Background: Comparative effects on physical activity of mono and dual bronchodilators remain unclear in patients with treatment-naïve chronic obstructive pulmonary disease (COPD). We sought to compare the changes in physical activity before and after tiotropium and tiotropium/olodaterol treatment in treatment-naïve COPD patients. Methods: A prospective, multicenter, randomized, open-labeled, and parallel interventional study was conducted. Eighty Japanese patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Spirometry and dyspnea index were assessed, and COPD assessment test (CAT) and the 6-minute walk distance (6MWD) were conducted before and after treatment. Evaluation of physical activity was assessed by a triaxle accelerometer over a 2-week period before and after treatment. Results: There were no differences in the mean age (69.8 vs 70.4 years), body mass index (BMI) (22.5 vs 22.6 kg/m²) and mean % forced expiratory volume in 1 second (%FEV1) at baseline (61.5 vs 62.6%) between the two groups. Changes in FEV1 (mean±standard error, 242.8± 28.8 mL) and transient dyspnea index (TDI) (2.4± 0.3 points) before and after tiotropium/olodaterol treatment were greater than with tiotropium treatment (104.1± 31.9 mL, p< 0.01 and 1.5± 0.3, p=0.02, respectively). Changes in the duration of physical activity with 1.0– 1.5 metabolic equivalents (METs) estimated in the sedentary position following tiotropium/olodaterol treatment (− 38.7± 14.7 min) tended to be reduced more than with tiotropium treatment (− 4.6± 10.6 min) (p=0.06), although those with ≥ 2.0 METs numerically increased with both treatments (+10.8± 7.6 min for tiotropium/olodaterol vs +8.3± 7.6 min for tiotropium, p=0.82). Tiotropium/olodaterol treatment reduced the duration of physical activity with 1.0– 1.5 METs (regression coefficient, − 43.6 [95% CI − 84.1, − 3.1], p=0.04) in a multiple regression model adjusted for cofounding factors such as age, FEV1, total CAT scores, 6MWD, and TDI. Conclusion: This is the first study to report the impact of dual bronchodilator on physical activity in treatment-naïve COPD patients of Japanese with low BMI.

IL-33, an IL-1 family cytokine, is constitutively expressed in mucosal tissues and other organs in healthy humans and animals, and expression levels increase in inflammatory conditions. Although IL-33–mediated promotion of type 2 immune responses has been well established, a gap in our knowledge regarding the functional diversity of this pleiotropic cytokine remains. To address this gap, we developed a new IL-33 transgenic mouse model in which overexpression of full-length IL-33 is induced in lung epithelial cells under conditional control. In adult mice, an ∼3-fold increase in the steady-state IL-33 levels produced no pathologic effects in the lungs. When exposed to airborne allergens, adult transgenic mice released more IL-33 extracellularly and exhibited robust type 2 immune responses. In neonatal transgenic mice, up to postnatal day 14, a similar increase in steady-state IL-33 levels resulted in increased mortality, enlarged alveolar spaces resembling bronchopulmonary dysplasia, and altered expression of genes associated with tissue morphogenesis. Processed 25-kDa IL-33 protein was detected in bronchoalveolar lavage fluids without any exogenous stimuli, and pathologic changes were abolished in mice deficient in the IL-33 receptor ST2. These findings suggest that adult lungs are relatively resistant to IL-33 overexpression unless they encounter environmental insults, whereas developing lungs are highly susceptible, with IL-33 overexpression resulting in detrimental and pathologic outcomes.

Introduction: Obesity is associated with severe asthma, but no specific treatment has been established. The gut microbiome is increasingly recognized as a crucial factor, but specific treatments focused on the gut microbiome have not been established. Recently, azithromycin has been found to have the capacity to attenuate exacerbations, a characteristic of severe asthma. The effect of azithromycin on obesity-induced severe asthma is not understood. Methods: The purpose of the present study is to clarify the effect of azithromycin on exacerbations in asthmatic patients with obesity. To explore the mechanism, the gut microbiome, metabolites of microbes such as short-chain fatty acids, and blood inflammatory cytokines will be analyzed to evaluate the correlation with the effect of azithromycin on exacerbations in obesity-induced severe asthma. A multi-center, prospective, single-arm intervention study is planned. Discussion: The present study will allow us to evaluate the effect of azithromycin on exacerbations, particularly in asthma patients with obesity, and explore biomarkers, targeting molecules including the gut microbiome, which are correlated with decreased exacerbations. The present results could contribute to identifying new therapeutic prospects and targeted microbes or molecules associated with severe clinical characteristics in asthmatic patients with obesity. Trial registration: This study has been registered as a prospective study with the University Hospital Medical Information Network (UMIN0000484389) and the Japan Registry of Clinical Trials (jRCTs071220023).

Weight loss is a factor that affects prognosis in patients with chronic obstructive pulmonary disease (COPD) independent of lung function. One of the major factors for weight loss is energy malnutrition. There have been no reports on the factors related to energy malnutrition in COPD patients. This retrospective observational study aimed to investigate these factors. We included 163 male subjects with COPD. Respiratory quotient (RQ), an index of energy malnutrition, was calculated by expiratory gas analysis using an indirect calorimeter. RQ < 0.85 was defined as the energy-malnutrition group and RQ ≥ 0.85 as the no energy-malnutrition group. Factors related to energy malnutrition were examined by multivariate and decision-tree analysis. We finally analyzed data from 56 selected subjects (median age: 74 years, BMI: 22.5 kg/m²). Energy malnutrition was observed in 43%. The independent factors associated with energy malnutrition were tidal volume (VT) (OR 0.99; 95% CI 0.985–0.998; p = 0.015) and Th12 erector spinae muscle cross-sectional area SMI (Th12ESM_SMI) (OR 0.71; 95% CI 0.535–0.946; p = 0.019). In decision-tree profiling of energy malnutrition, VT was extracted as the first distinguishable factor, and Th12ESM_SMI as the second. In ROC analysis, VT < 647 mL (AUC, 0.72) or Th12ESM_SMI < 10.1 (AUC, 0.70) was the cutoff value for energy malnutrition. Energy malnutrition may be an early warning sign of nutritional disorders.

Background: Prolonged sedentary behavior is associated with worse prognosis in patients with chronic obstructive pulmonary disease (COPD). Our previous study found that first-line dual therapy with tiotropium/olodaterol significantly reduces sedentary time compared to tiotropium monotherapy in Japanese patients with treatment-naïve COPD, although the characteristics of responders to dual-therapy versus monotherapy for COPD are still unclear. Methods: Patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Physical activity was assessed using a triaxle accelerometer for 2 weeks before and after treatment. This analysis focused on the change in sedentary time, indicated by physical activity of 1.0– 1.5 metabolic equivalents (METs), with stratification for the following factors: age, body mass index (BMI), pulmonary function, COPD assessment test (CAT), the 6-minute walk distance (6MWD), and physical activity level at study entry. Results: Thirty-five patients received tiotropium/olodaterol and 34 patients received tiotropium. In patients with lower inspiratory capacity at study entry, a significant reduction in sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: − 12.8 ± 13.5 min, Tio/Olo: − 65.1 ± 21.0 min, mean difference, − 52.2 min, 95% CI − 103.6 to 0.88, p = 0.046). In patients with a shorter duration of physical activity of ≥ 2 METs at study entry, a significant reduction of sedentary time was observed in the tiotropium/olodaterol group compared with the tiotropium group (Tio: − 3.3 ± 17.5 min, Tio/Olo: − 72.9 ± 23.1 min, mean difference, − 69.7 min, 95% CI − 128.7 to − 10.6, p = 0.02). There were no differences in terms of age, BMI, CAT score, 6MWD, FEV1, FVC, VC, and physical activity of 1.0– 1.5 METs and ≥ 3.0 METs. Conclusion: This study showed that COPD patients with lower inspiratory capacity or shorter active time of ≥ 2.0 METs at study entry are likely to exhibit significantly greater reduction in sedentary time with tiotropium/olodaterol treatment.