression were male sex, BMI <18.5 kg/m2, initial bronchoscopic sample AFS grade ≥2, and ICS use.
      Because of the indolent clinical course of NTM-PD, not every patient who meets the diagnostic criteria of NTM-PD requires immediate antimicrobial therapy [
      • Griffith D.E.
      • Aksamit T.
      • Brown-Elliott B.A.
      • Catanzaro A.
      • Daley C.
      • Gordin F.
      • Holland S.M.
      • Horsburgh R.
      • Huitt G.
      • Iademarco M.F.
      • Iseman M.
      • Olivier K.
      • Ruoss S.
      • von Reyn C.F.
      • Wallace Jr., R.J.
      • Winthrop K.
      An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases.
      ,
      • Haworth C.S.
      • Banks J.
      • Capstick T.
      • Fisher A.J.
      • Gorsuch T.
      • Laurenson I.F.
      • Leitch A.
      • Loebinger M.R.
      • Milburn H.J.
      • Nightingale M.
      • Ormerod P.
      • Shingadia D.
      • Smith D.
      • Whitehead N.
      • Wilson R.
      • Floto R.A.
      British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).
      ]. The current study demonstrated that the 2-year radiographic progression rate of untreated NTM-PD diagnosed through bronchoscopy (28%) was lower than that of either in MAC-PD [
      • Hayashi M.
      • Takayanagi N.
      • Kanauchi T.
      • Miyahara Y.
      • Yanagisawa T.
      • Sugita Y.
      Prognostic factors of 634 HIV-negative patients with Mycobacterium avium complex lung disease.
      ,
      • Hwang J.A.
      • Kim S.
      • Jo K.W.
      • Shim T.S.
      Natural history of Mycobacterium avium complex lung disease in untreated patients with stable course.
      ,
      • Pan S.W.
      • Shu C.C.
      • Feng J.Y.
      • Wang J.Y.
      • Chan Y.J.
      • Yu C.J.
      • Su W.J.
      Microbiological persistence in patients with Mycobacterium avium complex lung disease: the predictors and the impact on radiographic progression.
      ] or M. abscessus-PD [
      • Lee M.R.
      • Keng L.T.
      • Shu C.C.
      • Lee S.W.
      • Lee C.H.
      • Wang J.Y.
      • Lee L.N.
      • Yu C.J.
      • Yang P.C.
      Risk factors for Mycobacterium chelonae-abscessus pulmonary disease persistence and deterioration.
      ,
      • Kim S.J.
      • Park J.
      • Lee H.
      • Lee Y.J.
      • Park J.S.
      • Cho Y.J.
      • Yoon H.I.
      • Lee C.T.
      • Lee J.H.
      Risk factors for deterioration of nodular bronchiectatic Mycobacterium avium complex lung disease.
      ,
      • Jeon K.
      • Kwon O.J.
      • Lee N.Y.
      • Kim B.J.
      • Kook Y.H.
      • Lee S.H.
      • Park Y.K.
      • Kim C.K.
      • Koh W.J.
      Antibiotic treatment of Mycobacterium abscessus lung disease: a retrospective analysis of 65 patients.
      ] diagnosed using expectorated sputum samples, with 35%–50% and 40%–60% deterioration if untreated within 3 years, respectively. The low progression rate in the current study was probably due to the culture negativity of the initial expectorated sputum samples, implying a lower mycobacterial burden [
      • Griffith D.E.
      Nontuberculous Mycobacterial Disease: A Comprehensive Approach to Diagnosis and Management.
      ]. Therefore, regular monitoring rather than immediate anti-NTM treatment may be an appropriate option.
      To date, several studies have explored the predictors of clinical and radiological deterioration in patients with NTM-PD diagnosed using expectorated sputum samples. In a study including 57 patients with MAC-PD, risk factors for radiographic progression were old age, slenderness, positive sputum smear for acid-fast bacilli, and cavitation [
      • Yamazaki Y.
      • Kubo K.
      • Takamizawa A.
      • Yamamoto H.
      • Honda T.
      • Sone S.
      Markers indicating deterioration of pulmonary Mycobacterium avium-intracellulare infection.
      ]. The results of 2 studies of NB MAC-PD conducted in South Korea and Japan suggest that radiographic progression tends to occur in patients with malnutrition, old age, and extensive lung involvement [
      • Kim S.J.
      • Park J.
      • Lee H.
      • Lee Y.J.
      • Park J.S.
      • Cho Y.J.
      • Yoon H.I.
      • Lee C.T.
      • Lee J.H.
      Risk factors for deterioration of nodular bronchiectatic Mycobacterium avium complex lung disease.
      ,
      • Kitada S.
      • Uenami T.
      • Yoshimura K.
      • Tateishi Y.
      • Miki K.
      • Miki M.
      • Hashimoto H.
      • Fujikawa T.
      • Mori M.
      • Matsuura K.
      • Kuroyama M.
      • Maekura R.
      Long-term radiographic outcome of nodular bronchiectatic Mycobacterium avium complex pulmonary disease.
      ]. Regarding M. abscessus-PD, some genetic determinants of its virulence have been widely studied [
      • Park J.
      • Cho J.
      • Lee C.H.
      • Han S.K.
      • Yim J.J.
      Progression and treatment outcomes of lung disease caused by Mycobacterium abscessus and Mycobacterium massiliense.
      ]. In addition to subspecies, patients with cavitation, multiple lung involvement, and old age have been reported as predictors for M. abscessus-PD progression [
      • Park J.
      • Cho J.
      • Lee C.H.
      • Han S.K.
      • Yim J.J.
      Progression and treatment outcomes of lung disease caused by Mycobacterium abscessus and Mycobacterium massiliense.
      ,
      • Nagano H.
      • Amitani R.
      • Okamoto N.
      • Yoshida M.
      • Taki M.
      • Hanaoka K.
      • Nakamura Y.
      • Yoshimura C.
      • Nishizaka Y.
      [A clinical study of pulmonary Mycobacterium abscessus infection].
      ,
      • Shin S.J.
      • Choi G.E.
      • Cho S.N.
      • Woo S.Y.
      • Jeong B.H.
      • Jeon K.
      • Koh W.J.
      Mycobacterial genotypes are associated with clinical manifestation and progression of lung disease caused by Mycobacterium abscessus and Mycobacterium massiliense.
      ]. In agreement with other reports, the current study demonstrated that malnutrition is associated with radiographic deterioration. Poor leptin–adiponectin regulation in lean patients has been demonstrated to alter the immune modulation of T-cell response and increase the susceptibility of the patient to inflammation that causes lung injury [
      • Kartalija M.
      • Ovrutsky A.R.
      • Bryan C.L.
      • Pott G.B.
      • Fantuzzi G.
      • Thomas J.
      • Strand M.J.
      • Bai X.
      • Ramamoorthy P.
      • Rothman M.S.
      • Nagabhushanam V.
      • McDermott M.
      • Levin A.R.
      • Frazer-Abel A.
      • Giclas P.C.
      • Korner J.
      • Iseman M.D.
      • Shapiro L.
      • Chan E.D.
      Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes.
      ,
      • Fantuzzi G.
      Adipose tissue, adipokines, and inflammation.
      ].
      As noted in patients with tuberculosis, AFS positivity implies a high mycobacterial load and is associated with severe disease [
      • Kang H.K.
      • Jeong B.H.
      • Lee H.
      • Park H.Y.
      • Jeon K.
      • Huh H.J.
      • Ki C.S.
      • Lee N.Y.
      • Koh W.J.
      Clinical significance of smear positivity for acid-fast bacilli after >/=5 months of treatment in patients with drug-susceptible pulmonary tuberculosis.
      ,
      • Perrin F.M.
      • Woodward N.
      • Phillips P.P.
      • McHugh T.D.
      • Nunn A.J.
      • Lipman M.C.
      • Gillespie S.H.
      Radiological cavitation, sputum mycobacterial load and treatment response in pulmonary tuberculosis.
      ]. In addition, high-grade sputum AFS positivity (≥3) was associated with radiographic progression within 1 year in a study enrolling 221 patients with MK-PD in Taiwan [
      • Liu C.J.
      • Huang H.L.
      • Cheng M.H.
      • Lu P.L.
      • Shu C.C.
      • Wang J.Y.
      • Chong I.W.
      Outcome of patients with and poor prognostic factors for Mycobacterium kansasii-pulmonary disease.
      ]. In agreement with these reports, the current study demonstrated that an AFS grade ≥2 of index bronchoscopic samples was significantly associated with subsequent disease progression.
      The finding of this study that male sex is an independent predictor of radiographic progression is interesting. A nationwide population-based study conducted in Denmark revealed that male sex was associated with poorer long-term prognosis of NTM-PD [
      • Andrejak C.
      • Thomsen V.O.
      • Johansen I.S.
      • Riis A.
      • Benfield T.L.
      • Duhaut P.
      • Sorensen H.T.
      • Lescure F.X.
      • Thomsen R.W.
      Nontuberculous pulmonary mycobacteriosis in Denmark: incidence and prognostic factors.
      ]. In another study conducted in Japan, male patients with MAC-PD had a higher 5-year mortality rate than their female counterparts [
      • Hayashi M.
      • Takayanagi N.
      • Kanauchi T.
      • Miyahara Y.
      • Yanagisawa T.
      • Sugita Y.
      Prognostic factors of 634 HIV-negative patients with Mycobacterium avium complex lung disease.
      ]. In addition, male patients were more likely than female patients to have FC lesions and a history of cigarette smoking with more pulmonary comorbidities [
      • Griffith D.E.
      Nontuberculous Mycobacterial Disease: A Comprehensive Approach to Diagnosis and Management.
      ]. The presence of FC lesions has been demonstrated to be a poor prognostic factor for MK-PD [
      • Liu C.J.
      • Huang H.L.
      • Cheng M.H.
      • Lu P.L.
      • Shu C.C.
      • Wang J.Y.
      • Chong I.W.
      Outcome of patients with and poor prognostic factors for Mycobacterium kansasii-pulmonary disease.
      ] and MAC-PD [
      • Kim S.J.
      • Park J.
      • Lee H.
      • Lee Y.J.
      • Park J.S.
      • Cho Y.J.
      • Yoon H.I.
      • Lee C.T.
      • Lee J.H.
      Risk factors for deterioration of nodular bronchiectatic Mycobacterium avium complex lung disease.
      ]. In the current study, a significantly higher prevalence of FC disease and nonsignificantly higher prevalence of structural lung disease and MK-PD were noted in the male patients. MK is considered one of the most virulent NTM species and has a radiographic progression rate and mortality rate within 1 year of 64% and 28%, respectively [
      • Liu C.J.
      • Huang H.L.
      • Cheng M.H.
      • Lu P.L.
      • Shu C.C.
      • Wang J.Y.
      • Chong I.W.
      Outcome of patients with and poor prognostic factors for Mycobacterium kansasii-pulmonary disease.
      ].
      The present study revealed that ICS use within the 1 year prior to diagnosis of NTM-PD was associated with subsequent radiographic progression. Many concerns have been raised that ICS can alter pulmonary immunity by suppressing multiple cytokine mediators of the host response to intracellular pathogens [
      • Patterson C.M.
      • Morrison R.L.
      • D'Souza A.
      • Teng X.S.
      • Happel K.I.
      Inhaled fluticasone propionate impairs pulmonary clearance of Klebsiella pneumoniae in mice.
      ,
      • Janson C.
      • Stratelis G.
      • Miller-Larsson A.
      • Harrison T.W.
      • Larsson K.
      Scientific rationale for the possible inhaled corticosteroid intraclass difference in the risk of pneumonia in COPD.
      ] and attenuate the adaptive cellular immune response through the interferon-gamma-mediated pathway [
      • Cowman S.A.
      • Jacob J.
      • Hansell D.M.
      • Kelleher P.
      • Wilson R.
      • Cookson W.O.C.
      • Moffatt M.F.
      • Loebinger M.R.
      Whole-blood gene expression in pulmonary nontuberculous mycobacterial infection.
      ]. Clinical studies conducted in Taiwan, Japan, and Denmark have shown that patients with COPD using an ICS had a dose-dependent increase in the risk of subsequent NTM-PD than those not using an ICS [
      • Ni S.
      • Fu Z.
      • Zhao J.
      • Liu H.
      Inhaled corticosteroids (ICS) and risk of mycobacterium in patients with chronic respiratory diseases: a meta-analysis.
      ,
      • Andrejak C.
      • Nielsen R.
      • Thomsen V.O.
      • Duhaut P.
      • Sorensen H.T.
      • Thomsen R.W.
      Chronic respiratory disease, inhaled corticosteroids and risk of non-tuberculous mycobacteriosis.
      ,
      • Hojo M.
      • Iikura M.
      • Hirano S.
      • Sugiyama H.
      • Kobayashi N.
      • Kudo K.
      Increased risk of nontuberculous mycobacterial infection in asthmatic patients using long-term inhaled corticosteroid therapy.
      ]. In a case–control study in which data retrieved from a healthcare delivery system in northern California were analysed, the risk of NTM disease was discovered to be 1.8- to 2.7-fold higher among ICS users than nonusers, regardless of age [
      • Liu V.X.
      • Winthrop K.L.
      • Lu Y.
      • Sharifi H.
      • Nasiri H.U.
      • Ruoss S.J.
      Association between inhaled corticosteroid use and pulmonary nontuberculous mycobacterial infection.
      ]. Although ICS-containing treatment of COPD can reduce the number of exacerbations and improve symptoms [
      • Festic E.
      • Scanlon P.D.
      Incident pneumonia and mortality in patients with chronic obstructive pulmonary disease. A double effect of inhaled corticosteroids?.
      ], carefully assessing the phenotypes and using inhaled long-acting bronchodilators as an alternative are essential if potential risks are to be minimised [
      • Singh D.
      • Agusti A.
      • Anzueto A.
      • Barnes P.J.
      • Bourbeau J.
      • Celli B.R.
      • Criner G.J.
      • Frith P.
      • Halpin D.M.G.
      • Han M.
      • Lopez Varela M.V.
      • Martinez F.
      • Montes de Oca M.
      • Papi A.
      • Pavord I.D.
      • Roche N.
      • Sin D.D.
      • Stockley R.
      • Vestbo J.
      • Wedzicha J.A.
      • Vogelmeier C.
      Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease: the GOLD science committee report 2019.
      ], especially in patients with concomitant NTM-PD.
      This retrospective study has two limitations. The first is lacking of a standardised follow-up and treatment protocol. The time point at which treatment was initiated was dependent on clinicians’ decisions. Therefore, we are unable to make any conclusions regarding to treatment and outcome. The second is that in this cohort study, only small proportion of patients harbouring negative culture for NTM from expectorated sputum samples received bronchoscopy, and the indication for bronchoscopy was difficult to analyse retrospectively.

      5. Conclusions

      In conclusion, radiographic progression occurred within 2 years was noted in one quarter of patients with NTM-PD diagnosed through bronchoscopy. The predictors of progression include male sex, BMI <18.5 kg/m2, ICS use, and bronchoscopic sample AFS grade ≥2. For patients with these risk factors, immediate treatment or close monitoring is recommended. For others, conservative management by regular microbiological monitoring for sputum samples and image follow-up may be the optimal choice.

      Data sharing statement

      All data were deposited in the Information Technology Office of NTUH and the Statistical Analysis Laboratory, Department of Medical Research, KMUH. The data are not available for sharing without permission.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgements

      The authors thank the Information Technology Office of NTUH and the Statistical Analysis Laboratory, Department of Medical Research, KMUH, for providing patient data. This manuscript was edited by Wallace Academic Editing.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      Funding

      This study was supported by the Taiwan Ministry of Science and Technology (MOST107-2314-B-037-106-MY3), Ministry of Health and Welfare (MOHW108-TDU-B-212-133006), and Kaohsiung Medical University Hospital Research Program (KMUH107-7R12). The funders had no role in the study design, data analysis, or manuscript writing.

      Author contributions

      HLH, JYW, and IWC designed the study. MHC, MRL, CJL, and PLL performed the database analysis. HLH and CJL contributed to the statistical analysis. HLH, JYW, and IWC contributed to data interpretation and prepared the first draft of the manuscript. MHC, MRL, and PLL critically revised the draft manuscript. JYW and IWC were responsible for coordination. All authors provided final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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