Krishnan, Jerry A

Abstract Rationale Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation (n = 1,367) versus above 4,000 ft (1,219 m) elevation (n = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (−32.3 m [95% confidence interval, −49.8 to −14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George’s Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT 01969344).

Importance People who smoked cigarettes may experience respiratory symptoms without spirometric airflow obstruction. These individuals are typically excluded from chronic obstructive pulmonary disease (COPD) trials and lack evidence-based therapies. Objective To define the natural history of persons with tobacco exposure and preserved spirometry (TEPS) and symptoms (symptomatic TEPS). Design, Setting, and Participants SPIROMICS II was an extension of SPIROMICS I, a multicenter study of persons aged 40 to 80 years who smoked cigarettes (>20 pack-years) with or without COPD and controls without tobacco exposure or airflow obstruction. Participants were enrolled in SPIROMICS I and II from November 10, 2010, through July 31, 2015, and followed up through July 31, 2021. Exposures Participants in SPIROMICS I underwent spirometry, 6-minute walk distance testing, assessment of respiratory symptoms, and computed tomography of the chest at yearly visits for 3 to 4 years. Participants in SPIROMICS II had 1 additional in-person visit 5 to 7 years after enrollment in SPIROMICS I. Respiratory symptoms were assessed with the COPD Assessment Test (range, 0 to 40; higher scores indicate more severe symptoms). Participants with symptomatic TEPS had normal spirometry (postbronchodilator ratio of forced expiratory volume in the first second [FEV 1 ] to forced vital capacity >0.70) and COPD Assessment Test scores of 10 or greater. Participants with asymptomatic TEPS had normal spirometry and COPD Assessment Test scores of less than 10. Patient-reported respiratory symptoms and exacerbations were assessed every 4 months via phone calls. Main Outcomes and Measures The primary outcome was assessment for accelerated decline in lung function (FEV 1 ) in participants with symptomatic TEPS vs asymptomatic TEPS. Secondary outcomes included development of COPD defined by spirometry, respiratory symptoms, rates of respiratory exacerbations, and progression of computed tomographic–defined airway wall thickening or emphysema. Results Of 1397 study participants, 226 had symptomatic TEPS (mean age, 60.1 [SD, 9.8] years; 134 were women [59%]) and 269 had asymptomatic TEPS (mean age, 63.1 [SD, 9.1] years; 134 were women [50%]). At a median follow-up of 5.76 years, the decline in FEV 1 was −31.3 mL/y for participants with symptomatic TEPS vs −38.8 mL/y for those with asymptomatic TEPS (between-group difference, −7.5 mL/y [95% CI, −16.6 to 1.6 mL/y]). The cumulative incidence of COPD was 33.0% among participants with symptomatic TEPS vs 31.6% among those with asymptomatic TEPS (hazard ratio, 1.05 [95% CI, 0.76 to 1.46]). Participants with symptomatic TEPS had significantly more respiratory exacerbations than those with asymptomatic TEPS (0.23 vs 0.08 exacerbations per person-year, respectively; rate ratio, 2.38 [95% CI, 1.71 to 3.31], P < .001). Conclusions and Relevance Participants with symptomatic TEPS did not have accelerated rates of decline in FEV 1 or increased incidence of COPD vs those with asymptomatic TEPS, but participants with symptomatic TEPS did experience significantly more respiratory exacerbations over a median follow-up of 5.8 years.

Abstract Study Objectives Sleep is an important dimension in the care of chronic obstructive pulmonary disease (COPD), but its relevance to exacerbations is unclear. We wanted to assess whether sleep quality as measured by the Pittsburgh Sleep Quality Index (PSQI) is associated with an increased risk of COPD exacerbations and does this differ by socio-environmental exposures. Methods We included 1647 current and former smokers with spirometrically confirmed COPD from the SPIROMICS cohort. We assessed incidence rate ratios for exacerbation using zero-inflated negative binomial regression adjusting for demographics, medical comorbidities, and multiple metrics of disease severity, including respiratory medications, airflow obstruction, and symptom burden. Our final model adjusted for socio-environmental exposures using the Area Deprivation Index, a composite measure of contemporary neighborhood quality, and Adversity–Opportunity Index, a composite measure of individual-level historic and current socioeconomic indicators. We used a pre-determined threshold of 20% missingness to undertake multiple imputation by chained equations. As sensitivity analyses, we repeated models in those with complete data and after controlling for prior exacerbations. As an exploratory analysis, we considered an interaction between socio-environmental condition and sleep quality. Results After adjustment for all co-variates, increasing PSQI scores (range 0–21) were associated with a 5% increased risk for exacerbation per point (p = .001) in the imputed dataset. Sensitivity analyses using complete cases and after controlling for prior exacerbation history were similar. Exploratory analysis suggested less effect among those who lived in poor-quality neighborhoods (p-for-interaction = .035). Conclusions Poor sleep quality may contribute to future exacerbations among patients with COPD. This represents one target for improving disease control. Clinical Trial Registration Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). ClinicalTrials.gov Identifier# NCT01969344. Registry URL: https://clinicaltrials.gov/ct2/show/.