Annals of the American Thoracic Society最新文献

Background: COPD remains a leading cause of morbidity and mortality worldwide. Acute exacerbations are associated with progressive decline in lung function and quality of life. After recognition of the role of type 2 inflammation in the pathogenesis of eosinophilic COPD, there was increased interest in studying monoclonal antibodies as a therapeutic agent. Multiple randomized control trials (RCTs) showed promising results, yet no consensus exist. Our study aims to summarize the current evidence regarding the role of monoclonal antibodies in the management of patients with eosinophilic COPD.

Methodology: We systematically searched multiple databases using pre-specified search terms. We included only RCTs comparing monoclonal antibodies to placebo in patients with objective evidence of eosinophilic COPD receiving standard of care. The primary outcome of interest was annualized rate of COPD exacerbation. Absolute changes in FEV1, and SGRQ scores were secondary outcomes. We also reported serious adverse effects and all-cause mortality. Statistical analysis was conducted via random effects model, using RevMan software.

Results: We identified and included 8 double blinded, placebo-controlled trials with a total of 4,512 patients, and a median follow up of 52 weeks. The patients mean age was 65±8 years, with 85% male majority. 70% of patients were former smokers, with a mean of 43±25 pack-years. The majority of patients were on triple inhaled therapy. The mean serum eosinophil count on enrollment was 398±297 cell/µL. Monoclonal antibodies were Dupilumab, Mepolizumab, Benralizumab, Astegolimab, and Itepekimab. Compared to placebo, patients who received monoclonal antibody had a significantly decreased annualized COPD exacerbation rate [RR 0.79; 95% CI (0.73, 0.86), P<0.001]. The serious adverse effect rate was significantly lower in monoclonal antibody arm compared to placebo, [OR 0.80, 95% CI (0.69, 0.93, P=0.004)]. All-cause mortality rate was not statistically different between the groups, [OR of 0.91, 95% CI (0.63, 1.3, P=0.6)]. Dupilumab showed a trend of efficacy over Mepolizumab and Benralizumab.

Conclusion: In patients with eosinophilic COPD receiving standard of care therapy, the use of monoclonal antibodies led to a significant reduction in annualized COPD exacerbation rate compared to placebo. Monoclonal antibodies have an acceptable tolerability and safety profile.

Rationale: Previous studies have identified exercise intolerance in patients with mild-to-moderate chronic obstructive pulmonary disease (COPD). The associations of exercise tolerance with lung function decline and acute exacerbation risk in mild-to-moderate COPD is unclear, especially in the community population. Objectives: We evaluated exercise tolerance in mild-to-moderate COPD and analyzed its associations with respiratory health outcomes. Methods: We analyzed data from the Early Chronic Obstructive Pulmonary Disease community-based study of patients with mild-to-moderate COPD (post- bronchodilator FEV₁/FVC <0.70 and FEV₁ ≥50% predicted). Patients who completed questionnaires, spirometry, and cardiopulmonary exercise testing at baseline were included. Annual exacerbation assessment and spirometry testing were conducted for 2 years consecutively. Exercise tolerance was defined as the percentage of predicted peak oxygen uptake (VO_2peak %predicted). We analyzed the association between exercise tolerance, annual lung function decline, and acute exacerbation risk. Measurements and Main Results: Overall, 338 patients were included in the baseline analysis, and 319 completed the 2-year follow-up. The mean and standard deviation (SD) of VO_2peak %predicted was 79.8±13.7. Low VO_2peak %predicted was associated with more chronic respiratory symptoms, worse lung function, severe emphysema, and air trapping at baseline. During the 2-year follow-up, a decrease of 13.7% (1-SD) in VO_2peak %predicted was associated with a decline in pre-bronchodilator FEV₁/FVC (difference=0.4%, 95% CI: 0.1%-0.7%, P= 0.003), and higher total exacerbation risk (relative risk [RR]=1.25, 95% CI: 1.08-1.46, P=0.004) after adjustment. Conclusions: Mild-to-moderate COPD patients with exercise intolerance have worse respiratory health outcomes, for which a low exercise tolerance as a prognostic marker.

Background-Among tobacco-exposed persons with preserved spirometry (TEPS), we previously demonstrated that different lung volume indices, specifically elevated total lung capacity (TLC) versus elevated ratio of functional residual capacity-to-TLC (FRC/TLC), identify different lung disease characteristics in the COPDGene cohort. Objective-Determine differential disease characteristics and trajectories associated with the lung volume indices among TEPS in the SPIROMICS cohort. Methods-We categorized TEPS (n=814) by tertiles (low, intermediate, high) of TLC or residual volume-to-TLC (RV/TLC) derived from baseline CT images, and then examined clinical and spirometric disease trajectories in mutually exclusive categories of participants with high TLC without high RV/TLC ([TLC]^high) versus high RV/TLC without high TLC ([RV/TLC]^high). We examined differences in CT-measured emphysema (HU≤-950; PRM^EMPH), airway trapping (HU≤-856; PRM^fSAD; DPM_GasTrap), and airway geometry (Pi10), respiratory symptoms (mMRC; CAT; SGRQ; SF12), and outcomes (annualized exacerbation rate) between the two categories at baseline and over follow-up time up to 8.5 years, using regression modeling adjusted for age, sex, height, weight, and smoking status (current versus former) and burden (pack-years). Results-In TEPS participants, the pattern of spirometric disease progression differed between [TLC]high and [RV/TLC]^high: increased FVC with stable FEV₁ in [TLC]^high versus unchanged FVC but nominally decreased FEV₁ in [RV/TLC]^high. Compared to [TLC]^high, TEPS with [RV/TLC]^high had less emphysema (by HU≤-950) but more airway disease (by HU≤-856; PRM^fSAD; DPM_GasTrap, and Pi10), more respiratory symptoms (by mMRC; CAT; SGRQ; SF12), and more severe exacerbations at baseline. Over an average follow-up time of 4.1±2.4 years (range: 0.5 to 8.5 years), [RV/TLC]^high TEPS also had higher likelihood of developing more severe spirometric disease (PRISm or GOLD-2) and worsening of their respiratory symptoms (by CAT and SGRQ). Although the incidence rates of respiratory exacerbations, hospitalizations, and mortality were not different between the two categories over the follow-up time, [RV/TLC]^high TEPS were more likely to have been placed on a respiratory inhaler at their last follow-up visit. Conclusions-In these TEPS from SPIROMICS cohort, lung volume stratification by TLC versus RV/TLC identifies two pre-COPD phenotypes with distinct respiratory symptoms, radiographic features, and clinical trajectories. The characteristics of these pre-COPD phenotypes match those previously described from COPDGene cohort using TLC versus FRC/TLC stratification.

Rationale: In the United States (U.S.), ambulatory oxygen is recommended for patients with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) who experience symptomatic exertional hypoxemia. Ambulatory oxygen need is often determined by submaximal hall walk testing; however, this may fail to accurately characterize exertional hypoxemia in some patients.

Objectives: Assess for differences in ambulatory oxygen needs between IPF and COPD patients who completed a ramped treadmill protocol exercise test (RTPET) and correlate oxygen flow rates determined at highest level exertion with lung function and exercise parameters. Oxygen "need" is defined as flow rate needed to maintain oxygen saturation >90% in patients who desaturate to <88%.

Methods: We conducted a retrospective review of RTPET results for IPF and COPD patients who also recently completed spirometry. The RTPET has three phases: rest, submaximal usual pace walking at 0% treadmill grade for 3 minutes, and highest level walking at the UP walk speed with increasing treadmill grade by 2% every 2 minutes. IPF patients were part of a clinical registry while COPD patients were identified based on diagnosis coding and spirometry (FEV1/FVC <0.70). The RTPET for both groups was completed based on a pulmonologist's referral.

Measurements and main results: We included 329 IPF and 2,343 COPD patients. A greater proportion of IPF patients required ambulatory oxygen to maintain saturation >90%. After adjusting for demographic covariates and exercise parameters, IPF patients required higher ambulatory oxygen flow rates compared to COPD subjects with similar DLCO values. Of patients who did not require oxygen with submaximal usual pace testing, 49% with IPF and 24% with COPD required oxygen at highest level exertion.

Conclusions: The RTPET identified higher oxygen flow needs at highest level exertion in IPF versus COPD patients; however, in both diseases, there was a significant proportion of patients who were only found to have exertional desaturation at highest level exertion. Current oxygen policies and reliance on submaximal testing may fail to meet the needs of patients with IPF and COPD. Further studies are needed to determine if oxygen prescriptions targeting highest level desaturation improve clinical outcomes, symptoms, or quality-of-life.

Rationale: While exposure to air pollution is a known risk factor for adverse pulmonary outcomes, its impact in individuals with idiopathic pulmonary fibrosis (IPF) is less well understood.

Objective: To investigate the effects of long-term exposure to air pollution on disease severity and progression in patients with IPF and to determine whether genomic factors, such as MUC5B promoter polymorphism or telomere length, modify these associations.

Methods: We performed analyses at enrollment and after one year of follow-up in the IPF-PRO Registry, a prospective observational registry that enrolled individuals with IPF at 46 US sites from June 2014 to October 2018. Five-year average pollution exposures (PM_2.5, NO₂, O₃) prior to enrollment date were estimated at participants' residential addresses with validated national spatio-temporal models. Multivariable regression models estimated associations between pollution exposure and physiologic measurements (FVC, DL_CO, supplemental oxygen use at rest) and quality of life measurements (St. George's Respiratory Questionnaire [SGRQ], EuroQoL, Cough and Sputum Assessment Questionnaire) at enrollment. Cox proportional hazard models estimated associations between pollutants and a composite outcome of death, lung transplant, or >10% absolute decline in FVC % predicted in the year after enrollment. Models were adjusted for individual-level and spatial confounders, including proxies for disease onset. Gene-environment interactions with MUC5B and telomere length were assessed.

Results: Of 835 participants, 94% were non-Hispanic Whites, 76% were male, mean (SD) age was 70 (7.7) years. In fully adjusted analyses, higher PM_2.5 exposure was associated with worse quality of life per SGRQ activity score (3.48 [95% confidence interval (CI) 0.64, 6.32] per 2µg/m³ PM_2.5) and EuroQoL scores (-0.04 [95%CI -0.06, -0.01] per 2µg/m³ PM_2.5), and lower FVC % predicted and lower DL_CO% predicted at enrollment. Each 3 parts per billion difference in O₃ exposure was associated with a 1.57% [95% CI 0.15, 2.98] higher FVC % predicted at enrollment, although this effect was attenuated in multi-pollutant models. There was no association between NO₂ and enrollment measures, between pollution exposure and one-year outcomes, or evidence for gene-environment interactions.

Conclusion: In the IPF-PRO Registry, long-term exposure to PM_2.5 was associated with worse quality of life and lung function at enrollment, but not with short-term disease progression or mortality. There was no evidence of effect modification by interaction of genomic factors with pollution. The reason for the unexpected relationship between O₃ exposure and higher FVC is unclear.

Rationale: Numerous studies indicate that preserved ratio impaired spirometry (PRISm) is associated with adverse clinical outcomes. However, the impact of PRISm severity, particularly about FVC, on mortality risk remains unclear.

Objectives: To determine whether PRISm was associated with mortality and to identify specific groups with particularly increased mortality rates.

Methods: This retrospective study enrolled individuals older than 40 years who underwent comprehensive health screening at the Center for Health Promotion, Samsung Medical Center, between 2003 and 2020. PRISm was characterized by FEV₁/FVC ≥ 0.7 and FEV₁ <80% of predicted values. Participants were classified into three groups: normal lung function, PRISm with normal FVC, and PRISm with low FVC (FVC <80% predicted). We compared all-cause mortality rates using the Kaplan-Meier method and the Cox proportional hazard ratio model.

Results: Among 106,458 individuals, 86,208 exhibited normal lung function, while 6,249 had PRISm with normal FVC, and 14,001 had PRISm with low FVC. Over a median follow-up of 10.1 years, 2,219 participants succumbed. Individuals with PRISm experienced a higher cumulative mortality rate compared to those with normal lung function (39 vs. 16 per 10,000 person-years; adjusted HR 1.43, 95% CI 1.31-1.56). The fully-adjusted HRs for all-cause mortality in PRISm with normal and low FVC were 1.25 (95% CI 1.03-1.52) and 1.47 (95% CI 1.33-1.62) relative to those with normal lung function, respectively.

Conclusions: PRISm is associated with an increased risk of death, particularly when accompanied by low FVC.

Rationale: Equivocal interstitial lung abnormality (ILA) involves less than 5% of any lung zone or presents unilaterally without satisfying the diagnostic criteria for ILA; however, the prevalence and prognosis of equivocal ILA are unknown.

Objectives: To investigate the prevalence and long-term prognosis of equivocal ILA.

Methods: This retrospective cohort study included individuals who underwent chest CT as part of a health check-up program in 2010 at St. Luke's International Hospital in Tokyo, Japan. ILA and equivocal ILA were diagnosed using the Fleischner Society criteria. The primary outcome was the annual rate of forced vital capacity (FVC) decline in the ILA, Equivocal ILA, and No ILA groups, evaluated using a mixed-effects model. Radiological progression was also evaluated.

Results: Among the 20,896 individuals included in the study, ILA and equivocal ILA were present in 2.0% (95% CI: 1.8-2.2%) and 0.4% (95% CI: 0.4-0.5%) of individuals, respectively. Follow-up pulmonary function tests were available for 18,101 (87%) individuals, with a median follow-up time of 8.3 (interquartile range: 4.0-9.0) years. Individuals with equivocal ILA showed a significantly greater rate of FVC decline than those without ILA (-36.7 vs. -27.7 mL/year, P = 0.008). Of the 86 individuals with equivocal ILA, 20 (23%) exhibited progression during the follow-up period; of these, 19 progressed to definite ILA.

Conclusions: Individuals with equivocal ILA showed a significant tendency for FVC decline compared to those without ILA. A considerable number of cases progressed to definite ILA, warranting careful attention. Clinicians should be aware that even mild interstitial changes that do not meet the current criteria for ILA may deteriorate.

The prevalence of obstructive sleep apnea (OSA) is on the rise, driven by various factors including more sensitive diagnostic criteria, increased awareness, enhanced technology through at-home testing enabling easy and cost-effective diagnosis, and a growing incidence of comorbid conditions such as obesity. Treating symptomatic patients with OSA syndrome to enhance quality of life remains a cornerstone approach. However, there is a lack of consensus regarding treatment to improve cardiovascular disease (CVD) outcomes, particularly in light of overall negative results from several randomized controlled trials (RCT) indicating no benefit of positive airway pressure (PAP) therapy on primary and secondary CVD events. These RCTs were limited by suboptimal PAP adherence, use of composite CVD outcomes, and limited diversity and generalizability to Sleep Clinic patients. As such, this workshop assembled clinical experts, as well as researchers in basic and translational science, epidemiology, clinical trials, and population health to discuss the current state, and future research directions to guide personalized therapeutic strategies and future research directions in OSA. There was overall consensus among workshop participants that OSA represents a heterogeneous disease with variable endotypes and phenotypes, and heterogeneous responses to treatment. Future research should prioritize employing multi-modal therapeutic approaches within innovative and adaptive trial designs, focusing on specific subgroups of OSA patients hypothesized to benefit from a CVD perspective. Future work should also be inclusive of diverse populations and consider the life-course of OSA to better comprehend treatment strategies that can address the disproportionate impact of OSA on racially minoritized groups. Further, a more holistic approach to sleep must be adopted to include broader assessments of symptoms, sleep duration, and comorbid sleep and circadian disorders. Finally, it is imperative to establish a sleep research consortium dedicated to collecting raw data and biospecimens categorized by OSA subtypes. This will facilitate mechanistic determinations, foster collaborative research, and help bolster the pipeline of early-career researchers.