American journal of respiratory and critical care medicine最新文献

Rationale: Most emphysema is believed to arise from small airways disease, but recent data suggest emphysema begets more emphysema and that its progression may be due to the mechanical stress experienced by normal lung regions adjacent to existing emphysema.

Objective: To determine whether new emphysema arises from this penumbra of mechanically affected lung (MAL) or from small airways disease.

Methods: We co-registered inspiratory chest computed tomography (CT) scans acquired at enrollment and 5 years later in 4,972 participants enrolled in a multicenter cohort. Using adaptive Gaussian smoothing, we quantified the 3D effect of all emphysema clusters on adjacent normal voxels by assuming that the mechanical effect of each emphysema cluster on surrounding voxels depends on cluster size and decays with increasing distance. The cumulative mechanical effect on each voxel was used to calculate MAL. Based on the probability distribution of normal voxels progressing to emphysema, we classified voxels into High (≥10.5), Intermediate (>0 to <10.5), and Zero MAL. We co-registered baseline inspiratory and expiratory CT images to quantify functional small airways disease. We quantified the proportion of new emphysema arising from each risk region.

Measurements and main results: In adjusted analyses, higher MAL was associated with faster FEV₁ decline (-2.2 ml/year, 95%CI -2.6 to -1.7; p<0.001) and emphysema progression (-0.14 g/L/year, 95%CI -0.16 to -0.12; p<0.001), and greater all-cause mortality (adjusted hazards ratio = 1.07, 95%CI 1.05-1.09; p<0.001). The relative mean contributions of high and intermediate MAL to new emphysema were 60.5% and 37.1%, respectively, in contrast to zero MAL (2.4%) and small airways disease (4.8%).

Conclusions: Most new emphysema arises from areas of high MAL and in substantially higher proportion than areas of small airways disease.

Rationale: Obstructive sleep apnea (OSA) is associated with cognitive impairment. The effects of continuous positive airway pressure (CPAP) on neuroimaging biomarkers and cognitive performance among middle-aged patients with OSA and normal cognition remain unclear.

Objectives: To investigate the effects of CPAP therapy over 12 months on neuroimaging biomarkers and cognitive performance.

Methods: In this multicenter, randomized clinical trial, we randomly assigned 148 participants with normal cognition and an apnea-hypopnea index ≥15/hour into two groups: patients receiving CPAP with best supportive care (BSC); and patients receiving BSC alone. The primary endpoint was MoCA score at 6 months after enrollment. The secondary endpoints were intranetwork functional connectivity (FC) of default mode network (DMN) and cortical thickness assessed by functional and structural magnetic resonance imaging, other neuroimaging biomarkers and neurobehavioral tests.

Measurements and main results: Between 2017 and 2021, 148 patients were recruited from 5 hospitals. Linear mixed models showed that there was no significant difference in MoCA scores at 6 months between the CPAP and BSC groups (difference, -0.04, 95% confidence interval (CI), -0.72 to 0.65, P=0.91). However, there were significant differences in the FC of DMN (difference, -13.73, 95% CI, -23.40 to -4.06, P=0.01) and cortical thickness (difference, -0.06 mm, 95% CI, -0.10 to -0.01mm, P=0.02) between CPAP and BSC groups at 6 months after treatment. No serious adverse events occurred.

Conclusions: CPAP improved cortical thickness and FC of DMN, suggesting that patients with OSA may recover from brain atrophic processes following CPAP treatment. However, no improvement in MoCA was found. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT02886156.

Rationale: Rademikibart (formerly CBP-201) is an IL-4Rα-targeting antibody.

Objectives: To evaluate rademikibart in adults with moderate-to-severe, persistent, uncontrolled asthma.

Methods: In this global phase 2b trial (NCT04773678), 322 patients were randomized 1:1:1 to two rademikibart groups (150 mg or 300 mg every other week, following a 600 mg loading dose) or placebo, administered subcutaneously, for 24 weeks.

Measurements and main results: Prebronchodilator (trough) forced expiratory volume in the first second of expiration (FEV₁) at Week 12 (primary endpoint) improved with rademikibart 150 mg and 300 mg: least squares mean changes (95% CI), above placebo, were +140 mL (+44-236 mL; p=0.005) and +189 mL (+92-286 mL; p<0.001), respectively. Prebronchodilator trough FEV₁ improvements occurred rapidly during Week 1, were sustained through Week 24, and greatest in patients with high baseline blood eosinophils (patients with ≥300 eosinophils/mL experienced placebo-adjusted FEV₁ improvement at Week 24 of +420 mL [95% CI, +239-600 mL] in the 300 mg group). Rapid and sustained statistically significant improvements were also observed in percent predicted FEV₁ and Asthma Control Questionnaire score across 24 weeks. Through Week 24, proportions of patients with ≥1 exacerbation were 7.5% (150 mg) and 9.3% (300 mg) vs 16.7% (placebo). 88% of patients completed treatment. Treatment-emergent adverse events (TEAEs) were generally similar to placebo, and no eosinophilia was observed. Injection site reactions were mostly mild. The most common TEAEs (10-12% of patients) were cough, COVID-19, and dyspnea.

Conclusions: Rapid and sustained improvements in lung function and asthma control were gained across 24 weeks of rademikibart therapy. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT04773678.

Background: A subset of asthma patients have airway pathology characterized by a thickened subepithelial basement membrane zone ("BMZ-thick asthma").

Objectives: To characterize the clinical features of BMZ-thick asthma and to determine if BMZ thickness accompanies specific patterns of inflammation in the airway epithelium.

Methods: Design-based stereology was used to quantify BMZ thickness in endobronchial biopsy tissue sections from 109 asthma patients and 41 healthy controls from the Severe Asthma Research Program-3 whose participants had undergone spirometry and gene expression profiling in airway epithelial brushings.

Results: The upper 90th percentile value for BMZ thickness in the healthy cohort was 2.9 µM, and 35% of the asthma cohort had values above this upper limit. Compared to BMZ-thin asthma patients, BMZ-thick asthma patients were younger and had higher blood eosinophil numbers and serum immunoglobulin E levels that were specific to animal proteins. Mean pre-bronchodilator FEV1 was significantly lower in BMZ-thick than in BMZ-thin patients, but post-bronchodilator FEV1 was not. Upregulation of genes signifying interleukin-13 activation and presence of mast cells were evident in epithelial brushings in BMZ-thick patients, but gene signatures for activation by interferon gamma or interleukin-17 were not.

Conclusions: A thickened BMZ marks a subset of younger asthma patients characterized by higher IgE levels to animal aeroallergens and by increased bronchomotor tone occurring in the context of airway epithelial cells activated by interleukin-13 and infiltrated by mast cells.