Old age is associated with worse treatment outcome and frequent adverse drug reaction in Mycobacterium avium complex pulmonary disease

Background : The number of patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) is rapidly increasing globally, especially in the older population. However, there is a dearth of evidence regarding the impact of aging on the treatment outcomes of NTM-PD. Methods : We analyzed consecutive patients who satisfied the diagnostic criteria for Mycobacterium avium complex (MAC)-PD and received antibiotic treatment between January 2009 and December 2020 at a tertiary referral hospital in Korea. The main outcomes were (1) long-term treatment success, defined by negative culture conversion for more than 12 months; and (2) adverse drug reactions (ADRs). Multivariable logistic regression model was used to evaluate the association between age and main outcomes. Results : A total of 614 patients (median age, 65 years, interquartile range [IQR] 57–73 years; men, 35.3%) were included. Median treatment duration (530 days, IQR 290–678 days; P for trend < 0.001) and long-term treatment success (P for trend = 0.026) decreased, whereas ADRs (P for trend < 0.001) increased significantly with age. Multivariable analyses demonstrated that age ≥ 80 years was an independent factor associated with ADRs (adjusted odds ratio [aOR] 3.29; 95% confidence interval [CI] 1.05–10.28) and worse treatment outcome (aOR 0.42; 95% CI 0.19–0.91). Conclusions : Aging is associated with worse treatment outcome and frequent ADRs of patients with MAC-PD. Individualized treatment with reduced-intensity may be a reasonable alternative for older adults

Longitudinal changes in health-related quality of life according to clinical course among patients with non-tuberculous mycobacterial pulmonary disease: a prospective cohort study

Improvement in health-related quality of life (HRQL) has been suggested as an alternative treatment goal of non-tuberculous mycobacterial pulmonary disease (NTM-PD). This study was performed to elucidate the longitudinal changes in HRQL using St. Georges Respiratory Questionnaire (SGRQ) among patients with NTM-PD according to their clinical course. Patients with NTM-PD who participated in Seoul National University Hospitals prospective NTM cohort were screened. Participants for whom the SGRQ score was estimated with the one-year interval for ≥ three times were included. The longitudinal trends of the SGRQ score were assessed. The impact of the clinical course on the change in the SGRQ score was elucidated using multilevel mixed-effects linear regression with a repeated-measures model. In total, 114 patients were analyzed. During the median 5-year observation period, 53 patients started anti-mycobacterial treatment and 61 patients were observed without treatment. Among the treated patients, 24 (45.2%) achieved microbiological cure. Patients who required treatment eventually had worsening SGRQ scores with time compared with patients who could be observed without treatment (P < 0.001). In cured patients, the SGRQ score decreased from 33.9 at baseline to 20.8 at 1 year post-treatment (P < 0.001), 21.3 at 2 years (P < 0.001), and 17.6 at 3 years (P < 0.001). The SGRQ scores also decreased for 2 years of treatment in patients with NTM-PD that could not be cured, although this decrease did not last for 3 years of treatment. Worsening HRQL scores were associated with the initiation of treatment and, in turn, treatment improved HRQL scores of patients with NTM-PD. This study was registered to the ClinicalTrials.gov (Identifier: NCT01616745 / registration date: June 12, 2012). The protocol was retrospectively registered

Role of ethambutol and rifampicin in the treatment of Mycobacterium avium complex pulmonary disease

Abstract Background A three-drug regimen (macrolide, ethambutol, and rifampicin) is recommended for the treatment of Mycobacterium avium complex pulmonary disease (MAC-PD). Although macrolide has proven efficacy, the role of ethambutol and rifampicin in patients without acquired immune deficiency syndrome is not proven with clinical studies. We aimed to clarify the roles of ethambutol and rifampicin in the treatment of MAC-PD. Methods Patients treated for MAC-PD between March 1st, 2009 and October 31st, 2018 were reviewed retrospectively. Rates of culture conversion, microbiological cure, treatment failure, and recurrence were compared according to the maintenance (≥6 months) of ethambutol or rifampicin with macrolide. Results Among the 237 patients, 122 (51.5%) maintained ethambutol and rifampicin with macrolide, 58 (24.5%) maintained ethambutol and macrolide, 32 (13.5%) maintained rifampicin and macrolide, and 25 (10.6%) maintained macrolide only. Culture conversion was reached for 190/237 (80.2%) patients and microbiological cure was achieved for 129/177 (72.9%) who completed the treatment. Treatment failure despite ≥12 months of treatment was observed in 66/204 (32.4%), and recurrence was identified in 16/129 (12.4%) who achieved microbiological cure. Compared with maintenance of macrolide only, maintenance of ethambutol, rifampicin or both with macrolide were associated with higher odds of culture conversion [odds ratio (OR), 95% confidence interval (CI): 18.06, 3.67–88.92; 15.82, 2.38–105.33; and 17.12, 3.93–74.60, respectively]. Higher odds of microbiological cure were associated with maintenance of both ethambutol and rifampicin with macrolide (OR, 95% CI: 5.74, 1.54–21.42) and macrolide and ethambutol (OR, 95% CI: 5.12, 1.72–15.24) but not macrolide and rifampicin. Maintenance of both ethambutol and rifampicin with macrolide was associated with lower odds of treatment failure (OR, 95% CI: 0.09, 0.01–0.53) compared with macrolide only, while maintenance of one of these with macrolide was not. Maintenance of both ethambutol and rifampicin or one of these with macrolide did not decrease the probability of recurrence when compared with macrolide only. Conclusions Maintenance (≥6 months) of ethambutol and rifampicin with macrolide was associated with the most favorable treatment outcomes among patients with MAC-PD. Given the association between ongoing ethambutol use and microbiological cure, clinicians should maintain ethambutol unless definite adverse events develop

Outcomes of adjunctive surgery for nontuberculous mycobacterial pulmonary disease

Background Owing to the unsatisfactory results of antibiotic treatment alone, surgical resection is currently considered as adjunctive therapy in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD). However, reports regarding the outcomes of surgery vary considerably by institution. Here, we investigated the surgical outcomes and risk factors associated with unfavorable outcomes after surgery. Methods We analyzed patients with NTM-PD who underwent pulmonary resection at Seoul National University Hospital between January 1, 2006, and December 31, 2020, and assessed the types of surgical procedures, complications, and long-term outcomes. Multivariate logistic regression analysis was used to identify the risk factors associated with treatment refractoriness or recurrence after surgery. Results Among 67 patients who underwent surgery during the study period, the most common indication for surgery was persistent culture positivity despite rigorous medical treatment (80.6%), followed by longstanding cavitary lesions or radiographic aggravation (10.4%) and massive hemoptysis (4.5%). Among 53 patients with positive mycobacterial cultures at the time of surgery, 38 (71.7%) achieved initial negative culture conversion, 9 (17.0%) of whom experienced recurrence. Nine (13.4%) patients experienced postoperative complications, which were managed without lasting morbidity and mortality. Female sex (adjusted odds ratio [aOR] 6.63; 95% confidence interval [CI] 1.04–42.4; P = .046), preoperative positive mycobacterial culture (aOR 5.87; 95 %CI 1.04–33.08; P = .045), and residual lesions (aOR 6.86; 95 %CI 1.49–31.56; P = .013) were associated with refractoriness or recurrence. Conclusions Pulmonary resection is a reasonable treatment modality for patients with refractory NTM-PD or major complications such as massive hemoptysis. The potential risk factors associated with unfavorable outcomes included female sex, preoperative positive mycobacterial culture, and residual lesions after surgery

Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial

Background : The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. Methods : This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. Discussion : This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. Trial registration : ClinicalTrials.gov NCT04485156.Registered on July 24, 2020.This work was supported by a grant from the Korea National Institute of Health (2020-ER5201-01), Republic of Korea. High-dose rifampicin tablets and capsules were donated from Yuhan (Seoul, Republic of Korea) for this study. The funder and donor had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

New-onset nontuberculous mycobacterial pulmonary disease in bronchiectasis: tracking the clinical and radiographic changes

Background The close association between bronchiectasis and nontuberculous mycobacterial pulmonary disease (NTM-PD) is well-known. However, the clinical impact of subsequent new-onset NTM-PD in bronchiectasis patients has not been elucidated. The aim of this study is to investigate the clinical courses and radiographic changes of patients with bronchiectasis in whom NTM-PD subsequently developed. Methods A total of 221 patients with bronchiectasis who had participated in a non-NTM bronchiectasis cohort between July 1st 2011 and August 31st 2019 at Seoul National University Hospital were included in this study. The data of patients in whom NTM-PD developed during this observation period were analyzed; specifically, changes in the Bronchiectasis Severity Index (BSI) and lesions on computerized tomography (CT) scan of the chest arising during the observation period. Results During the observation period, NTM was isolated from 35 patients. A total of 31 patients (14.0%) satisfied the diagnostic criteria of NTM-PD. The median time from enrollment in the cohort to the development of subsequent NTM-PD was 37 months (Interquartile range [IQR], 18–78 months). Mycobacterium avium complex was the most common pathogen (80.6%). Twelve patients underwent antibiotic treatment for NTM-PD with a median interval of 20 months (IQR, 13–30) from the time of NTM-PD diagnosis. When NTM-PD developed, the severity and extent of bronchiectasis, cellular bronchiolitis, and the extent of nodules worsened on CT scans, while BSI did not change. Conclusions NTM-PD can develop in previously negative bronchiectasis patients. It is associated with worsening radiographic lesions. Active screening of non-NTM bronchiectasis patients for new-onset NTM infection should be considered, especially if radiographic findings worsen. The BSI is not a reliable predictor of new-onset NTM-PD. Trial registration This study was performed at Seoul National University Hospital ( NCT01616745 )

Del-1 Plays a Protective Role against COPD Development by Inhibiting Inflammation and Apoptosis

Neutrophilic inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD). Developmental endothelial locus-1 (Del-1) has been reported to limit excessive neutrophilic inflammation by inhibiting neutrophil adhesion to the vascular endothelial cells. However, the effects of Del-1 in COPD are not known. We investigated the role of Del-1 in the pathogenesis of COPD. Del-1 protein expression was decreased in the lungs of COPD patients, especially in epithelial cells and alveolar macrophages. In contrast to human lung tissue, Del-1 expression was upregulated in lung tissue from mice treated with cigarette smoke extracts (CSE). Overexpression of Del-1 significantly suppressed IL-8 release and apoptosis in CSE-treated epithelial cells. In contrast, knockdown of Del-1 enhanced IL-8 release and apoptosis. In macrophages, overexpression of Del-1 significantly suppressed inflammatory cytokine release, and knockdown of Del-1 enhanced it. This anti-inflammatory effect was mediated by inhibiting the phosphorylation and acetylation of NF-κB p65. Nuclear factor erythroid 2-related factor 2 (Nrf2) activators, such as quercetin, resveratrol, and sulforaphane, increased Del-1 in both cell types. These results suggest that Del-1, mediated by Nrf2, plays a protective role against the pathogenesis of COPD, at least in part through anti-inflammatory and anti-apoptotic effects

The Association Between Bacille Calmette-Guerin Vaccination and Nontuberculous Mycobacterial Pulmonary Disease

This study aimed to investigate the association between Bacille Calmette-Gu??rin (BCG) vaccination and nontuberculous mycobacterial pulmonary disease (NTM-PD). Patients in the prospective NTM-PD cohort were matched to healthy controls to measure the association between BCG and NTM-PD development. The clinical course of NTM-PD patients was also evaluated to investigate the association between BCG and NTM-PD progression. BCG scars were not associated with NTM-PD development (adjusted odds ratio [OR], 2.04; 95% confidence interval [CI], 0.96???4.34) or progression (adjusted OR, 1.61; 95% CI, 0.92???2.81). In conclusion, BCG vaccination was not associated with the development or progression of NTM-PD.N