The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are greater in patients with evidence of eosinophilic airway inflammation. We ...investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency.
We did a post-hoc analysis of data from two replicate, randomised, double-blind trials of 12 months' duration (Sept 25, 2009 to Oct 21, 2011 and Oct 17, 2011) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg, 100 μg, or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year. We compared exacerbation rates according to two baseline eosinophil cell count strata (<2% and ≥2%), and according to four baseline percentage groupings. We also assessed lung function and incidence of pneumonia per strata in treatment groups.
We included 3177 patients in the analyses, with 2083 patients (66%) having an eosinophil count of 2% or higher at study entry. Across all doses of inhaled corticosteroids, fluticasone furoate and vilanterol reduced exacerbations by 29% compared with vilanterol alone (mean 0·91 vs 1·28 exacerbations per patient per year; p<0·0001) in patients with eosinophil counts of 2% or higher, and by 10% (0·79 vs 0·89; p=0·2827) in patients with eosinophil counts lower than 2%. Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone, were 24% in patients with baseline eosinophil counts of ≥2-<4%, 32% for those with counts of 4-<6%, and 42% for those with eosinophil counts of ≥6%. In patients treated with vilanterol alone, exacerbation rates increased progressively with increasing eosinophil count percentage category. Improvement in trough forced expiratory volume in 1 s (FEV1) and the increased risk of pneumonia with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count.
Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD. Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies.
GlaxoSmithKline (study ID 201595).
Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lung associated with progressive airflow limitation and punctuated by episodes of acute exacerbation. There is growing ...recognition that the inflammatory state associated with COPD is not confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs. Epidemiologic and mechanistic studies indicate that COPD is associated with a high frequency of coronary artery disease, congestive heart failure and cardiac arrhythmias, independent of shared risk factors. Possible pathways include complex interrelationships between chronic low-grade systemic inflammation and oxidative stress as well as shared risk factors such as age, cigarette smoking, and environmental pollutants. In this review, we provide an overview of the epidemiologic data linking COPD with cardiovascular disease, comment on the interrelationships among COPD, inflammation, and cardiovascular disease, and highlight diagnostic and therapeutic challenges.
Mucus stasis in chronic obstructive pulmonary disease (COPD) is a significant contributor to morbidity and mortality. Potentiators of cystic fibrosis transmembrane conductance regulator (CFTR) ...activity pharmacologically enhance CFTR function; ivacaftor is one such agent approved to treat CF patients with the G551D-CFTR gating mutation. CFTR potentiators may also be useful for other diseases of mucus stasis, including COPD.
In primary human bronchial epithelial cells, exposure to cigarette smoke extract diminished CFTR-mediated anion transport (65.8±0.2% of control, P<0.005) and mucociliary transport (0.17±0.05 µm/sec vs. 2.4±0.47 µm/sec control, P<0.05) by reducing airway surface liquid depth (7.3±0.6 µm vs. 13.0±0.6 µm control, P<0.005) and augmenting mucus expression (by 64%, P<0.05) without altering transepithelial resistance. Smokers with or without COPD had reduced CFTR activity measured by nasal potential difference compared to age-matched non-smokers (-6.3±1.4 and -8.0±2.0 mV, respectively vs. -15.2±2.7 mV control, each P<0.005, n = 12-14/group); this CFTR decrement was associated with symptoms of chronic bronchitis as measured by the Breathlessness Cough and Sputum Score (r = 0.30, P<0.05) despite controlling for smoking (r = 0.31, P<0.05). Ivacaftor activated CFTR-dependent chloride transport in non-CF epithelia and ameliorated the functional CFTR defect induced by smoke to 185±36% of non-CF control (P<0.05), thereby increasing airway surface liquid (from 7.3±0.6 µm to 10.1±0.4 µm, P<0.005) and mucociliary transport (from 0.27±0.11 µm/s to 2.7±0.28 µm/s, P<0.005).
Cigarette smoking reduces CFTR activity and is causally related to reduced mucus transport in smokers due to inhibition of CFTR dependent fluid transport. These effects are reversible by the CFTR potentiator ivacaftor, representing a potential therapeutic strategy to augment mucociliary clearance in patients with smoking related lung disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
...analysis from the Global Burden of Diseases, Injuries, and Risk Factors Study shows that in 2019, pollution from ambient particulate matter and occupational exposure to particulate matter, gases, ...and fumes accounted for 36·3% of the attributable risk for COPD compared with 46% of cases attributable to smoking.2–4 In addition, since 1990, the risk for COPD attributable to smoking has declined globally while that related to ambient and occupational exposures has continued to increase, particularly in low-income and lower-middle-income countries.3,4 Although never-smokers with COPD tend to have milder respiratory symptoms, less emphysema, and less lung function impairment, exacerbations can still be frequent.2 One objective of the Commission was to highlight the changing epidemiology of COPD risk factors, not to detract from efforts to control tobacco and support smoking cessation, but to raise awareness of what might be the next drivers of the COPD epidemic. MTD reports grants or contracts from the American Lung Association, the US Department of Defense, and the US National Institutes of Health; consulting fees from AstraZeneca, GlaxoSmithKline, Novartis, Pulmonx, and Teva; and support for attending meetings from Pulmonx. DS reports a grant from the Swiss National Foundation (SNF 320030_189280); unrestricted grants from Curetis, AstraZeneca, and Boston Scientifics (paid to their institution); honoraria for participation in data safety monitoring or advisory boards or talks for CSL Behring, Berlin-Chemie Menarini, Novartis, GlaxoSmithKline, AstraZeneca, Vifor, Merck, Sanofi, Merck Sharp & Dohme, Boehringer Ingelheim, and Chiesi; and is the current Global Initiative for Chronic Obstructive Lung Disease representative for Switzerland, the immediate past Education Council Chair of the European Respiratory Society, and current President of the Education Committee of the Swiss Respiratory Society.
Background COPD is associated with significant morbidity primarily driven by acute exacerbations. Relative pulmonary artery (PA) enlargement, defined as a PA to ascending aorta (A) diameter ratio ...greater than one (PA:A > 1) identifies patients at increased risk for exacerbations. However, little is known about the correlation between PA:A, echocardiography, and invasive hemodynamics in COPD. Methods A retrospective observational study of patients with severe COPD being evaluated for lung transplantation at a single center between 2007 and 2011 was conducted. Clinical characteristics, CT scans, echocardiograms, and right-sided heart catheterizations were reviewed. The PA diameter at the bifurcation and A diameter from the same CT image were measured. Linear and logistic regression were used to examine the relationships between PA:A ratio by CT scan and PA systolic pressure (PASP) by echocardiogram with invasive hemodynamics. Receiver operating characteristic analysis assessed the usefulness of the PA:A ratio and PASP in predicting resting pulmonary hypertension (PH) (mean pulmonary artery pressure mPAP > 25 mm Hg). Results Sixty patients with a mean predicted FEV1 of 27% ± 12% were evaluated. CT scan-measured PA:A correlated linearly with mPAP after adjustment for multiple covariates ( r = 0.30, P = .03), a finding not observed with PASP. In a multivariate logistic model, mPAP was independently associated with PA:A > 1 (OR, 1.44; 95% CI, 1.02-2.04; P = .04). PA:A > 1 was 73% sensitive and 84% specific for identifying patients with resting PH (area under the curve, 0.83; 95% CI, 0.72-0.93; P < .001), whereas PASP was not useful. Conclusions A PA:A ratio > 1 on CT scan outperforms echocardiography for diagnosing resting PH in patients with severe COPD.
Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are common, associated with acute inflammation, and may increase subsequent cardiovascular disease (CVD) risk.
Determine whether ...AECOPD events are associated with increased risk of subsequent CVD.
We performed a secondary cohort analysis of the SUMMIT (Study to Understand Mortality and Morbidity) trial, a convenience sample of current/former smokers with moderate COPD from 1,368 centers in 43 countries. All had CVD or increased CVD risk. AECOPD was defined as an increase in respiratory symptoms requiring treatment with antibiotics, systemic corticosteroids, and/or hospitalization. CVD events were a composite outcome of cardiovascular death, myocardial infarction, stroke, unstable angina, and transient ischemic attack. All CVD events were adjudicated. Cox proportional hazards models compared the hazard for a CVD event before AECOPD versus after AECOPD.
Among 16,485 participants in SUMMIT, 4,704 participants had at least one AECOPD and 688 had at least one CVD event. The hazard ratio (HR) for CVD events after AECOPD was increased, particularly in the first 30 days after AECOPD (HR, 3.8; 95% confidence interval, 2.7-5.5) and was elevated up to 1 year after AECOPD. The 30-day HR after hospitalized AECOPD was more than twofold greater (HR, 9.9; 95% confidence interval, 6.6-14.9).
In patients with COPD with CVD or risk factors for CVD, exacerbations confer an increased risk of subsequent CVD events, especially in hospitalized patients and within the first 30 days after exacerbation. Patients and clinicians should have heightened vigilance for early CVD events after AECOPD. Clinical trial registered with www.clinicaltrials.gov (NCT 01313676).
IMPORTANCE: Chronic lung diseases are a leading cause of morbidity and mortality. Unlike chronic obstructive pulmonary disease, clinical outcomes associated with proportional reductions in expiratory ...lung volumes without obstruction, otherwise known as preserved ratio impaired spirometry (PRISm), are poorly understood. OBJECTIVE: To examine the prevalence, correlates, and clinical outcomes associated with PRISm in US adults. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study was a retrospective study with harmonized pooled data from 9 US general population-based cohorts (enrollment, 65 251 participants aged 18 to 102 years of whom 53 701 participants had valid baseline lung function) conducted from 1971-2011 (final follow-up, December 2018). EXPOSURES: Participants were categorized into mutually exclusive groups by baseline lung function. PRISm was defined as the ratio of forced expiratory volume in the first second to forced vital capacity (FEV1:FVC) greater than or equal to 0.70 and FEV1 less than 80% predicted; obstructive spirometry FEV1:FVC ratio of less than 0.70; and normal spirometry FEV1:FVC ratio greater than or equal to 0.7 and FEV1 greater than or equal to 80% predicted. MAIN OUTCOMES AND MEASURES: Main outcomes were all-cause mortality, respiratory-related mortality, coronary heart disease (CHD)–related mortality, respiratory-related events (hospitalizations and mortality), and CHD-related events (hospitalizations and mortality) classified by adjudication or validated administrative criteria. Absolute risks were adjusted for age and smoking status. Poisson and Cox proportional hazards models comparing PRISm vs normal spirometry were adjusted for age, sex, race and ethnicity, education, body mass index, smoking status, cohort, and comorbidities. RESULTS: Among all participants (mean SD age, 53.2 15.8 years, 56.4% women, 48.5% never-smokers), 4582 (8.5%) had PRISm. The presence of PRISm relative to normal spirometry was significantly associated with obesity (prevalence, 48.3% vs 31.4%; prevalence ratio PR, 1.68 95% CI, 1.55-1.82), underweight (prevalence, 1.4% vs 1.0%; PR, 2.20 95% CI, 1.72-2.82), female sex (prevalence, 60.3% vs 59.0%; PR, 1.07 95% CI, 1.01-1.13), and current smoking (prevalence, 25.2% vs 17.5%; PR, 1.33 95% CI, 1.22-1.45). PRISm, compared with normal spirometry, was significantly associated with greater all-cause mortality (29.6/1000 person-years vs 18.0/1000 person-years; difference, 11.6/1000 person-years 95% CI, 10.0-13.1; adjusted hazard ratio HR, 1.50 95% CI, 1.42-1.59), respiratory-related mortality (2.1/1000 person-years vs 1.0/1000 person-years; difference, 1.1/1000 person-years 95% CI, 0.7-1.6; adjusted HR, 1.95 95% CI, 1.54-2.48), CHD-related mortality (5.4/1000 person-years vs 2.6/1000 person-years; difference, 2.7/1000 person-years 95% CI, 2.1-3.4; adjusted HR, 1.55 95% CI, 1.36-1.77), respiratory-related events (12.2/1000 person-years vs 6.0/1000 person-years; difference, 6.2/1000 person-years 95% CI, 4.9-7.5; adjusted HR, 1.90 95% CI, 1.69-2.14), and CHD-related events (11.7/1000 person-years vs 7.0/1000 person-years; difference, 4.7/1000 person-years 95% CI, 3.7-5.8; adjusted HR, 1.30 95% CI, 1.18-1.42). CONCLUSIONS AND RELEVANCE: In a large, population-based sample of US adults, baseline PRISm, compared with normal spirometry, was associated with a small but statistically significant increased risk for mortality and adverse cardiovascular and respiratory outcomes. Further research is needed to explore whether this association is causal.
Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are both significant burdens on the healthcare system and often coexist. Mechanistic links between the two conditions and ...their clinical impact are increasingly understood.
Recent studies demonstrate multiple mechanisms by which the pathobiology of COPD may have negative effects on the cardiovascular system. These include extrapulmonary consequences of the COPD inflammatory state, cardiac autonomic dysfunction, which has been recently implicated in worsening respiratory symptoms and exacerbation risk, and mechanical effects of lung hyperinflation on left ventricular diastolic function.Clinical studies have consistently shown a high prevalence of CVD in COPD patients and worsened outcomes (and vice versa ). Exacerbations of COPD have also been demonstrated to dramatically increase the risk of cardiovascular events. While some safety concerns exist, medications for COPD and cardiovascular disease should be used in accordance with respective guidelines. However, real-world data show suboptimal management for patients with COPD and CVD.
COPD and cardiovascular disease have complicated interrelationships. Further mechanistic studies may lead to defining better targets for interventions. Education for medical professionals and implementation of novel screening protocols should be encouraged to fill in the gaps in clinical care for these patients.
IMPORTANCE: According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced ...vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial. OBJECTIVE: To determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality. DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population–based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016. EXPOSURES: Presence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN). MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach. RESULTS: Among 24 207 adults in the pooled cohort (mean SD age at enrollment, 63 10.5 years; 12 990 54% women; 16 794 69% non-Hispanic white; 15 181 63% ever smokers), complete follow-up was available for 11 077 (77%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 95% CI, −0.002 to 0.004) but was more accurate than the LLN threshold (difference, 0.034 95% CI, 0.028 to 0.041). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models. CONCLUSIONS AND RELEVANCE: Defining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.
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