Epidemiology of non-cystic fibrosis bronchiectasis at a single center in Japan: a retrospective cohort study

Epidemiology of non-cystic fibrosis bronchiectasis at a single center in Japan: a retrospective cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Epidemiology of non-cystic fibrosis bronchiectasis at a single center in Japan: a retrospective cohort study Kazuki Hashimoto, Yuko Abe, Kiyoharu Fukushima, Takayuki Niitsu, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4592641/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 24 Oct, 2024 Read the published version in BMC Pulmonary Medicine → Version 1 posted 10 You are reading this latest preprint version Abstract Background: The characteristics of non-cystic fibrosis bronchiectasis (NCBE) in Asia, including Japan, remain largely unknown. We aimed to provide insights into the clinical characteristics and treatment outcomes of NCBE, especially regarding nontuberculous mycobacteria (NTM) infection, and establish a basis for comparison with global datasets. In addition, long-term macrolide antibiotic use in patients with NCBE and a history of exacerbations is established, but the effects in patients without exacerbations remain unclear. Methods: In this single-center, retrospective study, the medical records of patients who satisfied the NCBE criteria between 1 January 2012 and 31 August 2023 were reviewed. Severe exacerbations and mortality during the observation period were recorded. Baseline characteristics, prognostic factors, and overall survival of patients with and without non-NTM infection were evaluated; effects of long-term macrolide antibiotic use in patients without severe exacerbations were estimated using inverse probability weighting (IPW). Results: In 1044 patients with bronchiectasis, severe exacerbation rates were 22·32%, with mortality rates of 3·16% at 3 years. Notably, the high prevalence of NTM infection (n=458, 43·87%) in this cohort was distinctive. Compared with the NTM group, the non-NTM group had a higher proportion of elevated inflammatory markers, with significant differences in C-reactive protein levels (p=0·0023) and blood neutrophil counts (p<0·001). Pseudomonas aeruginosa was more frequently identified as having colonization and was associated with severe exacerbations (p<0·001) in the non-NTM group. NTM infection was not associated with mortality (p=0·4621, hazard ratio=0·79). Among patients with non-NTM infection and without a history of exacerbation in the past 2 years, 34·3% received long-term macrolide antibiotics that did not invariably reduce severe exacerbations (P=0·3801, IPW P=0·7222). Conclusions: This study highlights NCBE epidemiology in Japan, advising caution in the casual use of macrolides for mild cases. Clinical Trial Registration: UMIN Clinical Trials Registry Number: UMIN000054726 (Registered on 21 June 2024) non-cystic fibrosis bronchiectasis macrolides nontuberculous mycobacteria TB Figures Figure 1 Figure 2 Figure 3 Figure 4 1 BACKGROUND Bronchiectasis (BE) is a syndrome characterized by chronic respiratory symptoms and bronchial dilation confirmed by imaging studies, with a wide variety of causative conditions [ 1 ]. Among these, cystic fibrosis (CF) resulting from genetic abnormalities in chloride ion channels has garnered considerable attention in Western countries, leading to numerous studies. However, non-CF BE (NCBE) has received insufficient attention due to diagnostic difficulties, its heterogeneous nature, and limited treatment options; it was considered an orphan disease [ 2 ]. Interest in non-cystic BE has increased owing to an increase in the number of patients, especially older women, and the widespread use of computed tomography (CT), which has made diagnosis easier. Large-scale registries, such as the European Multicenter Bronchiectasis Adult and Research Collaboration (EMBARC) in Europe [ 3 ] and the United States Bronchiectasis Research Registry in the United States [ 4 ] have been established. Guidelines have been developed in succession, positioning it as a major category of respiratory disease. In regions such as Japan, and other parts of Asia, where the prevalence of CF is low [ 5 ], BE has been neglected and is often perceived as a secondary phenomenon associated with more common conditions such as chronic obstructive pulmonary disease (COPD), bronchial asthma (BA), and nontuberculous mycobacteria (NTM) infection. Consequently, there is a lack of clear recognition of BE as a distinct clinical entity, and therapeutic interventions have been insufficiently applied. Moreover, the prevalence of diffuse panbronchiolitis (DPB) is high in East Asia, including Japan [ 6 ], and the successful use of low-dose macrolide antibiotics for DPB [ 7 ] may promote the casual use of macrolides for chronic airway inflammation in Japan. This approach may diverge from internationally accepted care standards [ 8 , 9 ] that generally emphasize treatment regimens for BE that is responsive to exacerbation events, which is based on evidence that long-term macrolide antibiotics improve the prognosis of patients with NCBE and a history of exacerbations [ 10 ]. However, the effects of long-term macrolide antibiotic use in patients without exacerbations remain unclear. Furthermore, the indiscriminate use of macrolides contributes to increased resistance in potentially coexisting NTM. Recently, the global incidence of NTM infections has increased [ 11 ], sparking growing interest in their association with BE. Japan, and other parts of Asia, exhibits a higher incidence and prevalence of NTM infection than the rest of the world [ 12 ]. However, epidemiological data on BE in Asia, including Japan, are limited, with only 147 cases reported by Kadowaki et al. in Japan [ 5 ]. Thus, the precise impact of NTM on disease progression, prognosis, and pathogen colonization in BE remains poorly understood, accentuating the need for further research into the consequences of NTM infection in patients with BE. This study aimed to elucidate the epidemiological profiles of this region, particularly with respect to NTM, to enable comparative verification overseas and to highlight the need for region-specific public health and clinical epidemiological strategies for the effective management and treatment of BE. Additionally, we aimed to evaluate the use and outcomes of long-term macrolide antibiotics in patients with non-NTM bronchiectasis without prior exacerbation events. 2 METHODS 2.1 Study design and patient population In this single-center, retrospective, observational study, we reviewed the medical records of patients diagnosed with BE between 1 January 2012 and 31 August 2023 at the National Hospital Organization Osaka Toneyama Medical Centre. The inclusion criteria were based on international consensus recommendations [ 2 ]: a clinical history consistent with bronchiectasis (cough, chronic sputum production, and/or recurrent respiratory infections) and chest CT demonstrating bronchiectasis (bronchial dilatation) affecting one or more lobes. The exclusion criteria were bronchiectasis due to known CF and age < 18 years. The study was approved by the Institutional Review Board of the National Hospital Organization of Osaka Toneyama Medical Centre (approval no. TNH-R-2024002). Informed consent was obtained from all participants for the use of their data in this study. 2.2 Baseline clinical characteristics Baseline clinical information collected at enrolment included age, sex, body mass index (BMI), modified Medical Research Council dyspnea scale (mMRC), Bronchiectasis Severity Index (BSI) score, FACED score (F: forced expiratory volume in 1 s [FEV1·0], A: age, C: chronic colonization by Pseudomonas aeruginosa , E: radiological extension [number of pulmonary lobes affected], and D: dyspnea), smoking history, BE-causing comorbidities, blood neutrophil counts (BNCs), blood eosinophil count (BEC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-glycopeptidolipid (GPL)-core IgA antibody, myeloperoxidase-anti-neutrophil cytoplasmic antibody, pulmonary function test (PFT) results (FEV1·0, forced vital capacity [FVC]), disease extension cystic bronchiectasis and cavities on CT, evidence of chronic colonization (defined as colonization detected within 180 days before or after the date of diagnosis), and exacerbation history. One radiologist and four pulmonologists independently reviewed the CT images and reached a consensus on the findings. 2.3 Outcome measurements The time to the first exacerbation was defined as the time from diagnosis to severe exacerbation or the conclusion of the study on 31 August 2023. Overall survival (OS) was defined as the time from diagnosis to death from any cause or the conclusion of the study on 31 August 2023. Censoring was performed at the point of loss to follow-up or at the end of the study. For patients monitored at external hospitals, clinical progression data, including mortality, were predominantly sourced from the regional medical liaison office given the central role of the hospital in the region. 2.4 Diagnostic criteria for NTM Based on official clinical practice guidelines [ 10 ], the diagnostic criteria for NTM pulmonary disease required clinical and radiological evidence, specifically pulmonary or systemic symptoms with nodular or cavitary opacities on radiography or CT, that also demonstrated bronchiectasis with multiple small nodules. Diagnosis was confirmed when these criteria were met in conjunction with one of the following microbiological findings: [ 1 ] positive culture results from at least two separate expectorated sputum samples (if the results were non-diagnostic, sputum acid-fast bacilli [AFB] smears and cultures were repeated); [ 2 ] positive culture results from at least one bronchial wash or lavage; or [ 3 ] transbronchial or other lung biopsy with mycobacterial histologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings culture positive for NTM. 2.5 Definition of severe exacerbation Bronchiectasis exacerbation was defined as [ 1 ] deterioration in three or more of the key symptoms (including cough, sputum volume and/or consistency, sputum purulence, dyspnea and/or exercise tolerance, fatigue and/or malaise, and hemoptysis) for at least 48 h and [ 2 ] a clinician’s assessment that a change in treatment was required [ 13 ]. Severe exacerbations were defined according to the British thoracic society guidelines as unscheduled hospitalizations or emergency department visits for severe bronchiectasis exacerbations or complications and were recorded from patient histories and verified using administrative databases [ 8 ]. 2.6 Long-term macrolide antibiotic exposure To assess the impact of long-term macrolide antibiotic (azithromycin, clarithromycin, and erythromycin) use, patients were divided into those using them for at least 3 months and those not receiving long-term macrolide antibiotics, without considering the dosage between diagnosis and the first severe exacerbation or death. The analysis was conducted on patients without NTM because macrolides are key therapeutic agents for NTM and their effects are well-established. 2.7 Statistical analysis Continuous data are presented as medians and interquartile ranges (IQRs), and categorical data as frequencies and percentages. For continuous variables, the Wilcoxon rank-sum test was used to compare two groups. For categorical variables, differences between groups were assessed using Fisher’s exact test. Regarding outcomes, the time to the first severe exacerbation after diagnosis among patients with and without NTM was analyzed using univariate and multivariate Cox proportional hazards regression. The time to death was compared between the non-NTM and NTM patient groups using Kaplan–Meier survival analysis (note that adjustments for the covariates mentioned below were not made, as NTM was considered a background rather than an exposure variable) and further analyzed using multivariable Cox proportional hazard regression. Variables for univariate and multivariate Cox proportional hazard regression were selected based on previous literature [ 10 , 14 – 17 ] and their clinical significance, with an effort to exclude correlated variables wherever feasible, as follows: sex, age, BMI, mMRC, COPD, asthma, rheumatoid arthritis (RA), CRP, BNC, disease extension over three lobes, cystic bronchiectasis, cavity, and P. aeruginosa colonization. Finally, to assess the effects of macrolide exposure on the time to exacerbation after diagnosis, patients without NTM or exacerbations for 2 years before diagnosis, were divided into treatment and non-treatment groups according to the definition of long-term macrolide antibiotic exposure described above. To address immortal time bias, time zero was defined as 3 months after diagnosis. We also estimated the average treatment effect (ATE) of the treatment utilizing inverse probability weighting (IPW) by propensity scores calculated using all predefined covariates; ATE weight was applied to each patient to create a pseudo-population. Regarding covariates, we pre-configured sex, age, BMI, mMRC, smoking history, cystic bronchiectasis and cavities on CT, CRP, BNC, and P. aeruginosa colonization as time-fixed covariates by referring to previous studies [ 10 , 14 – 19 ]. To assess the balance between the groups before and after adjustment, we used the standardized mean difference (SMD). An SMD variation exceeding 25% was considered indicative of significant imbalance. All statistical analyses were performed using JMP Pro 17 (SAS Institute, Cary, NC, USA) and R software version 4.3.2 ( https://www.r-project.org/ ). Statistical significance was defined as p < 0·05; all p-values reported in the results section were assessed against this threshold. 3 RESULTS 3.1 Study population and baseline characteristics In total, 1044 patients were diagnosed with bronchiectasis and followed up until their last visit, death, or the end of the observation period. The cohort comprised 586 (56·13%) patients without NTM and 458 (43·87%) patients with NTM (Fig. 1 ). Most patients were women (n = 807, 77·3%), with a median age of 72 (IQR 63–77) years and a median BMI of 19·33 (IQR 17·54 − 21·36) kg/m 2 . Regarding BE-causing comorbidities, post-pneumonia conditions were confirmed in 215 patients (20·59%), with 100 having a history of tuberculosis (TB). Other comorbidities included chronic sinusitis in 97 patients (9·29%), airway abnormalities and aspiration syndrome in 82 (7·85%), asthma in 74 (7·09%), COPD in 59 (5·65%), RA in 54 (5·17%), allergic bronchopulmonary aspergillosis in 4 (0·38%), and other conditions in 3 (0·29%). Cases without known causes of BE, considered idiopathic BE, accounted for 408 patients (39·08%). The three most common colonizations were by P. aeruginosa (n = 119, 11·4%), Staphylococcus species (n = 33, 3·16%), and Haemophilus influenza (n = 22, 2·11%). In the 2 years prior to diagnosis, 14·94% (156/1044) of patients with bronchiectasis had experienced severe exacerbation episodes. The rates of severe exacerbation 1 and 3 years after diagnosis were 14·08% (n = 147) and 22·32% (n = 233), respectively. The mortality rates at 1 and 3 years were 1·25% (n = 13) and 3·16% (n = 33), respectively (Table 1 ). Table 1 Demographic and clinical characteristics of patients with bronchiectasis Characteristics Overall (n = 1044) Sex, female 807 (77·3) ‡ Age (years) 72 [63–77] BMI (kg/m 2 ) (n = 933) 19·33 [17·54 − 21·36] mMRC 0, 1, 2, 3, 4, No (%) 535 (51·25), 351 (33·62), 104 (9·96), 45 (4·31), 9 (0·86) Bronchiectasis Severity Index (n = 363), No (%) Mild, Moderate, Severe 32 (8·82), 99 (27·27), 232 (63·91) FACED score (n = 363), No (%) Mild, Moderate, Severe 180 (49·59), 147 (40·50), 36 (9·91) Smoking status, No (%) Never 789 (75·58) Former, Current 255 (24·43) NTM diagnosis 458 (43·87) Comorbidities, No (%) Post infection 1 215 (20·59) Airway abnormality and aspiration syndrome 2 82 (7·85) COPD 59 (5·65) Asthma 74 (7·09) Allergic bronchopulmonary aspergillosis 4 (0·38) Chronic sinusitis 97 (9·29) Rheumatoid arthritis 54 (5·17) Others 3 3 (0·29) Laboratory findings Blood neutrophils, /µL (n = 980) 3705 [2820–5118] Blood eosinophils, /µL (n = 980) 130 [80–210] CRP, mg/L (n = 979) 0·17 [0·1 − 0·82] ESR, mm (n = 704) 31 [14–60] Positive anti-GPL-core IgA antibody (n = 891) 437 (49·05) Positive MPO-ANCA, unit/ml (n = 180) 4 (2·22) Lung function test results (n = 364) FEV1·0 1·62 [1·21 − 2·07] FVC 2·21 [1·68 − 2·70] %FEV1·0 80·65 [63·28–98·9] FEV1·0/FVC 76·16 [68·94 − 84·67] Disease extension on CT, No (%) >2 lobes affected 659 (63·12) Cystic bronchiectasis 156 (14·94) Cavities 236 (22·61) Chronic colonization, No (%) Pseudomonas aeruginosa 119 (11·4) Staphylococcus species 33 (3·16) Haemophilus influenza 22 (2·11) Streptococcus pneumoniae 14 (1·34) Klebsiella pneumoniae 9 (0·86) Aspergillus species 18 (1·72) Others 30 (2·87) Outcome, No (%) Severe exacerbation in the past 2 years 161 (15·42) Severe exacerbation during 1-year follow-up 147 (14·08) Severe exacerbation during 3-year follow-up 233 (22·32) Mortality during 1-year follow-up 13 (1·25) Mortality during 3-year follow-up 33 (3·16) 1 After bacterial or viral pneumonia (n = 115) or tuberculosis (n = 100). 2 Airway obstruction by tumor or foreign body and vocal cord disease or dysfunction; esophageal disease or dysmotility (head and neck cancer, prior radiation treatment, neurologic disease, esophageal motility disorder, gastroesophageal reflux disease). 3 Immunodeficiency (n = 1), Sjögren’s syndrome (n = 1), Scleroderma (n = 1). *Abbreviations: BMI, body mass index; mMRC, modified Medical Research Council dyspnea scale; NTM, nontuberculous mycobacteria; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GPL, glycopeptidolipid; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibodies; FEV1·0, forced expiratory volume in one second; FVC, forced vital capacity; CT, computed tomography. ‡Data are presented as n (%) or median [interquartile range]. The baseline characteristics of the patients with and without NTM are summarized in Table 2 . In the non-NTM group, a higher proportion of males (p = 0·0074), higher BMI (p = 0·0010), and elevated inflammatory profiles, such as BNCs (p = 0·0002), CRP (p = 0·0023), and ESR (p = 0·0007) were observed. While %FEV1·0 was lower (p = 0·0171), CT scans showed more localized lesions (p < 0·0001) and less frequent cavitation in the non-NTM group (p < 0·0001) than in the NTM group. Additionally, P. aeruginosa colonization was more common in patients without NTM than in those with (p = 0·0008), with a significantly higher detection rate during exacerbations (p < 0·0001) (Table 2 and Supplementary Table S1 [see Additional file 1]). There was no significant difference in the number of culture tests between patients with and without NTM (P = 0·867). Table 2 Comparative baseline characteristics between patients with and without NTM Characteristics Overall (n = 1044) Non-NTM* (n = 586) NTM (n = 458) p Value § Sex, female 807 (77·3) ‡ 435 (74·23) ‡ 372 (81·22) 0·0074 Age (years) 72 [63–77] 72 [63·25–77] 72 [63–78] 0·7374 BMI (kg/m 2 ) 19·33 [17·54 − 21·36] 19·64 [17·75 − 21·88] 19·12 [17·23 − 20·77] 0·0010 mMRC > 1 158 (15·13) 83 (14·16) 75 (16·38) 0·3391 Bronchiectasis Severity Index (n = 363), No (%) Mild 32 (8·82) 17 (9·04) 15 (8·57) 1 Moderate 99 (27·27) 56 (29·79) 43 (24·57) 0·2895 Severe 232 (63·91) 115 (61·17) 117 (66·86) 0·2755 Smoking status, No (%) Never 789 (75·58) 433 (73·89) 356 (77·73) Former, Current 255 (24·43) 153 (26·11) 102 (22·27) 0·1679 Laboratory findings Blood neutrophils, /µL (n = 980) 3705 [2820–5118] 3860 [2950–5455] 3510 [2680–4780] 0·0002 Blood eosinophils, /µL (n = 980) 130 [80–210] 130 [80–210] 130 [80–200] 0·9695 CRP, mg/L (n = 979) 0·17 [0·1 − 0·82] 0·23 [0·1 − 0·9975] 0·12 [0·1 − 0·62] 0·0023 ESR, mm (n = 704) 31 [14–60] 36 [16–67·5] 26 [13–53] 0·0007 Positive anti-GPL-core IgA antibody, (n = 891) 437 (49·05) 106 (23·45) 331 (75·40) < 0·0001 Lung function test results (n = 364) FEV1·0 1·62 [1·21 − 2·07] 1·575 [1·16 − 2·09] 1·64 [1·29 − 2·04] 0·2492 FVC 2·21 [1·68 − 2·70] 2·18 [1·56 − 2·67] 2·25 [1·79 − 2·71] 0·3383 %FEV1·0 80·65 [63·28–98·9] 76·05 [61–96·9] 84·35 [65·15–103·68] 0·0171 FEV1·0/FVC 76·16 [68·94 − 84·67] 75·75 [68·01–84·64] 76·59 [70·04–84·87] 0·5511 Disease extension on CT, No (%) >2 lobes affected 659 (63·12) 325 (55·46) 334 (72·93) < 0·0001 Cystic bronchiectasis 156 (14·94) 76 (12·97) 80 (17·47) 0·0466 Cavities 236 (22·61) 96 (16·38) 140 (30·57) < 0·0001 Chronic colonization, No (%) Pseudomonas aeruginosa 119 (11·4) 84 (14·33) 35 (7·64) 0·0008 § Differences among continuous variables were assessed using the Wilcoxon rank-sum test; differences among categorical variables were assessed using the Fisher’s exact test, as appropriate. *Abbreviations: NTM, nontuberculous mycobacteria; SMD, standardized mean difference; IPW, inverse probability weighting; ATE, average treatment effect; BMI, body mass index. ‡Data are presented as n (%) or median (interquartile range). Abbreviations: NTM, nontuberculous mycobacteria; IPW, inverse probability weighting; BMI, body mass index; mMRC, modified Medical Research Council dyspnea scale; CT, computed tomography; CRP, C-reactive protein; P. aeruginosa, Pseudomonas aeruginosa . 3.2 Effect of each risk factor on time to first severe exacerbation We then conducted univariate and multivariate Cox proportional hazards analyses to identify potential risk factors for the first exacerbation in patients with and without NTM (Supplementary Table S2 [see Additional file 1]). In patients without NTM, multivariable analysis revealed that while higher BMI (hazard ratio [HR] = 0·89, 95% confidence interval [CI], 0·84 − 0·95) was associated with a significantly lower risk of first exacerbation, male sex (HR = 1·74, 95% CI, 1·11 − 2·75), higher mMRC (the scale is 2; HR = 1·9, 95% CI 1·05 − 3·58 and the scale is 3; HR = 2·7, 95% CI 1·27 − 5·63), COPD (HR = 2·01, 95% CI, 1·15 − 3·54), CRP (HR = 1·09, 95% CI, 1·03 − 1·15), disease extension over three lobes (HR = 2·01, 95% CI, 1·17 − 3·46), cystic bronchiectasis on CT (HR = 1·9, 95% CI, 1·18 − 3·06), and P. aeruginosa colonization (HR = 2·07, 95% CI, 1·34 − 3·2) were associated with significantly higher risks of severe exacerbation (Fig. 2 a). In patients with NTM, the multivariable analysis revealed that COPD (HR = 2·24, 95% CI, 1·19 − 4·2), RA (HR = 2·35, 95% CI, 1·21 − 4·6), disease extension of three or more lobes (HR = 1·68, 95% CI, 1·08 − 2·6), and cystic bronchiectasis (HR = 1·65, 95% CI, 1·03 − 2·6) and cavities (HR = 1·55, 95% CI 1·1–2·2) on CT were associated with a significantly higher risk of first exacerbation, while lower mMRC score, elevated inflammatory profiles, and P. aeruginosa colonization were not statistically significant (Fig. 2 b). 3.3 Effect of NTM on OS in NCBE We compared the time to death between the non-NTM and NTM groups using Kaplan–Meier survival analysis. The median follow-up time (IQR) from diagnosis was 27·8 (5·6–56·7) months in patients with and without NTM. Additionally, the median survival time was not reached. By the end of the follow-up, 64/1044 (6·13%) patients had died. The OS was not significantly different between the two groups (log-rank p = 0·4621) (Fig. 3 a). We further used Cox proportional hazard regression for multivariate analyses to evaluate the effect of each risk factor, including NTM, on overall OS in NCBE (Fig. 3 b). The results suggested that higher BMI (HR = 0·74, 95% CI, 0·65 − 0·84) was associated with a significantly lower risk of mortality and that male sex (HR = 2·06, 95% CI, 1·02–4·13), higher age (HR = 1·10, 95% CI, 1·06 − 1·15), higher mMRC (the scale is 4; HR = 3·73, 95% CI, 1·01–13·72), COPD (HR = 2·93, 95% CI, 1·41 − 6·12), elevated CRP (HR = 1·08, 95% CI, 1·02 − 1·15), cystic bronchiectasis (HR = 3·05, 95% CI, 1·59 − 5·83) and cavities (HR = 3·38, 95% CI, 1·75 − 6·55) on CT were associated with a significantly higher risk of mortality. However, NTM was not significantly associated with OS in non-cystic bronchiectasis (HR = 0·80, 95% CI, 0·43 − 1·47). 3.4 Effect of long-term macrolide antibiotic use Of the 586 patients without NTM, 208 (35·5%) received macrolide antibiotics, and 43 (7·34%) received inhaled steroids. Macrolides were more frequently administered to patients without a history of exacerbation (391 of 500, 78·2%) than to those who had experienced such events (109 of 500, 21·8%) (Table 1 and Supplementary Table S3 [see Additional file 1]). Given this pattern, we evaluated the effects of macrolide (azithromycin, clarithromycin, and erythromycin) exposure in patients who had not experienced exacerbations for 2 years before diagnosis. Among 320 patients, 201 (62·8%) were not receiving long-term macrolide antibiotics, while 119 (37·2%) were receiving them. In both subsets, all covariates were adjusted for balance using the IPW (ATE-weighted) (Supplementary Table S4 [see Additional file 1]). The time to first exacerbation leading to hospitalization did not differ between the groups (log-rank P = 0·3801) (Fig. 4 a). Similar results were observed after IPW adjustment (log-rank test, P = 0·7222) (Fig. 4 b). 4 DISCUSSION This is the largest retrospective cohort study of NCBE in Japan and serves as a benchmark for the epidemiological understanding of NCBE in Asia, shedding light on prognostic indicators. We found that the mortality rate was low and identified a significant prevalence of comorbidities, including NTM, prior TB, and sinusitis infections. Prognostic factors were similar to those from previous studies: higher BMI was associated with a lower risk of exacerbations and mortality, while factors such as COPD and disease severity on CT significantly increased risk, and NTM did not affect prognosis. Moreover, although many patients with non-NTM BE received long-term macrolide antibiotics, a significant proportion of these were patients without a history of exacerbations. This treatment did not significantly affect the time to the first severe exacerbation post-diagnosis in patients with non-NTM BE. Regarding patient characteristics, our population had more older patients, women, patients with lower BMI, and never-smokers than those in the EMBARC registry data [ 3 ]. Although the incidence of severe exacerbations aligns with previously reported data, our 1- and 3-year mortality rates were notably lower (Table 1 ). These gaps may be due to capturing milder cases by the widespread availability of CT, variations in insurance coverage, differing criteria for hospitalization, and prevalence of the screening system [ 20 – 23 ]. Our study did not aim to identify specific etiologies but to document the frequency of comorbidities that can lead to this condition, emphasizing their prevalence. The significant co-occurrence of NTM aligns with the findings of previous research [ 4 ]. The frequency of idiopathic and post-infection BE cases was similar to that reported in previous studies [ 5 , 24 ]. However, a predominance of older patients with TB was observed (n = 100). Logistic regression analysis revealed a significant correlation between age and TB (p < 0·0001) (data not shown). These findings may represent subsets that are particularly prevalent in Asia populations. Numerous patients within the cohort were categorized as having severe disease based on the BSI score, a classification that appears incongruent with the observed mortality rates. In the Japanese context, factors such as older age and physically lower BMI may contribute to elevated BSI scores (Table 1 ). These scores may not provide clinicians with insight into the specific management strategies required in routine clinical practice [ 25 ]. Determining whether NTM infection precedes the development of BE remains challenging [ 16 ]. However, similar to that reported in recent U.S. cohorts [ 26 ], many NCBE patients met the American Thoracic Society/Infectious Diseases Society of America criteria for NTM pulmonary disease. The 5-year mortality rate was low, and survival outcomes did not differ significantly between patients with and without NTM, aligning with findings from the U.S. registry. Our validation reaffirms the high prevalence of NTM in Japan and represents Asia and Japanese landscape. When focusing on the differences between the non-NTM and NTM groups, we found that the non-NTM group had a significantly higher proportion of men and elevated BMI and inflammatory markers, such as BNCs, CRP, and ESR. Previous large-scale database and cohort analyses have not reported data specifically focusing on this inflammatory profile [ 11 , 27 , 28 ]. In future studies, it may be crucial to categorize patients with NCBE based on their endotypes and phenotype [ 29 ] for precision medicine. Regarding the results for each prognostic indicator utilized in daily practice, COPD, inflammatory markers such as CRP, cavities, and cystic bronchiectasis were associated with mortality and severe exacerbation, similar to previous reports [ 22 , 30 – 33 ] (Figs. 2 a, 2 b, and 3 b). Notably, in patients without NTM, inflammation may play a crucial role in exacerbation (Table 2 and Fig. 2 a), highlighting the pathophysiological vortex of disease progression [ 1 , 15 , 34 , 35 ]. Therefore, these results suggest the need to manage the inflammatory process [ 35 ]. In contrast, P. aeruginosa is a well-established prognostic factor for bronchiectasis [ 18 ]; however, in our study, it was more frequently identified as a colonizing or pathogenic microorganism with severe exacerbations in the non-NTM group but not in the NTM group (Table 2 and Supplementary Table S1 [see Additional file 1]). Additionally, in a recent U.S. study focusing on the presence or absence of NTM in the BE registry, P. aeruginosa was not identified as a prognostic factor [ 26 ]. This raises questions about whether differences exist in prognostic factors between patients with and without NTM. One study indicated that bacterial coinfections can occur after starting treatment for Mycobacterium avium complex pulmonary disease [ 36 ]. Under certain conditions, NTM might provide a protective effect against Pseudomonas infection, or they may regulate each other’s virulence. These findings suggest complex interactions within the bacterial flora that warrant further investigation. We focused on the prescription pattern in patients without NTM infection. Compared with Western registries such as EMBARC [ 3 ], this cohort showed higher use of macrolides and lower use of inhaled steroids and inhaled antibiotics. In Japan, macrolide antibiotics are indicated for neutrophilic airway inflammation and can be used in a wide range of conditions, including COPD, DPB, bronchiectasis, and bronchial asthma, with or without a history of exacerbations. However, the indiscriminate use of macrolides contributes to increased resistance in potentially co-existing NTM. Additionally, the use of inhaled corticosteroids (ICSs) in this cohort was primarily noted in cases with coexisting asthma, highlighting regional differences in treatment practices; in Western countries, ICSs are more commonly prescribed directly for bronchiectasis. In Japan, inhaled tobramycin is only approved for CF, and amikacin liposomal inhalation is only approved for treatment-resistant Mycobacterium avium complex, reflecting further limitations in treatment options for BE. We also found substantial prescription of clarithromycin monotherapy for milder cases. Moreover, very few instances of erythromycin or azithromycin use have been observed. These behaviors may not reflect widely recognized guidelines (Supplementary Table S4 [see Additional file 1]) [ 8 , 9 ]. The results of our covariate-adjusted IPW analysis suggested that the prophylactic use of long-term macrolide antibiotics did not invariably reduce further severe exacerbations in patients with no history of such events (Fig. 4 a, b). We speculate that there is high awareness and active research on DPB in Japan [ 7 ]. NCBE has long been considered an orphan disease [ 2 ]. Furthermore, successful experiences with macrolides in DPB [ 7 ] may have led to a dependency on these medications. Additionally, the lack of inhaled antibiotic options for non-CF BE in Japan may have contributed to this dependency. Our findings serve as a cautionary note for routine clinical practice in Japan. The unrestricted prescription of macrolides can lead to refractoriness and resistance in NTM. Further verification of the effectiveness of macrolides in mild cases is required, not only in suppressing exacerbations but also in improving symptoms, quality of life, and effects on comorbid chronic sinusitis. In summary, this cohort study clarified the epidemiology of NCBE and the potential parameters that guide patient management in Japan. Moreover, our findings critically verify the application of macrolides in routine clinical settings and underscore the need for further investigation in this field. This study had some limitations. First, its retrospective design precluded elimination of all potential confounding factors. Although substantial cohorts exist globally, the evidence is particularly sparse in Japan, underscoring the necessity for ongoing real-world cohort studies in future. Second, there was a lack of PFT data. In a Cox proportional hazard regression for multivariate analysis, a variable with missing data was not suitable for evaluation as a prognostic value, and we did not consider PFTs or each severity index as prognostic variables. This study highlights the need to increase our awareness and understanding of BE, perform PFTs, and regularly follow-up in daily clinical practice. Third, the lack of a validation cohort within our study precluded the verification of predictive accuracy. However, our primary goal was not to construct a prediction model but to provide the first epidemiological overview relevant to Japan and Asia. Further research is needed to identify predictors of poor outcomes. Fourth, the retrospective nature of the study also means that treatment decisions regarding the timing and choice of macrolide antibiotics were at the discretion of individual pulmonary physicians, introducing the potential for immortal time bias in assessing the ATE of long-term macrolide antibiotics. Future randomized controlled trials in patient populations with no previous exacerbations are needed for an accurate evaluation. Fifth, the end point of follow-up termination may have introduced a measurement bias affecting the interpretation of the results. Efforts have been made to mitigate this through extensive follow-up via regional medical liaison offices and interhospital communication, minimizing loss to death or follow-up discontinuation. Sixth, this study does not identify the specific etiology of bronchiectasis because bronchiectasis can have multiple potential causes, making it impossible to pinpoint a single etiology. Seventh, approximately 23% of patients without NTM tested positive for IgA antibodies to glycopeptidolipid core antigen, suggesting that NTM might be underestimated. Hence, it is challenging to capture the true NTM population. 5 CONCLUSION Our study represents an inaugural large-scale epidemiological cohort study of patients with NCBE in a real-world setting in Japan. Our findings highlight the distinct characteristics of this patient population, signifying a clear need for future therapeutic strategies. Additionally, this study illuminates poor prognostic factors warranting attention in clinical practice and underscores the importance of diligent follow-up. Abbreviations non-cystic fibrosis bronchiectasis (NCBE) nontuberculous mycobacteria (NTM) inverse probability weighting (IPW) European Multicenter Bronchiectasis Adult and Research Collaboration (EMBARC) chronic obstructive pulmonary disease (COPD) bronchial asthma (BA) diffuse panbronchiolitis (DPB) body mass index (BMI) modified Medical Research Council dyspnea scale (mMRC) Bronchiectasis Severity Index (BSI) blood neutrophil counts (BNCs) blood eosinophil count (BEC) C-reactive protein (CRP) erythrocyte sedimentation rate (ESR) glycopeptidolipid (GPL) pulmonary function test (PFT) forced vital capacity (FVC) overall survival (OS) acid-fast bacilli (AFB) interquartile ranges (IQRs) rheumatoid arthritis (RA) standardized mean difference (SMD) tuberculosis (TB) hazard ratio (HR) confidence interval (CI) inhaled corticosteroids (ICSs) Declarations Ethics approval and consent to participate: The study was approved by the Institutional Review Board of the National Hospital Organization of Osaka Toneyama Medical Centre (approval no. TNH-R-2024002). Informed consent was obtained from all participants for the use of their data in this study. Consent for publication: Not applicable. Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests. Funding This work was supported in part by AMED (grant numbers JP20fk0108129, JP21fk0108129h0702, JP21lm02007), JSPS KAKENHI (Grant numbers JP21K16118, JP21K08194), Takeda Science Foundation, Uehara Memorial Foundation, MSD Life Science Foundation, Japanese Respiratory Society Boehringer Ingelheim Research Grant Program, Foundation of Kinoshita Memorial Enterprise, Senri Life Science Foundation, and the Japan Intractable Diseases (Nanbyo) Research Foundation (Grant Number 2020B02), Osaka Medical Research Foundation for Intractable Diseases, and Inamori Foundation. The funders had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript, this should be declared. Authors’ contributions: KH, YA, and KF designed the project. KH, YA, KF, and NT analyzed the clinical data. KH, KF, Takayuki Niitsu, and SM conducted CT image analysis. KH, KF, Takayuki Niitsu, and SM conducted clinical data extraction. SM, Takuro Nii, TM, and HK assisted with clinical data extraction. SK assisted with data analysis. KH, YA, KF, and Takayuki Niitsu performed statistical analysis. KM and HK supervised the project. KF and HK are responsible for the overall content as guarantors. All authors read and approved the final manuscript. Acknowledgments: We thank the pulmonary radiologists at Osaka Toneyama Medical Centre for their helpful discussions regarding chest computed tomography assessments. We also thank E. Akiba for assistance with data collection and helpful discussions. 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Chandrasekaran R, Mac Aogain M, Chalmers JD, Elborn SJ, Chotirmall SH: Geographic variation in the aetiology, epidemiology and microbiology of bronchiectasis . BMC Pulm Med 2018, 18 (1):83. Henkle E, Aksamit TR, Barker AF, Curtis JR, Daley CL, Anne Daniels ML, DiMango A, Eden E, Fennelly K, Griffith DE et al : Pharmacotherapy for Non-Cystic Fibrosis Bronchiectasis: Results From an NTM Info & Research Patient Survey and the Bronchiectasis and NTM Research Registry . Chest 2017, 152 (6):1120-1127. Pollock J, Goeminne PC: Eosinophils in Bronchiectasis: A U-Turn for Bronchiectasis Management . Chest 2023, 164 (3):561-563. Sin S, Yun SY, Kim JM, Park CM, Cho J, Choi SM, Lee J, Park YS, Lee SM, Yoo CG et al : Mortality risk and causes of death in patients with non-cystic fibrosis bronchiectasis . Respir Res 2019, 20 (1):271. Choi H, Park HY, Han K, Yoo J, Shin SH, Yang B, Kim Y, Park TS, Park DW, Moon JY et al : Non-Cystic Fibrosis Bronchiectasis Increases the Risk of Lung Cancer Independent of Smoking Status . Ann Am Thorac Soc 2022, 19 (9):1551-1560. Mao B, Lu HW, Li MH, Fan LC, Yang JW, Miao XY, Xu JF: The existence of bronchiectasis predicts worse prognosis in patients with COPD . Sci Rep 2015, 5 :10961. Chalmers JD, Chotirmall SH: Bronchiectasis: new therapies and new perspectives . Lancet Respir Med 2018, 6 (9):715-726. Flume PA, Chalmers JD, Olivier KN: Advances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity . Lancet 2018, 392 (10150):880-890. Chalmers JD, Haworth CS, Metersky ML, Loebinger MR, Blasi F, Sibila O, O'Donnell AE, Sullivan EJ, Mange KC, Fernandez C et al : Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis . N Engl J Med 2020, 383 (22):2127-2137. Urabe N, Sakamoto S, Shimanuki Y, Kanokogi T, Motohashi T, Anzai N, Kato C, Yamaguchi A, Tokita N, Homma S et al : Impact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation . BMC Pulm Med 2022, 22 (1):157. Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterial.docx Additional file File name: Additional file 1 File format: .docx Title of data: Supplementary material Description of data: Cite Share Download PDF Status: Published Journal Publication published 24 Oct, 2024 Read the published version in BMC Pulmonary Medicine → Version 1 posted Editorial decision: Revision requested 07 Aug, 2024 Reviews received at journal 06 Aug, 2024 Reviews received at journal 20 Jul, 2024 Reviewers agreed at journal 19 Jul, 2024 Reviewers agreed at journal 19 Jul, 2024 Reviewers invited by journal 25 Jun, 2024 Editor invited by journal 24 Jun, 2024 Editor assigned by journal 24 Jun, 2024 Submission checks completed at journal 24 Jun, 2024 First submitted to journal 17 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4592641","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":320743956,"identity":"657f8aa5-337b-4758-a16d-22ff2fce1799","order_by":0,"name":"Kazuki Hashimoto","email":"","orcid":"","institution":"Osaka University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kazuki","middleName":"","lastName":"Hashimoto","suffix":""},{"id":320743957,"identity":"3361dd72-bed9-427e-87af-de0dc8658bc3","order_by":1,"name":"Yuko Abe","email":"","orcid":"","institution":"Osaka University Graduate School of 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08:02:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4592641/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4592641/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-024-03337-7","type":"published","date":"2024-10-24T15:57:10+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60625548,"identity":"aa9ca659-62dd-431e-8c6f-fbf8f69a9dd4","added_by":"auto","created_at":"2024-07-18 22:24:59","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":547200,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient population and cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e*Abbreviations: NTM, nontuberculous mycobacteria\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4592641/v1/5520f53cb8439135146693d7.jpg"},{"id":60626146,"identity":"7b576747-c12a-479f-9456-82287c6177ef","added_by":"auto","created_at":"2024-07-18 22:32:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":191725,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePrognostic index model for predicting time to first severe exacerbation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(a) in patients with non-NTM; n= 462, number of events= 114 (124 observations deleted because they were missing).\u003c/p\u003e\n\u003cp\u003e(b) in patients with NTM; n= 423, number of events= 169 (35 observations deleted because they were missing).\u003c/p\u003e\n\u003cp\u003eSignificant. codes: 0 ‘***’ 0·001 ‘**’ 0·01 ‘*’ 0·05 ‘.’ 0·1 ‘ ’ 1\u003c/p\u003e\n\u003cp\u003e*Abbreviations: BMI, body mass index; mMRC, modified Medical Research Council dyspnea scale; ICS, inhaled corticosteroid; CRP, C-reactive protein;\u003cem\u003e P. aeruginosa, Pseudomonas aeruginosa.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4592641/v1/0a8191261095442d30b00cbe.jpg"},{"id":60625545,"identity":"a7fcd8fb-1119-4312-b81d-0d8ae5e7a560","added_by":"auto","created_at":"2024-07-18 22:24:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":153947,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOverall survival comparison and prognostic index model for NTM vs. non-NTM patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(a) Overall survival between patients with non-NTM and NTM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(b)\u003c/strong\u003e \u003cstrong\u003eA prognostic index model for predicting overall survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eN= 885, number of events= 62 (159 observations deleted because they were missing)\u003c/p\u003e\n\u003cp\u003eSignificant. codes: 0 ‘***’ 0·001 ‘**’ 0·01 ‘*’ 0·05 ‘.’ 0·1 ‘ ’ 1\u003c/p\u003e\n\u003cp\u003e*Abbreviations: NTM, nontuberculous mycobacteria; BMI, body mass index; mMRC, modified Medical Research Council dyspnea scale; ICS, inhaled corticosteroid; CRP, C-reactive protein; \u003cem\u003eP. aeruginosa, Pseudomonas\u003c/em\u003e \u003cem\u003eaeruginosa\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4592641/v1/394d3dba028af5e69ccdeac7.jpg"},{"id":60625549,"identity":"f60220cb-c72a-4214-acdf-b7d0886d3bd9","added_by":"auto","created_at":"2024-07-18 22:24:59","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":104210,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTime to first exacerbation with and without long-term macrolide antibiotic use\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe time to first exacerbation in patients who had not experienced a severe exacerbation for 2 years before diagnosis is shown.\u003c/p\u003e\n\u003cp\u003e(a) Without adjustment, and (b) with adjustment for multiple covariates* using IPW.\u003c/p\u003e\n\u003cp\u003e* Adjusted by sex, age, BMI, mMRC, smoking, cystic bronchiectasis and cavities on CT, CRP, neutrophil count, \u003cem\u003eP. aeruginosa \u003c/em\u003ecolonization.\u003c/p\u003e\n\u003cp\u003eAbbreviations: NTM, nontuberculous mycobacteria; IPW, inverse probability weighting; BMI, body mass index; mMRC, modified Medical Research Council dyspnea scale; CT, computed tomography; CRP, C-reactive protein; \u003cem\u003eP. aeruginosa, Pseudomonas aeruginosa\u003c/em\u003e.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4592641/v1/1643034661cd0730b5261778.jpg"},{"id":67681746,"identity":"fbf4044f-e933-4861-968c-1b950c1e4014","added_by":"auto","created_at":"2024-10-28 16:09:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2807054,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4592641/v1/2974840e-1fcd-4284-bdeb-506c4c012874.pdf"},{"id":60625547,"identity":"f7916a8e-56f9-47c7-af54-548080987710","added_by":"auto","created_at":"2024-07-18 22:24:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":32894,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFile name: Additional file 1\u003c/p\u003e\n\u003cp\u003eFile format: .docx\u003c/p\u003e\n\u003cp\u003eTitle of data: Supplementary material\u003c/p\u003e\n\u003cp\u003eDescription of data:\u003c/p\u003e","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4592641/v1/cdaf83997175246a31b669f5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Epidemiology of non-cystic fibrosis bronchiectasis at a single center in Japan: a retrospective cohort study","fulltext":[{"header":"1 BACKGROUND","content":"\u003cp\u003eBronchiectasis (BE) is a syndrome characterized by chronic respiratory symptoms and bronchial dilation confirmed by imaging studies, with a wide variety of causative conditions [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Among these, cystic fibrosis (CF) resulting from genetic abnormalities in chloride ion channels has garnered considerable attention in Western countries, leading to numerous studies. However, non-CF BE (NCBE) has received insufficient attention due to diagnostic difficulties, its heterogeneous nature, and limited treatment options; it was considered an orphan disease [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eInterest in non-cystic BE has increased owing to an increase in the number of patients, especially older women, and the widespread use of computed tomography (CT), which has made diagnosis easier. Large-scale registries, such as the European Multicenter Bronchiectasis Adult and Research Collaboration (EMBARC) in Europe [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and the United States Bronchiectasis Research Registry in the United States [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] have been established. Guidelines have been developed in succession, positioning it as a major category of respiratory disease.\u003c/p\u003e \u003cp\u003eIn regions such as Japan, and other parts of Asia, where the prevalence of CF is low [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], BE has been neglected and is often perceived as a secondary phenomenon associated with more common conditions such as chronic obstructive pulmonary disease (COPD), bronchial asthma (BA), and nontuberculous mycobacteria (NTM) infection. Consequently, there is a lack of clear recognition of BE as a distinct clinical entity, and therapeutic interventions have been insufficiently applied.\u003c/p\u003e \u003cp\u003eMoreover, the prevalence of diffuse panbronchiolitis (DPB) is high in East Asia, including Japan [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and the successful use of low-dose macrolide antibiotics for DPB [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] may promote the casual use of macrolides for chronic airway inflammation in Japan. This approach may diverge from internationally accepted care standards [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] that generally emphasize treatment regimens for BE that is responsive to exacerbation events, which is based on evidence that long-term macrolide antibiotics improve the prognosis of patients with NCBE and a history of exacerbations [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, the effects of long-term macrolide antibiotic use in patients without exacerbations remain unclear. Furthermore, the indiscriminate use of macrolides contributes to increased resistance in potentially coexisting NTM.\u003c/p\u003e \u003cp\u003eRecently, the global incidence of NTM infections has increased [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], sparking growing interest in their association with BE. Japan, and other parts of Asia, exhibits a higher incidence and prevalence of NTM infection than the rest of the world [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, epidemiological data on BE in Asia, including Japan, are limited, with only 147 cases reported by Kadowaki et al. in Japan [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Thus, the precise impact of NTM on disease progression, prognosis, and pathogen colonization in BE remains poorly understood, accentuating the need for further research into the consequences of NTM infection in patients with BE.\u003c/p\u003e \u003cp\u003eThis study aimed to elucidate the epidemiological profiles of this region, particularly with respect to NTM, to enable comparative verification overseas and to highlight the need for region-specific public health and clinical epidemiological strategies for the effective management and treatment of BE. Additionally, we aimed to evaluate the use and outcomes of long-term macrolide antibiotics in patients with non-NTM bronchiectasis without prior exacerbation events.\u003c/p\u003e"},{"header":"2 METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and patient population\u003c/h2\u003e \u003cp\u003eIn this single-center, retrospective, observational study, we reviewed the medical records of patients diagnosed with BE between 1 January 2012 and 31 August 2023 at the National Hospital Organization Osaka Toneyama Medical Centre. The inclusion criteria were based on international consensus recommendations [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]: a clinical history consistent with bronchiectasis (cough, chronic sputum production, and/or recurrent respiratory infections) and chest CT demonstrating bronchiectasis (bronchial dilatation) affecting one or more lobes. The exclusion criteria were bronchiectasis due to known CF and age\u0026thinsp;\u0026lt;\u0026thinsp;18 years.\u003c/p\u003e \u003cp\u003e The study was approved by the Institutional Review Board of the National Hospital Organization of Osaka Toneyama Medical Centre (approval no. TNH-R-2024002). Informed consent was obtained from all participants for the use of their data in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Baseline clinical characteristics\u003c/h2\u003e \u003cp\u003eBaseline clinical information collected at enrolment included age, sex, body mass index (BMI), modified Medical Research Council dyspnea scale (mMRC), Bronchiectasis Severity Index (BSI) score, FACED score (F: forced expiratory volume in 1 s [FEV1\u0026middot;0], A: age, C: chronic colonization by \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e, E: radiological extension [number of pulmonary lobes affected], and D: dyspnea), smoking history, BE-causing comorbidities, blood neutrophil counts (BNCs), blood eosinophil count (BEC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-glycopeptidolipid (GPL)-core IgA antibody, myeloperoxidase-anti-neutrophil cytoplasmic antibody, pulmonary function test (PFT) results (FEV1\u0026middot;0, forced vital capacity [FVC]), disease extension cystic bronchiectasis and cavities on CT, evidence of chronic colonization (defined as colonization detected within 180 days before or after the date of diagnosis), and exacerbation history. One radiologist and four pulmonologists independently reviewed the CT images and reached a consensus on the findings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Outcome measurements\u003c/h2\u003e \u003cp\u003eThe time to the first exacerbation was defined as the time from diagnosis to severe exacerbation or the conclusion of the study on 31 August 2023. Overall survival (OS) was defined as the time from diagnosis to death from any cause or the conclusion of the study on 31 August 2023. Censoring was performed at the point of loss to follow-up or at the end of the study. For patients monitored at external hospitals, clinical progression data, including mortality, were predominantly sourced from the regional medical liaison office given the central role of the hospital in the region.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Diagnostic criteria for NTM\u003c/h2\u003e \u003cp\u003eBased on official clinical practice guidelines [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], the diagnostic criteria for NTM pulmonary disease required clinical and radiological evidence, specifically pulmonary or systemic symptoms with nodular or cavitary opacities on radiography or CT, that also demonstrated bronchiectasis with multiple small nodules. Diagnosis was confirmed when these criteria were met in conjunction with one of the following microbiological findings: [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] positive culture results from at least two separate expectorated sputum samples (if the results were non-diagnostic, sputum acid-fast bacilli [AFB] smears and cultures were repeated); [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] positive culture results from at least one bronchial wash or lavage; or [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] transbronchial or other lung biopsy with mycobacterial histologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings culture positive for NTM.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Definition of severe exacerbation\u003c/h2\u003e \u003cp\u003eBronchiectasis exacerbation was defined as [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] deterioration in three or more of the key symptoms (including cough, sputum volume and/or consistency, sputum purulence, dyspnea and/or exercise tolerance, fatigue and/or malaise, and hemoptysis) for at least 48 h and [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] a clinician\u0026rsquo;s assessment that a change in treatment was required [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Severe exacerbations were defined according to the British thoracic society guidelines as unscheduled hospitalizations or emergency department visits for severe bronchiectasis exacerbations or complications and were recorded from patient histories and verified using administrative databases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Long-term macrolide antibiotic exposure\u003c/h2\u003e \u003cp\u003eTo assess the impact of long-term macrolide antibiotic (azithromycin, clarithromycin, and erythromycin) use, patients were divided into those using them for at least 3 months and those not receiving long-term macrolide antibiotics, without considering the dosage between diagnosis and the first severe exacerbation or death. The analysis was conducted on patients without NTM because macrolides are key therapeutic agents for NTM and their effects are well-established.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Statistical analysis\u003c/h2\u003e \u003cp\u003eContinuous data are presented as medians and interquartile ranges (IQRs), and categorical data as frequencies and percentages. For continuous variables, the Wilcoxon rank-sum test was used to compare two groups. For categorical variables, differences between groups were assessed using Fisher\u0026rsquo;s exact test.\u003c/p\u003e \u003cp\u003eRegarding outcomes, the time to the first severe exacerbation after diagnosis among patients with and without NTM was analyzed using univariate and multivariate Cox proportional hazards regression.\u003c/p\u003e \u003cp\u003eThe time to death was compared between the non-NTM and NTM patient groups using Kaplan\u0026ndash;Meier survival analysis (note that adjustments for the covariates mentioned below were not made, as NTM was considered a background rather than an exposure variable) and further analyzed using multivariable Cox proportional hazard regression.\u003c/p\u003e \u003cp\u003eVariables for univariate and multivariate Cox proportional hazard regression were selected based on previous literature [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and their clinical significance, with an effort to exclude correlated variables wherever feasible, as follows: sex, age, BMI, mMRC, COPD, asthma, rheumatoid arthritis (RA), CRP, BNC, disease extension over three lobes, cystic bronchiectasis, cavity, and \u003cem\u003eP. aeruginosa\u003c/em\u003e colonization.\u003c/p\u003e \u003cp\u003eFinally, to assess the effects of macrolide exposure on the time to exacerbation after diagnosis, patients without NTM or exacerbations for 2 years before diagnosis, were divided into treatment and non-treatment groups according to the definition of long-term macrolide antibiotic exposure described above. To address immortal time bias, time zero was defined as 3 months after diagnosis. We also estimated the average treatment effect (ATE) of the treatment utilizing inverse probability weighting (IPW) by propensity scores calculated using all predefined covariates; ATE weight was applied to each patient to create a pseudo-population.\u003c/p\u003e \u003cp\u003eRegarding covariates, we pre-configured sex, age, BMI, mMRC, smoking history, cystic bronchiectasis and cavities on CT, CRP, BNC, and \u003cem\u003eP. aeruginosa\u003c/em\u003e colonization as time-fixed covariates by referring to previous studies [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15 CR16 CR17 CR18\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo assess the balance between the groups before and after adjustment, we used the standardized mean difference (SMD). An SMD variation exceeding 25% was considered indicative of significant imbalance.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using JMP Pro 17 (SAS Institute, Cary, NC, USA) and R software version 4.3.2 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.r-project.org/\u003c/span\u003e\u003cspan address=\"https://www.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Statistical significance was defined as p\u0026thinsp;\u0026lt;\u0026thinsp;0\u0026middot;05; all p-values reported in the \u003cspan refid=\"Sec10\" class=\"InternalRef\"\u003eresults\u003c/span\u003e section were assessed against this threshold.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 RESULTS","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Study population and baseline characteristics\u003c/h2\u003e \u003cp\u003eIn total, 1044 patients were diagnosed with bronchiectasis and followed up until their last visit, death, or the end of the observation period. The cohort comprised 586 (56\u0026middot;13%) patients without NTM and 458 (43\u0026middot;87%) patients with NTM (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Most patients were women (n\u0026thinsp;=\u0026thinsp;807, 77\u0026middot;3%), with a median age of 72 (IQR 63\u0026ndash;77) years and a median BMI of 19\u0026middot;33 (IQR 17\u0026middot;54\u0026thinsp;\u0026minus;\u0026thinsp;21\u0026middot;36) kg/m\u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRegarding BE-causing comorbidities, post-pneumonia conditions were confirmed in 215 patients (20\u0026middot;59%), with 100 having a history of tuberculosis (TB). Other comorbidities included chronic sinusitis in 97 patients (9\u0026middot;29%), airway abnormalities and aspiration syndrome in 82 (7\u0026middot;85%), asthma in 74 (7\u0026middot;09%), COPD in 59 (5\u0026middot;65%), RA in 54 (5\u0026middot;17%), allergic bronchopulmonary aspergillosis in 4 (0\u0026middot;38%), and other conditions in 3 (0\u0026middot;29%). Cases without known causes of BE, considered idiopathic BE, accounted for 408 patients (39\u0026middot;08%).\u003c/p\u003e \u003cp\u003eThe three most common colonizations were by \u003cem\u003eP. aeruginosa\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;119, 11\u0026middot;4%), \u003cem\u003eStaphylococcus\u003c/em\u003e species (n\u0026thinsp;=\u0026thinsp;33, 3\u0026middot;16%), and \u003cem\u003eHaemophilus influenza\u003c/em\u003e (n\u0026thinsp;=\u0026thinsp;22, 2\u0026middot;11%).\u003c/p\u003e \u003cp\u003eIn the 2 years prior to diagnosis, 14\u0026middot;94% (156/1044) of patients with bronchiectasis had experienced severe exacerbation episodes. The rates of severe exacerbation 1 and 3 years after diagnosis were 14\u0026middot;08% (n\u0026thinsp;=\u0026thinsp;147) and 22\u0026middot;32% (n\u0026thinsp;=\u0026thinsp;233), respectively. The mortality rates at 1 and 3 years were 1\u0026middot;25% (n\u0026thinsp;=\u0026thinsp;13) and 3\u0026middot;16% (n\u0026thinsp;=\u0026thinsp;33), respectively (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of patients with bronchiectasis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall (n\u0026thinsp;=\u0026thinsp;1044)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e807 (77\u0026middot;3) \u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 [63\u0026ndash;77]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e) (n\u0026thinsp;=\u0026thinsp;933)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u0026middot;33 [17\u0026middot;54\u0026thinsp;\u0026minus;\u0026thinsp;21\u0026middot;36]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emMRC 0, 1, 2, 3, 4, No (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e535 (51\u0026middot;25), 351 (33\u0026middot;62), 104 (9\u0026middot;96), 45 (4\u0026middot;31), 9 (0\u0026middot;86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBronchiectasis Severity Index (n\u0026thinsp;=\u0026thinsp;363), No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild, Moderate, Severe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (8\u0026middot;82), 99 (27\u0026middot;27), 232 (63\u0026middot;91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFACED score (n\u0026thinsp;=\u0026thinsp;363), No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild, Moderate, Severe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e180 (49\u0026middot;59), 147 (40\u0026middot;50), 36 (9\u0026middot;91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking status, No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e789 (75\u0026middot;58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer, Current\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e255 (24\u0026middot;43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNTM diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e458 (43\u0026middot;87)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComorbidities, No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost infection\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e215 (20\u0026middot;59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAirway abnormality and aspiration syndrome\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (7\u0026middot;85)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59 (5\u0026middot;65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsthma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74 (7\u0026middot;09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAllergic bronchopulmonary aspergillosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (0\u0026middot;38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic sinusitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97 (9\u0026middot;29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRheumatoid arthritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54 (5\u0026middot;17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (0\u0026middot;29)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaboratory findings\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood neutrophils, /\u0026micro;L (n\u0026thinsp;=\u0026thinsp;980)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3705 [2820\u0026ndash;5118]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood eosinophils, /\u0026micro;L (n\u0026thinsp;=\u0026thinsp;980)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130 [80\u0026ndash;210]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP, mg/L (n\u0026thinsp;=\u0026thinsp;979)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026middot;17 [0\u0026middot;1\u0026thinsp;\u0026minus;\u0026thinsp;0\u0026middot;82]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR, mm (n\u0026thinsp;=\u0026thinsp;704)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 [14\u0026ndash;60]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive anti-GPL-core IgA antibody (n\u0026thinsp;=\u0026thinsp;891)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e437 (49\u0026middot;05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive MPO-ANCA, unit/ml (n\u0026thinsp;=\u0026thinsp;180)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2\u0026middot;22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLung function test results (n\u0026thinsp;=\u0026thinsp;364)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV1\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026middot;62 [1\u0026middot;21\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;07]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026middot;21 [1\u0026middot;68\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;70]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%FEV1\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u0026middot;65 [63\u0026middot;28\u0026ndash;98\u0026middot;9]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV1\u0026middot;0/FVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u0026middot;16 [68\u0026middot;94\u0026thinsp;\u0026minus;\u0026thinsp;84\u0026middot;67]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease extension on CT, No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;2 lobes affected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e659 (63\u0026middot;12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCystic bronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e156 (14\u0026middot;94)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCavities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e236 (22\u0026middot;61)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChronic colonization, No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119 (11\u0026middot;4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eStaphylococcus species\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (3\u0026middot;16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eHaemophilus influenza\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (2\u0026middot;11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eStreptococcus pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (1\u0026middot;34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (0\u0026middot;86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAspergillus species\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (1\u0026middot;72)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (2\u0026middot;87)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOutcome, No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere exacerbation in the past 2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e161 (15\u0026middot;42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere exacerbation during 1-year follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e147 (14\u0026middot;08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere exacerbation during 3-year follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e233 (22\u0026middot;32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMortality during 1-year follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (1\u0026middot;25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMortality during 3-year follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (3\u0026middot;16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e1\u003c/sup\u003eAfter bacterial or viral pneumonia (n\u0026thinsp;=\u0026thinsp;115) or tuberculosis (n\u0026thinsp;=\u0026thinsp;100).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e2\u003c/sup\u003eAirway obstruction by tumor or foreign body and vocal cord disease or dysfunction; esophageal disease or dysmotility (head and neck cancer, prior radiation treatment, neurologic disease, esophageal motility disorder, gastroesophageal reflux disease).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e3\u003c/sup\u003e Immunodeficiency (n\u0026thinsp;=\u0026thinsp;1), Sj\u0026ouml;gren\u0026rsquo;s syndrome (n\u0026thinsp;=\u0026thinsp;1), Scleroderma (n\u0026thinsp;=\u0026thinsp;1).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*Abbreviations: BMI, body mass index; mMRC, modified Medical Research Council dyspnea scale; NTM, nontuberculous mycobacteria; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GPL, glycopeptidolipid; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibodies; FEV1\u0026middot;0, forced expiratory volume in one second; FVC, forced vital capacity; CT, computed tomography.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u0026Dagger;Data are presented as n (%) or median [interquartile range].\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe baseline characteristics of the patients with and without NTM are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In the non-NTM group, a higher proportion of males (p\u0026thinsp;=\u0026thinsp;0\u0026middot;0074), higher BMI (p\u0026thinsp;=\u0026thinsp;0\u0026middot;0010), and elevated inflammatory profiles, such as BNCs (p\u0026thinsp;=\u0026thinsp;0\u0026middot;0002), CRP (p\u0026thinsp;=\u0026thinsp;0\u0026middot;0023), and ESR (p\u0026thinsp;=\u0026thinsp;0\u0026middot;0007) were observed. While %FEV1\u0026middot;0 was lower (p\u0026thinsp;=\u0026thinsp;0\u0026middot;0171), CT scans showed more localized lesions (p\u0026thinsp;\u0026lt;\u0026thinsp;0\u0026middot;0001) and less frequent cavitation in the non-NTM group (p\u0026thinsp;\u0026lt;\u0026thinsp;0\u0026middot;0001) than in the NTM group. Additionally, \u003cem\u003eP. aeruginosa\u003c/em\u003e colonization was more common in patients without NTM than in those with (p\u0026thinsp;=\u0026thinsp;0\u0026middot;0008), with a significantly higher detection rate during exacerbations (p\u0026thinsp;\u0026lt;\u0026thinsp;0\u0026middot;0001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e [see Additional file 1]). There was no significant difference in the number of culture tests between patients with and without NTM (P\u0026thinsp;=\u0026thinsp;0\u0026middot;867).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparative baseline characteristics between patients with and without NTM\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOverall (n\u0026thinsp;=\u0026thinsp;1044)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-NTM* (n\u0026thinsp;=\u0026thinsp;586)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNTM (n\u0026thinsp;=\u0026thinsp;458)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep Value\u003csup\u003e\u0026sect;\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e807 (77\u0026middot;3) \u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e435 (74\u0026middot;23)\u003csup\u003e\u0026Dagger;\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e372 (81\u0026middot;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;0074\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72 [63\u0026ndash;77]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72 [63\u0026middot;25\u0026ndash;77]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72 [63\u0026ndash;78]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;7374\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19\u0026middot;33 [17\u0026middot;54\u0026thinsp;\u0026minus;\u0026thinsp;21\u0026middot;36]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19\u0026middot;64 [17\u0026middot;75\u0026thinsp;\u0026minus;\u0026thinsp;21\u0026middot;88]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19\u0026middot;12 [17\u0026middot;23\u0026thinsp;\u0026minus;\u0026thinsp;20\u0026middot;77]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;0010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emMRC\u0026thinsp;\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e158 (15\u0026middot;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83 (14\u0026middot;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75 (16\u0026middot;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;3391\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBronchiectasis Severity Index (n\u0026thinsp;=\u0026thinsp;363), No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMild\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (8\u0026middot;82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (9\u0026middot;04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (8\u0026middot;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eModerate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e99 (27\u0026middot;27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (29\u0026middot;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e43 (24\u0026middot;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;2895\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e232 (63\u0026middot;91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e115 (61\u0026middot;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e117 (66\u0026middot;86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;2755\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking status, No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e789 (75\u0026middot;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e433 (73\u0026middot;89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e356 (77\u0026middot;73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer, Current\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e255 (24\u0026middot;43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e153 (26\u0026middot;11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102 (22\u0026middot;27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;1679\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaboratory findings\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood neutrophils, /\u0026micro;L (n\u0026thinsp;=\u0026thinsp;980)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3705 [2820\u0026ndash;5118]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3860 [2950\u0026ndash;5455]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3510 [2680\u0026ndash;4780]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;0002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood eosinophils, /\u0026micro;L (n\u0026thinsp;=\u0026thinsp;980)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e130 [80\u0026ndash;210]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e130 [80\u0026ndash;210]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130 [80\u0026ndash;200]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;9695\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP, mg/L (n\u0026thinsp;=\u0026thinsp;979)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u0026middot;17 [0\u0026middot;1\u0026thinsp;\u0026minus;\u0026thinsp;0\u0026middot;82]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u0026middot;23 [0\u0026middot;1\u0026thinsp;\u0026minus;\u0026thinsp;0\u0026middot;9975]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u0026middot;12 [0\u0026middot;1\u0026thinsp;\u0026minus;\u0026thinsp;0\u0026middot;62]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;0023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eESR, mm (n\u0026thinsp;=\u0026thinsp;704)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 [14\u0026ndash;60]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 [16\u0026ndash;67\u0026middot;5]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 [13\u0026ndash;53]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;0007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePositive anti-GPL-core IgA antibody, (n\u0026thinsp;=\u0026thinsp;891)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e437 (49\u0026middot;05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e106 (23\u0026middot;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e331 (75\u0026middot;40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0\u0026middot;0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLung function test results (n\u0026thinsp;=\u0026thinsp;364)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV1\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u0026middot;62 [1\u0026middot;21\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;07]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u0026middot;575 [1\u0026middot;16\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;09]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u0026middot;64 [1\u0026middot;29\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;04]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;2492\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u0026middot;21 [1\u0026middot;68\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;70]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u0026middot;18 [1\u0026middot;56\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;67]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u0026middot;25 [1\u0026middot;79\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;71]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;3383\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e%FEV1\u0026middot;0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u0026middot;65 [63\u0026middot;28\u0026ndash;98\u0026middot;9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76\u0026middot;05 [61\u0026ndash;96\u0026middot;9]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84\u0026middot;35 [65\u0026middot;15\u0026ndash;103\u0026middot;68]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;0171\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV1\u0026middot;0/FVC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u0026middot;16 [68\u0026middot;94\u0026thinsp;\u0026minus;\u0026thinsp;84\u0026middot;67]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75\u0026middot;75 [68\u0026middot;01\u0026ndash;84\u0026middot;64]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e76\u0026middot;59 [70\u0026middot;04\u0026ndash;84\u0026middot;87]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;5511\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDisease extension on CT, No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;2 lobes affected\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e659 (63\u0026middot;12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e325 (55\u0026middot;46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e334 (72\u0026middot;93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0\u0026middot;0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCystic bronchiectasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e156 (14\u0026middot;94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76 (12\u0026middot;97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e80 (17\u0026middot;47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;0466\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCavities\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e236 (22\u0026middot;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e96 (16\u0026middot;38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e140 (30\u0026middot;57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0\u0026middot;0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChronic colonization, No (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119 (11\u0026middot;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84 (14\u0026middot;33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35 (7\u0026middot;64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u0026middot;0008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003csup\u003e\u0026sect;\u003c/sup\u003eDifferences among continuous variables were assessed using the Wilcoxon rank-sum test; differences among categorical variables were assessed using the Fisher\u0026rsquo;s exact test, as appropriate.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*Abbreviations: NTM, nontuberculous mycobacteria; SMD, standardized mean difference; IPW, inverse probability weighting; ATE, average treatment effect; BMI, body mass index.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u0026Dagger;Data are presented as n (%) or median (interquartile range).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: NTM, nontuberculous mycobacteria; IPW, inverse probability weighting; BMI, body mass index; mMRC, modified Medical Research Council dyspnea scale; CT, computed tomography; CRP, C-reactive protein; \u003cem\u003eP. aeruginosa, Pseudomonas aeruginosa\u003c/em\u003e.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Effect of each risk factor on time to first severe exacerbation\u003c/h2\u003e \u003cp\u003eWe then conducted univariate and multivariate Cox proportional hazards analyses to identify potential risk factors for the first exacerbation in patients with and without NTM (Supplementary Table S2 [see Additional file 1]).\u003c/p\u003e \u003cp\u003eIn patients without NTM, multivariable analysis revealed that while higher BMI (hazard ratio [HR]\u0026thinsp;=\u0026thinsp;0\u0026middot;89, 95% confidence interval [CI], 0\u0026middot;84\u0026thinsp;\u0026minus;\u0026thinsp;0\u0026middot;95) was associated with a significantly lower risk of first exacerbation, male sex (HR\u0026thinsp;=\u0026thinsp;1\u0026middot;74, 95% CI, 1\u0026middot;11\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;75), higher mMRC (the scale is 2; HR\u0026thinsp;=\u0026thinsp;1\u0026middot;9, 95% CI 1\u0026middot;05\u0026thinsp;\u0026minus;\u0026thinsp;3\u0026middot;58 and the scale is 3; HR\u0026thinsp;=\u0026thinsp;2\u0026middot;7, 95% CI 1\u0026middot;27\u0026thinsp;\u0026minus;\u0026thinsp;5\u0026middot;63), COPD (HR\u0026thinsp;=\u0026thinsp;2\u0026middot;01, 95% CI, 1\u0026middot;15\u0026thinsp;\u0026minus;\u0026thinsp;3\u0026middot;54), CRP (HR\u0026thinsp;=\u0026thinsp;1\u0026middot;09, 95% CI, 1\u0026middot;03\u0026thinsp;\u0026minus;\u0026thinsp;1\u0026middot;15), disease extension over three lobes (HR\u0026thinsp;=\u0026thinsp;2\u0026middot;01, 95% CI, 1\u0026middot;17\u0026thinsp;\u0026minus;\u0026thinsp;3\u0026middot;46), cystic bronchiectasis on CT (HR\u0026thinsp;=\u0026thinsp;1\u0026middot;9, 95% CI, 1\u0026middot;18\u0026thinsp;\u0026minus;\u0026thinsp;3\u0026middot;06), and \u003cem\u003eP. aeruginosa\u003c/em\u003e colonization (HR\u0026thinsp;=\u0026thinsp;2\u0026middot;07, 95% CI, 1\u0026middot;34\u0026thinsp;\u0026minus;\u0026thinsp;3\u0026middot;2) were associated with significantly higher risks of severe exacerbation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn patients with NTM, the multivariable analysis revealed that COPD (HR\u0026thinsp;=\u0026thinsp;2\u0026middot;24, 95% CI, 1\u0026middot;19\u0026thinsp;\u0026minus;\u0026thinsp;4\u0026middot;2), RA (HR\u0026thinsp;=\u0026thinsp;2\u0026middot;35, 95% CI, 1\u0026middot;21\u0026thinsp;\u0026minus;\u0026thinsp;4\u0026middot;6), disease extension of three or more lobes (HR\u0026thinsp;=\u0026thinsp;1\u0026middot;68, 95% CI, 1\u0026middot;08\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;6), and cystic bronchiectasis (HR\u0026thinsp;=\u0026thinsp;1\u0026middot;65, 95% CI, 1\u0026middot;03\u0026thinsp;\u0026minus;\u0026thinsp;2\u0026middot;6) and cavities (HR\u0026thinsp;=\u0026thinsp;1\u0026middot;55, 95% CI 1\u0026middot;1\u0026ndash;2\u0026middot;2) on CT were associated with a significantly higher risk of first exacerbation, while lower mMRC score, elevated inflammatory profiles, and \u003cem\u003eP. aeruginosa\u003c/em\u003e colonization were not statistically significant (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Effect of NTM on OS in NCBE\u003c/h2\u003e \u003cp\u003eWe compared the time to death between the non-NTM and NTM groups using Kaplan\u0026ndash;Meier survival analysis. The median follow-up time (IQR) from diagnosis was 27\u0026middot;8 (5\u0026middot;6\u0026ndash;56\u0026middot;7) months in patients with and without NTM. Additionally, the median survival time was not reached. By the end of the follow-up, 64/1044 (6\u0026middot;13%) patients had died. The OS was not significantly different between the two groups (log-rank p\u0026thinsp;=\u0026thinsp;0\u0026middot;4621) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe further used Cox proportional hazard regression for multivariate analyses to evaluate the effect of each risk factor, including NTM, on overall OS in NCBE (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). The results suggested that higher BMI (HR\u0026thinsp;=\u0026thinsp;0\u0026middot;74, 95% CI, 0\u0026middot;65\u0026thinsp;\u0026minus;\u0026thinsp;0\u0026middot;84) was associated with a significantly lower risk of mortality and that male sex (HR\u0026thinsp;=\u0026thinsp;2\u0026middot;06, 95% CI, 1\u0026middot;02\u0026ndash;4\u0026middot;13), higher age (HR\u0026thinsp;=\u0026thinsp;1\u0026middot;10, 95% CI, 1\u0026middot;06\u0026thinsp;\u0026minus;\u0026thinsp;1\u0026middot;15), higher mMRC (the scale is 4; HR\u0026thinsp;=\u0026thinsp;3\u0026middot;73, 95% CI, 1\u0026middot;01\u0026ndash;13\u0026middot;72), COPD (HR\u0026thinsp;=\u0026thinsp;2\u0026middot;93, 95% CI, 1\u0026middot;41\u0026thinsp;\u0026minus;\u0026thinsp;6\u0026middot;12), elevated CRP (HR\u0026thinsp;=\u0026thinsp;1\u0026middot;08, 95% CI, 1\u0026middot;02\u0026thinsp;\u0026minus;\u0026thinsp;1\u0026middot;15), cystic bronchiectasis (HR\u0026thinsp;=\u0026thinsp;3\u0026middot;05, 95% CI, 1\u0026middot;59\u0026thinsp;\u0026minus;\u0026thinsp;5\u0026middot;83) and cavities (HR\u0026thinsp;=\u0026thinsp;3\u0026middot;38, 95% CI, 1\u0026middot;75\u0026thinsp;\u0026minus;\u0026thinsp;6\u0026middot;55) on CT were associated with a significantly higher risk of mortality. However, NTM was not significantly associated with OS in non-cystic bronchiectasis (HR\u0026thinsp;=\u0026thinsp;0\u0026middot;80, 95% CI, 0\u0026middot;43\u0026thinsp;\u0026minus;\u0026thinsp;1\u0026middot;47).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Effect of long-term macrolide antibiotic use\u003c/h2\u003e \u003cp\u003eOf the 586 patients without NTM, 208 (35\u0026middot;5%) received macrolide antibiotics, and 43 (7\u0026middot;34%) received inhaled steroids. Macrolides were more frequently administered to patients without a history of exacerbation (391 of 500, 78\u0026middot;2%) than to those who had experienced such events (109 of 500, 21\u0026middot;8%) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Supplementary Table S3 [see Additional file 1]). Given this pattern, we evaluated the effects of macrolide (azithromycin, clarithromycin, and erythromycin) exposure in patients who had not experienced exacerbations for 2 years before diagnosis. Among 320 patients, 201 (62\u0026middot;8%) were not receiving long-term macrolide antibiotics, while 119 (37\u0026middot;2%) were receiving them. In both subsets, all covariates were adjusted for balance using the IPW (ATE-weighted) (Supplementary Table S4 [see Additional file 1]). The time to first exacerbation leading to hospitalization did not differ between the groups (log-rank P\u0026thinsp;=\u0026thinsp;0\u0026middot;3801) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). Similar results were observed after IPW adjustment (log-rank test, P\u0026thinsp;=\u0026thinsp;0\u0026middot;7222) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 DISCUSSION","content":"\u003cp\u003eThis is the largest retrospective cohort study of NCBE in Japan and serves as a benchmark for the epidemiological understanding of NCBE in Asia, shedding light on prognostic indicators. We found that the mortality rate was low and identified a significant prevalence of comorbidities, including NTM, prior TB, and sinusitis infections. Prognostic factors were similar to those from previous studies: higher BMI was associated with a lower risk of exacerbations and mortality, while factors such as COPD and disease severity on CT significantly increased risk, and NTM did not affect prognosis. Moreover, although many patients with non-NTM BE received long-term macrolide antibiotics, a significant proportion of these were patients without a history of exacerbations. This treatment did not significantly affect the time to the first severe exacerbation post-diagnosis in patients with non-NTM BE.\u003c/p\u003e \u003cp\u003eRegarding patient characteristics, our population had more older patients, women, patients with lower BMI, and never-smokers than those in the EMBARC registry data [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Although the incidence of severe exacerbations aligns with previously reported data, our 1- and 3-year mortality rates were notably lower (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These gaps may be due to capturing milder cases by the widespread availability of CT, variations in insurance coverage, differing criteria for hospitalization, and prevalence of the screening system [\u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study did not aim to identify specific etiologies but to document the frequency of comorbidities that can lead to this condition, emphasizing their prevalence. The significant co-occurrence of NTM aligns with the findings of previous research [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe frequency of idiopathic and post-infection BE cases was similar to that reported in previous studies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, a predominance of older patients with TB was observed (n\u0026thinsp;=\u0026thinsp;100). Logistic regression analysis revealed a significant correlation between age and TB (p\u0026thinsp;\u0026lt;\u0026thinsp;0\u0026middot;0001) (data not shown). These findings may represent subsets that are particularly prevalent in Asia populations.\u003c/p\u003e \u003cp\u003eNumerous patients within the cohort were categorized as having severe disease based on the BSI score, a classification that appears incongruent with the observed mortality rates. In the Japanese context, factors such as older age and physically lower BMI may contribute to elevated BSI scores (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). These scores may not provide clinicians with insight into the specific management strategies required in routine clinical practice [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDetermining whether NTM infection precedes the development of BE remains challenging [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, similar to that reported in recent U.S. cohorts [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], many NCBE patients met the American Thoracic Society/Infectious Diseases Society of America criteria for NTM pulmonary disease. The 5-year mortality rate was low, and survival outcomes did not differ significantly between patients with and without NTM, aligning with findings from the U.S. registry. Our validation reaffirms the high prevalence of NTM in Japan and represents Asia and Japanese landscape.\u003c/p\u003e \u003cp\u003eWhen focusing on the differences between the non-NTM and NTM groups, we found that the non-NTM group had a significantly higher proportion of men and elevated BMI and inflammatory markers, such as BNCs, CRP, and ESR. Previous large-scale database and cohort analyses have not reported data specifically focusing on this inflammatory profile [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In future studies, it may be crucial to categorize patients with NCBE based on their endotypes and phenotype [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] for precision medicine.\u003c/p\u003e \u003cp\u003eRegarding the results for each prognostic indicator utilized in daily practice, COPD, inflammatory markers such as CRP, cavities, and cystic bronchiectasis were associated with mortality and severe exacerbation, similar to previous reports [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan additionalcitationids=\"CR31 CR32\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb, and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). Notably, in patients without NTM, inflammation may play a crucial role in exacerbation (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea), highlighting the pathophysiological vortex of disease progression [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Therefore, these results suggest the need to manage the inflammatory process [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn contrast, \u003cem\u003eP. aeruginosa\u003c/em\u003e is a well-established prognostic factor for bronchiectasis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]; however, in our study, it was more frequently identified as a colonizing or pathogenic microorganism with severe exacerbations in the non-NTM group but not in the NTM group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e [see Additional file 1]). Additionally, in a recent U.S. study focusing on the presence or absence of NTM in the BE registry, \u003cem\u003eP. aeruginosa\u003c/em\u003e was not identified as a prognostic factor [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This raises questions about whether differences exist in prognostic factors between patients with and without NTM. One study indicated that bacterial coinfections can occur after starting treatment for \u003cem\u003eMycobacterium avium\u003c/em\u003e complex pulmonary disease [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Under certain conditions, NTM might provide a protective effect against \u003cem\u003ePseudomonas\u003c/em\u003e infection, or they may regulate each other\u0026rsquo;s virulence. These findings suggest complex interactions within the bacterial flora that warrant further investigation.\u003c/p\u003e \u003cp\u003eWe focused on the prescription pattern in patients without NTM infection. Compared with Western registries such as EMBARC [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], this cohort showed higher use of macrolides and lower use of inhaled steroids and inhaled antibiotics. In Japan, macrolide antibiotics are indicated for neutrophilic airway inflammation and can be used in a wide range of conditions, including COPD, DPB, bronchiectasis, and bronchial asthma, with or without a history of exacerbations. However, the indiscriminate use of macrolides contributes to increased resistance in potentially co-existing NTM. Additionally, the use of inhaled corticosteroids (ICSs) in this cohort was primarily noted in cases with coexisting asthma, highlighting regional differences in treatment practices; in Western countries, ICSs are more commonly prescribed directly for bronchiectasis. In Japan, inhaled tobramycin is only approved for CF, and amikacin liposomal inhalation is only approved for treatment-resistant \u003cem\u003eMycobacterium avium\u003c/em\u003e complex, reflecting further limitations in treatment options for BE. We also found substantial prescription of clarithromycin monotherapy for milder cases. Moreover, very few instances of erythromycin or azithromycin use have been observed. These behaviors may not reflect widely recognized guidelines (Supplementary Table S4 [see Additional file 1]) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The results of our covariate-adjusted IPW analysis suggested that the prophylactic use of long-term macrolide antibiotics did not invariably reduce further severe exacerbations in patients with no history of such events (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea, b). We speculate that there is high awareness and active research on DPB in Japan [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. NCBE has long been considered an orphan disease [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Furthermore, successful experiences with macrolides in DPB [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] may have led to a dependency on these medications. Additionally, the lack of inhaled antibiotic options for non-CF BE in Japan may have contributed to this dependency.\u003c/p\u003e \u003cp\u003eOur findings serve as a cautionary note for routine clinical practice in Japan. The unrestricted prescription of macrolides can lead to refractoriness and resistance in NTM. Further verification of the effectiveness of macrolides in mild cases is required, not only in suppressing exacerbations but also in improving symptoms, quality of life, and effects on comorbid chronic sinusitis.\u003c/p\u003e \u003cp\u003eIn summary, this cohort study clarified the epidemiology of NCBE and the potential parameters that guide patient management in Japan. Moreover, our findings critically verify the application of macrolides in routine clinical settings and underscore the need for further investigation in this field.\u003c/p\u003e \u003cp\u003eThis study had some limitations. First, its retrospective design precluded elimination of all potential confounding factors. Although substantial cohorts exist globally, the evidence is particularly sparse in Japan, underscoring the necessity for ongoing real-world cohort studies in future. Second, there was a lack of PFT data. In a Cox proportional hazard regression for multivariate analysis, a variable with missing data was not suitable for evaluation as a prognostic value, and we did not consider PFTs or each severity index as prognostic variables. This study highlights the need to increase our awareness and understanding of BE, perform PFTs, and regularly follow-up in daily clinical practice. Third, the lack of a validation cohort within our study precluded the verification of predictive accuracy. However, our primary goal was not to construct a prediction model but to provide the first epidemiological overview relevant to Japan and Asia. Further research is needed to identify predictors of poor outcomes. Fourth, the retrospective nature of the study also means that treatment decisions regarding the timing and choice of macrolide antibiotics were at the discretion of individual pulmonary physicians, introducing the potential for immortal time bias in assessing the ATE of long-term macrolide antibiotics. Future randomized controlled trials in patient populations with no previous exacerbations are needed for an accurate evaluation. Fifth, the end point of follow-up termination may have introduced a measurement bias affecting the interpretation of the results. Efforts have been made to mitigate this through extensive follow-up via regional medical liaison offices and interhospital communication, minimizing loss to death or follow-up discontinuation. Sixth, this study does not identify the specific etiology of bronchiectasis because bronchiectasis can have multiple potential causes, making it impossible to pinpoint a single etiology. Seventh, approximately 23% of patients without NTM tested positive for IgA antibodies to glycopeptidolipid core antigen, suggesting that NTM might be underestimated. Hence, it is challenging to capture the true NTM population.\u003c/p\u003e"},{"header":"5 CONCLUSION","content":"\u003cp\u003eOur study represents an inaugural large-scale epidemiological cohort study of patients with NCBE in a real-world setting in Japan. Our findings highlight the distinct characteristics of this patient population, signifying a clear need for future therapeutic strategies. Additionally, this study illuminates poor prognostic factors warranting attention in clinical practice and underscores the importance of diligent follow-up.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003enon-cystic fibrosis bronchiectasis (NCBE)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003enontuberculous mycobacteria (NTM)\u003c/p\u003e\n\u003cp\u003einverse probability weighting (IPW)\u003c/p\u003e\n\u003cp\u003eEuropean Multicenter Bronchiectasis Adult and Research Collaboration (EMBARC)\u003c/p\u003e\n\u003cp\u003echronic obstructive pulmonary disease (COPD)\u003c/p\u003e\n\u003cp\u003ebronchial asthma (BA)\u003c/p\u003e\n\u003cp\u003ediffuse panbronchiolitis (DPB)\u003c/p\u003e\n\u003cp\u003ebody mass index (BMI)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003emodified Medical Research Council dyspnea\u0026nbsp;scale (mMRC)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBronchiectasis Severity Index (BSI)\u003c/p\u003e\n\u003cp\u003eblood neutrophil counts (BNCs)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eblood eosinophil count (BEC)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eC-reactive protein (CRP)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eerythrocyte sedimentation rate (ESR)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eglycopeptidolipid (GPL)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003epulmonary function test (PFT)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eforced vital capacity (FVC)\u003c/p\u003e\n\u003cp\u003eoverall survival (OS)\u003c/p\u003e\n\u003cp\u003eacid-fast bacilli (AFB)\u003c/p\u003e\n\u003cp\u003einterquartile ranges (IQRs)\u003c/p\u003e\n\u003cp\u003erheumatoid arthritis (RA)\u003c/p\u003e\n\u003cp\u003estandardized mean difference (SMD)\u003c/p\u003e\n\u003cp\u003etuberculosis (TB)\u003c/p\u003e\n\u003cp\u003ehazard ratio (HR)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003econfidence interval (CI)\u003c/p\u003e\n\u003cp\u003einhaled corticosteroids (ICSs)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e The study was approved by the Institutional Review Board of the National Hospital Organization of Osaka Toneyama Medical Centre (approval no. TNH-R-2024002). Informed consent was obtained from all participants for the use of their data in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported in part by AMED (grant numbers JP20fk0108129, JP21fk0108129h0702, JP21lm02007), JSPS KAKENHI (Grant numbers JP21K16118, JP21K08194), Takeda Science Foundation, Uehara Memorial Foundation, MSD Life Science Foundation, Japanese Respiratory Society Boehringer Ingelheim Research Grant Program, Foundation of Kinoshita Memorial Enterprise, Senri Life Science Foundation, and the Japan Intractable Diseases (Nanbyo) Research Foundation (Grant Number 2020B02), Osaka Medical Research Foundation for Intractable Diseases, and Inamori Foundation. The funders had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript, this should be declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKH, YA, and KF designed the project. KH, YA, KF, and NT analyzed the clinical data. KH, KF, Takayuki Niitsu, and SM conducted CT image analysis. KH, KF, Takayuki Niitsu, and SM conducted clinical data extraction. SM, Takuro Nii, TM, and HK assisted with clinical data extraction. SK assisted with data analysis. KH, YA, KF, and Takayuki Niitsu performed statistical analysis. KM and HK supervised the project. KF and HK are responsible for the overall content as guarantors. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe thank the pulmonary radiologists at Osaka Toneyama Medical Centre for their helpful discussions regarding chest computed tomography assessments. We also thank E. Akiba for assistance with data collection and helpful discussions.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eO\u0026apos;Donnell AE: \u003cstrong\u003eBronchiectasis - A Clinical Review\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2022, \u003cstrong\u003e387\u003c/strong\u003e(6):533-545.\u003c/li\u003e\n\u003cli\u003eKinney WM: \u003cstrong\u003eBronchiectasis; a neglected disease\u003c/strong\u003e. \u003cem\u003eDis Chest \u003c/em\u003e1947, \u003cstrong\u003e13\u003c/strong\u003e(1):33-47.\u003c/li\u003e\n\u003cli\u003eChalmers JD, Polverino E, Crichton ML, Ringshausen FC, De Soyza A, Vendrell M, Burgel PR, Haworth CS, Loebinger MR, Dimakou K\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eBronchiectasis in Europe: data on disease characteristics from the European Bronchiectasis registry (EMBARC)\u003c/strong\u003e. \u003cem\u003eLancet Respir Med \u003c/em\u003e2023, 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Research Patient Survey and the Bronchiectasis and NTM Research Registry\u003c/strong\u003e. \u003cem\u003eChest \u003c/em\u003e2017, \u003cstrong\u003e152\u003c/strong\u003e(6):1120-1127.\u003c/li\u003e\n\u003cli\u003ePollock J, Goeminne PC: \u003cstrong\u003eEosinophils in Bronchiectasis: A U-Turn for Bronchiectasis Management\u003c/strong\u003e. \u003cem\u003eChest \u003c/em\u003e2023, \u003cstrong\u003e164\u003c/strong\u003e(3):561-563.\u003c/li\u003e\n\u003cli\u003eSin S, Yun SY, Kim JM, Park CM, Cho J, Choi SM, Lee J, Park YS, Lee SM, Yoo CG\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eMortality risk and causes of death in patients with non-cystic fibrosis bronchiectasis\u003c/strong\u003e. \u003cem\u003eRespir Res \u003c/em\u003e2019, \u003cstrong\u003e20\u003c/strong\u003e(1):271.\u003c/li\u003e\n\u003cli\u003eChoi H, Park HY, Han K, Yoo J, Shin SH, Yang B, Kim Y, Park TS, Park DW, Moon JY\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eNon-Cystic Fibrosis Bronchiectasis Increases the Risk of Lung Cancer Independent of Smoking Status\u003c/strong\u003e. \u003cem\u003eAnn Am Thorac Soc \u003c/em\u003e2022, \u003cstrong\u003e19\u003c/strong\u003e(9):1551-1560.\u003c/li\u003e\n\u003cli\u003eMao B, Lu HW, Li MH, Fan LC, Yang JW, Miao XY, Xu JF: \u003cstrong\u003eThe existence of bronchiectasis predicts worse prognosis in patients with COPD\u003c/strong\u003e. \u003cem\u003eSci Rep \u003c/em\u003e2015, \u003cstrong\u003e5\u003c/strong\u003e:10961.\u003c/li\u003e\n\u003cli\u003eChalmers JD, Chotirmall SH: \u003cstrong\u003eBronchiectasis: new therapies and new perspectives\u003c/strong\u003e. \u003cem\u003eLancet Respir Med \u003c/em\u003e2018, \u003cstrong\u003e6\u003c/strong\u003e(9):715-726.\u003c/li\u003e\n\u003cli\u003eFlume PA, Chalmers JD, Olivier KN: \u003cstrong\u003eAdvances in bronchiectasis: endotyping, genetics, microbiome, and disease heterogeneity\u003c/strong\u003e. \u003cem\u003eLancet \u003c/em\u003e2018, \u003cstrong\u003e392\u003c/strong\u003e(10150):880-890.\u003c/li\u003e\n\u003cli\u003eChalmers JD, Haworth CS, Metersky ML, Loebinger MR, Blasi F, Sibila O, O\u0026apos;Donnell AE, Sullivan EJ, Mange KC, Fernandez C\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003ePhase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis\u003c/strong\u003e. \u003cem\u003eN Engl J Med \u003c/em\u003e2020, \u003cstrong\u003e383\u003c/strong\u003e(22):2127-2137.\u003c/li\u003e\n\u003cli\u003eUrabe N, Sakamoto S, Shimanuki Y, Kanokogi T, Motohashi T, Anzai N, Kato C, Yamaguchi A, Tokita N, Homma S\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eImpact of chronic co-infection in pulmonary Mycobacterium avium complex disease after treatment initiation\u003c/strong\u003e. \u003cem\u003eBMC Pulm Med \u003c/em\u003e2022, \u003cstrong\u003e22\u003c/strong\u003e(1):157.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"non-cystic fibrosis bronchiectasis, macrolides, nontuberculous mycobacteria, TB","lastPublishedDoi":"10.21203/rs.3.rs-4592641/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4592641/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eThe characteristics of non-cystic fibrosis bronchiectasis (NCBE) in Asia, including Japan, remain largely unknown. We aimed to provide insights into the clinical characteristics and treatment outcomes of NCBE, especially regarding nontuberculous mycobacteria (NTM) infection, and establish a basis for comparison with global datasets. In addition, long-term macrolide antibiotic use in patients with NCBE and a history of exacerbations is established, but the effects in patients without exacerbations remain unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this single-center, retrospective study, the medical records of patients who satisfied the NCBE criteria between 1 January 2012 and 31 August 2023 were reviewed. Severe exacerbations and mortality during the observation period were recorded. Baseline characteristics, prognostic factors, and overall survival of patients with and without non-NTM infection were evaluated; effects of long-term macrolide antibiotic use in patients without severe exacerbations were estimated using inverse probability weighting (IPW).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e In 1044 patients with bronchiectasis, severe exacerbation rates were 22·32%, with mortality rates of 3·16% at 3 years. Notably, the high prevalence of NTM infection (n=458, 43·87%) in this cohort was distinctive. Compared with the NTM group, the non-NTM group had a higher proportion of elevated inflammatory markers, with significant differences in C-reactive protein levels (p=0·0023) and blood neutrophil counts (p\u0026lt;0·001). \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e was more frequently identified as having colonization and was associated with severe exacerbations (p\u0026lt;0·001) in the non-NTM group. NTM infection was not associated with mortality (p=0·4621, hazard ratio=0·79). Among patients with non-NTM infection and without a history of exacerbation in the past 2 years, 34·3% received long-term macrolide antibiotics that did not invariably reduce severe exacerbations (P=0·3801, IPW P=0·7222).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThis study highlights NCBE epidemiology in Japan, advising caution in the casual use of macrolides for mild cases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration: \u003c/strong\u003eUMIN Clinical Trials Registry Number: UMIN000054726 (Registered on 21 June 2024)\u003c/p\u003e","manuscriptTitle":"Epidemiology of non-cystic fibrosis bronchiectasis at a single center in Japan: a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 22:24:54","doi":"10.21203/rs.3.rs-4592641/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-08-07T08:26:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-06T20:34:04+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-20T08:49:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"235819150040127737385018205133967654086","date":"2024-07-19T21:30:47+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"185157282026392818668349670266906038209","date":"2024-07-19T16:11:27+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-25T08:59:48+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-06-24T13:05:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-24T11:49:14+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-24T11:46:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pulmonary Medicine","date":"2024-06-17T08:00:57+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4f1fad60-70c5-40bb-9c4e-b6d8782c8d27","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-28T15:59:48+00:00","versionOfRecord":{"articleIdentity":"rs-4592641","link":"https://doi.org/10.1186/s12890-024-03337-7","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2024-10-24 15:57:10","publishedOnDateReadable":"October 24th, 2024"},"versionCreatedAt":"2024-07-18 22:24:54","video":"","vorDoi":"10.1186/s12890-024-03337-7","vorDoiUrl":"https://doi.org/10.1186/s12890-024-03337-7","workflowStages":[]},"version":"v1","identity":"rs-4592641","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4592641","identity":"rs-4592641","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}