American journal of respiratory and critical care medicine最新文献

Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition of the lungs, characterized by chronic respiratory symptoms, primarily dyspnea, cough, and sputum production, due to airway and/or alveoli abnormalities that cause persistent, and often progressive, airflow obstruction. Although the underlying mechanisms responsible for COPD remain poorly understood, over the last several decades, clinical phenotypes and endotypes have been suggested. These include frequent exacerbator and eosinophilic groups that guide tailored therapies for patients with that clinical expression. In the developed world, smoking is the main known cause of COPD, responsible for ~80% of cases. Active smokers have more severe disease, with more rapid lung function decline and impaired quality of life, than former smokers. Unfortunately, smoking is still highly prevalent. Rates range between 3% and 37% globally, with factors including sex, age, race, education level, and geography influencing the rate of addiction. Importantly, several studies have shown that smoking detrimentally affects treatment efficacy of COPD medications; this is particularly true of inhaled corticosteroids and macrolides. In this review, we discuss the effects of smoking on the pathophysiology of COPD and the clinical impact of smoke exposure in patients with COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Rationale: In the WILLOW trial, the Dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease (NSP) activity and prolonged time to first exacerbation in patients with bronchiectasis.

Objectives: We hypothesized that, by reducing NSPs, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade.

Methods: The WILLOW trial was a phase 2 randomized trial of brensocatib (10mg and 25mg) versus placebo. Sputum was collected at baseline, week 4, week 24 (end of treatment) and week 28 (4 weeks post-treatment). The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3 were measured by ELISA, mucin-5AC (MUC5AC) by liquid chromatography mass spectrometry, myeloperoxidase by immunoassay and 45 inflammatory cytokines by Olink^® Target 48 assay. The relationship between these markers and sputum neutrophil elastase was validated using the EMBARC-BRIDGE bronchiectasis cohort.

Measurements and main results: Of 82 patients randomized to 10mg brensocatib, 87 to 25mg brensocatib, and 87 to placebo, 71, 71 and 73 with sputum available for at least two time points were included. SLPI and α-defensin-3 increased significantly with brensocatib compared to placebo at both week 4 and week 24. MUC5AC reduced in response to treatment. Sub-analysis showed this was primarily among patients with high baseline neutrophil elastase. Myeloperoxidase did not change. 15 cytokines and chemokines increased significantly compared to placebo at week 4 or 28. CXCL10, CCL8, CCL7, CCL3 and IL-6 increased at both doses at both timepoints. In the EMBARC-BRIDGE cohort neutrophil elastase correlated inversely with SLPI, CCL13, IL7, CCL11, CXCL10, CCL8, CCL7, all markers increased by brensocatib.

Conclusions: Brensocatib exerts broad anti-inflammatory effects beyond its known effects on serine proteases. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT03218917.

Rationale: Individuals surviving TB disease may experience chronic sequelae that reduce survival and quality-of-life. These post-TB sequalae are not generally considered in estimates of the health impact of TB disease.

Objectives: To estimate the TB-attributable reductions in life expectancy and quality-adjusted life expectancy for individuals developing TB disease in the United States, including post-TB sequelae.

Methods: We extracted national surveillance data on individuals diagnosed with TB during 2015-2019, including demographics, vital status at diagnosis, treatment duration, treatment outcome, and co-prevalent conditions. Using a mathematical model we simulated life expectancy and quality-adjusted life-years (QALYs) for the TB cohort, as compared to a no-TB counterfactual (same distribution of age, sex, race/ethnicity, and co-prevalent conditions as the TB cohort but without TB-attributable mortality and disutility). We disaggregated results to report the proportion due to post-TB sequelae, and stratified outcomes by age, sex, and race.

Measurements and main results: Estimated life expectancy after TB diagnosis was 30.3 (95% uncertainty interval: 29.9, 30.7) years for the TB cohort versus 32.3 (31.9, 32.7) without TB, a difference of 2.03 (1.84, 2.21) years and 1.93 (1.69, 2.18) QALYs. Life-years lost were greatest for 65-74-year-olds versus other age groups, for men versus women, and for American Indian or Alaska Native individuals versus persons from other race/ethnicities. Overall, 41% (35, 46) of life-years and 48% (42, 54) of QALYs lost were estimated to result from post-TB sequelae.

Conclusions: In the United States, a substantial fraction of the life-years and QALYs lost from TB are attributable to post-TB sequelae. Evidence is needed on approaches to prevent and repair post-TB lung damage, in the context of frequent co-prevalent health conditions.

Rationale: Pulmonary hypertension (PH) commonly complicates idiopathic pulmonary fibrosis (IPF). However, the rate of change in pulmonary hemodynamics in IPF remains poorly defined.

Objectives: To examine the rate of change in pulmonary hemodynamics among patients with IPF.

Methods: The rate of change in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) was examined in patients with IPF listed for lung transplantation. The 5th and 7th World Symposium on Pulmonary Hypertension definitions for precapillary PH were employed in this analysis.

Measurements and main results: There were 496 patients with IPF that had at least two right heart catheterizations (RHCs) while listed for lung transplantation. The median time between repeated RHCs was 9 months (interquartile range [IQR]: 6-14). PH was present in 25.8% and 46.8% at the first RHC, while 42.9% and 64.3% had PH by the two definitions respectively, at the time of the final RHC. The median rate of change in the mPAP and PVR were 3.8 mmHg/year (IQR: -0.9-11.8) and 0.8 Wood Units/year (IQR: -0.2-2.4), respectively. The rate of PVR change was slower for those with established PH compared with those without PH. 28.6% of the patients had accelerated progression of their hemodynamics, arbitrarily defined as an increase in PVR of ≥ 2 Wood Units/year.

Conclusions: PH associated with IPF tends to progress in an unpredictable fashion, with some patients demonstrating an accelerated phenotype. Among patients with RHC hemodynamics below the threshold for therapy, close vigilance is warranted with consideration for an early repeat RHC. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Rationale: The association between fine particulate matter (PM_2.5) and lung cancer incidence in non-smokers (LCINS) remains inconsistent. Objectives: To investigate the association between long-term PM_2.5 exposure and LCINS in a Chinese population and to assess the modifying effect of genetic factors. Methods: Time-dependent Cox proportional hazard models were employed to evaluate the hazard ratios (HR) and 95% confidence interval (CI) of PM_2.5 with LCINS risk and LCINS-related mortality. The polygenic risk score (PRS) was constructed to further explore the interactions between genetic risk and PM_2.5 exposure. Additionally, the population attributable fraction (PAF) of PM_2.5 to lung cancer risk and mortality was calculated. Measurements and Main Results: The results demonstrated significant associations between PM_2.5 exposure and LCINS incidence (HR: 1.10, 95% confidence interval [CI]: 1.04-1.17, per 10 µg/m³) and mortality (HR: 1.17, 95% CI: 1.08-1.27, per 10 µg/m³). Compared to the lowest-risk group, individuals exposed to the high PM_2.5 level (≥50.9 µg/m³) and high genetic risk (top 30%) exhibited the highest LCINS incidence (HR: 2.01, 95% CI: 1.39-2.87) and mortality (HR: 2.30, 95% CI: 1.38-3.82). A significant additive interaction between PM_2.5 and genetic risk on LCINS incidence was observed. Approximately 33.6% of LCINS cases and 48.5% of LCINS-related deaths in China could be prevented if PM_2.5 concentrations were reduced to meet WHO guidelines. Conclusion: Long-term exposure to outdoor PM_2.5 increases LCINS risk and LCINS-related mortality, especially in populations with high genetic risk. Strengthening air pollution control measures in China has the potential to significantly reduce the burden of LCINS.

Rationale: The mucoid phenotype of Staphylococcus aureus is caused by adaptation. Excessive biofilm formation associated with a protective effect for mucoid S. aureus was observed in isolates from respiratory samples of people with cystic fibrosis (pwCF). However, there is little knowledge about the prevalence of mucoid S. aureus in pwCF and a potential association with CF lung disease.

Methods: A prospective multicenter study was conducted (cross-sectional and longitudinal). Specimens and case report forms were sent to the central study laboratory for characterization of S. aureus and analysis of clinical parameters.

Measurements and main results: Cross-sectional study: In 41 of 451 S. aureus-positive pwCF (9.1%) from 13 CF-centers, mucoid S. aureus was cultured. Longitudinal study: The distribution of CFTR genotypes, the number of pwCF with highly effective modulator therapy and co-infection with Pseudomonas aeruginosa were equivalent in the mucoid (35 pwCF) versus the control group (only non-mucoid S. aureus, 36 pwCF). While lung function did not differ between groups as a whole, a subgroup analysis revealed significantly worse lung function for female pwCF with mucoid S. aureus as well as for pwCF if P. aeruginosa co-infection was excluded.

Conclusions: In the era of highly effective modulator therapy, worse lung function was associated with female and P. aeruginosa-negative pwCF with mucoid S. aureus compared to pwCF with only non-mucoid S. aureus. Therefore, appropriate culture conditions should be established to detect mucoid S. aureus. Further investigations are needed to elucidate the relationship between mucoid S. aureus and CF lung disease.