Proteomic Blood Profiles Obtained by Totally Blind Biological Clustering in Stable and Exacerbated COPD Patients.

Although Chronic Obstructive Pulmonary Disease (COPD) is highly prevalent, it is often underdiagnosed. One of the main characteristics of this heterogeneous disease is the presence of periods of acute clinical impairment (exacerbations). Obtaining blood biomarkers for either COPD as a chronic entity or its exacerbations (AECOPD) will be particularly useful for the clinical management of patients. However, most of the earlier studies have been characterized by potential biases derived from pre-existing hypotheses in one or more of their analysis steps: some studies have only targeted molecules already suggested by pre-existing knowledge, and others had initially carried out a blind search but later compared the detected biomarkers among well-predefined clinical groups. We hypothesized that a clinically blind cluster analysis on the results of a non-hypothesis-driven wide proteomic search would determine an unbiased grouping of patients, potentially reflecting their endotypes and/or clinical characteristics. To check this hypothesis, we included the plasma samples from 24 clinically stable COPD patients, 10 additional patients with AECOPD, and 10 healthy controls. The samples were analyzed through label-free liquid chromatography/tandem mass spectrometry. Subsequently, the Scikit-learn machine learning module and K-means were used for clustering the individuals based solely on their proteomic profiles. The obtained clusters were confronted with clinical groups only at the end of the entire procedure. Although our clusters were unable to differentiate stable COPD patients from healthy individuals, they segregated those patients with AECOPD from the patients in stable conditions (sensitivity 80%, specificity 79%, and global accuracy, 79.4%). Moreover, the proteins involved in the blind grouping process to identify AECOPD were associated with five biological processes: inflammation, humoral immune response, blood coagulation, modulation of lipid metabolism, and complement system pathways. Even though the present results merit an external validation, our results suggest that the present blinded approach may be useful to segregate AECOPD from stability in both the clinical setting and trials, favoring more personalized medicine and clinical research.

Real-world walking cadence in people with COPD.

Introduction: The clinical validity of real-world walking cadence in people with COPD is unsettled. Our objective was to assess the levels, variability and association with clinically relevant COPD characteristics and outcomes of real-world walking cadence. Methods: We assessed walking cadence (steps per minute during walking bouts longer than 10 s) from 7 days' accelerometer data in 593 individuals with COPD from five European countries, and clinical and functional characteristics from validated questionnaires and standardised tests. Severe exacerbations during a 12-month follow-up were recorded from patient reports and medical registries. Results: Participants were mostly male (80%) and had mean±sd age of 68±8 years, post-bronchodilator forced expiratory volume in 1 s (FEV1) of 57±19% predicted and walked 6880±3926 steps·day-1. Mean walking cadence was 88±9 steps·min-1, followed a normal distribution and was highly stable within-person (intraclass correlation coefficient 0.92, 95% CI 0.90-0.93). After adjusting for age, sex, height and number of walking bouts in fractional polynomial or linear regressions, walking cadence was positively associated with FEV1, 6-min walk distance, physical activity (steps·day-1, time in moderate-to-vigorous physical activity, vector magnitude units, walking time, intensity during locomotion), physical activity experience and health-related quality of life and negatively associated with breathlessness and depression (all p<0.05). These associations remained after further adjustment for daily steps. In negative binomial regression adjusted for multiple confounders, walking cadence related to lower number of severe exacerbations during follow-up (incidence rate ratio 0.94 per step·min-1, 95% CI 0.91-0.99, p=0.009). Conclusions: Higher real-world walking cadence is associated with better COPD status and lower severe exacerbations risk, which makes it attractive as a future prognostic marker and clinical outcome.

Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism in SARS-CoV-2.

INTRODUCTION: Chronic thromboembolic pulmonary disease (CTEPD) consists of persistent pulmonary vascular obstruction on imaging and involves long-term functional limitations, with or without chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to evaluate the incidence and risk factors of both persistent pulmonary vascular defects and CTEPH after hospitalization in patients with COVID-19 and PE during a 2-year follow-up. METHODS: A prospective observational study was carried out in a tertiary hospital center. Patients were hospitalized between March 2020 and December 2021 with a diagnosis of PE during SARS-CoV-2 infection. Patients received anticoagulant treatment for at least 3 months and were followed up for 2 years. Between the third and fourth months after discharge, all patients were evaluated for the presence of residual thrombotic defects by CTPA and/or perfusion pulmonary scintigraphy. Clinical findings, lung function tests with DLCO, exercise capacity, and echocardiograms were also assessed. RESULTS: Of the 133 patients included, 18% had persistent thrombotic defects on lung imaging at follow-up. The incidence of CTEPD was 0.75% at 2 years of follow-up. Patients with persistent defects were significantly older, had a higher prevalence of systemic arterial hypertension, higher D-dimer and NT-proBNP levels, and more severe PE at diagnosis. Furthermore, there was a higher prevalence of right ventricular dysfunction on echocardiogram at diagnosis of PE (25.0% vs. 2.7%, p = 0.006). This was the only variable independently related to persistent defects in multivariate analyses (OR: 8.13 [95% CI: 1.82-36.32], p = 0.006). CONCLUSION: The persistence of thrombotic defects after PE is a common finding after SARS-CoV-2 infection, affecting 18% of the population. However, the incidence of CTEPH appears to be lower (0.75%) in COVID-19-related PE compared to that previously observed in PE unrelated to COVID-19.

Short-term effects of air pollution and weather on physical activity in patients with chronic obstructive pulmonary disease (COPD).

INTRODUCTION: Patients with chronic obstructive pulmonary disease (COPD) accumulate low levels of physical activity. How environmental factors affect their physical activity in the short-term is uncertain. AIM: to assess the short-term effects of air pollution and weather on physical activity levels in COPD patients. METHODS: This multi-center panel study assessed 408 COPD patients from Catalonia (Spain). Daily physical activity (i.e., steps, time in moderate-to-vigorous physical activity (MVPA), locomotion intensity, and sedentary time) was recorded in two 7-day periods, one year apart, using the Dynaport MoveMonitor. Air pollution (nitrogen dioxide (NO2), particulate matter below 10 µm (PM10) and a marker of black carbon (absorbance of PM2.5: PM2.5ABS), and weather (average and maximum temperature, and rainfall) were estimated the same day (lag zero) and up to 5 days prior to each assessment (lags 1-5). Mixed-effect distributed lag linear regression models were adjusted for age, sex, weekday, public holidays, greenness, season, and social class, with patient and city as random effects. RESULTS: Patients (85% male) were on average (mean ± SD) 68 ± 9 years old with a post-bronchodilator forced expiratory volume in 1 s (FEV1) of 57 ± 18% predicted. Higher NO2, PM10 and PM2.5ABS levels at lag four were associated with fewer steps, less time in MVPA, reduced locomotion intensity, and longer sedentary time (e.g., coefficient (95% CI) of -60 (-105, -15) steps per 10 µg/m3 increase in NO2). Higher average and maximum temperatures at lag zero were related to more steps and time in MVPA, and less sedentary time (e.g., +85 (15, 154) steps per degree Celsius). Higher rainfall at lag zero was related to fewer steps and more sedentary time. CONCLUSION: Air pollution affects the amount and intensity of physical activity performed on the following days in COPD patients, whereas weather affects the amount of physical activity performed on the same day.

Pulmonary hypertension in interstitial lung disease and in chronic obstructive pulmonary disease: different entities?

PURPOSE OF REVIEW: Pulmonary hypertension (PH) is a common complication of both chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD), classified as Group 3 PH. To which extent PH presents and behaves similarly in COPD and ILD is unclear. This review examines the similarities and differences in pathogenesis, clinical presentation, natural history and treatment response of PH in COPD and ILD. RECENT FINDINGS: The latest studies on PH in chronic lung disease have re-evaluated the role of traditionally held etiopathogenetic factors such as tobacco exposure and hypoxia, although new ones such as airborne pollutant and genetic mutations are increasingly recognized. We examine common and diverging factors involved in PH development in COPD and ILD, as well as common and diverging clinical features of presentation, natural history and response to treatment and highlight areas for future research. SUMMARY: The development of PH in lung disease significantly worsens the morbidity and mortality of patients with COPD and ILD. However, recent findings show importance of recognizing distinct patterns and behaviors of pulmonary vascular disease, taking into account the specific underlying lung disease and severity of the hemodynamic involvement. Further studies are needed to build evidence on these aspects, especially in early disease.

Effects of Exercise Training on Circulating Biomarkers of Endothelial Function in Pulmonary Arterial Hypertension.

INTRODUCTION: In stable patients with pulmonary arterial hypertension (PAH), pulmonary rehabilitation (PR) is an effective, safe and cost-effective non-pharmacological treatment. However, the effects of PR on vascular function have been poorly explored. This study aimed to compare the amounts of circulating progenitor cells (PCs) and endothelial microvesicles (EMVs) in patients with PAH before and after 8 weeks of endurance exercise training as markers of vascular competence. METHODS: A prospective study of 10 consecutive patients with PAH that successfully finished a PR program (8 weeks) was carried out before and after this intervention. Levels of circulating PCs defined as CD34+CD45low progenitor cells and levels of EMVs (CD31+ CD42b-) were measured by flow cytometry. The ratio of PCs to EMVs was taken as a measure of the balance between endothelial damage and repair capacity. RESULTS: All patients showed training-induced increases in endurance time (mean change 287 s). After PR, the number of PCs (CD34+CD45low/total lymphocytes) was increased (p < 0.05). In contrast, after training, the level of EMVs (CD31+ CD42b-/total EMVs) was reduced. The ratio of PCs to EMVs was significantly higher after training (p < 0.05). CONCLUSION: Our study shows, for the first time, that endurance exercise training in patients with stable PAH has a positive effect, promoting potential mechanisms of damage/repair in favor of repair. This effect could contribute to a positive hemodynamic and clinical response.

Feasibility of a screening algorithm for chronic thromboembolic pulmonary hypertension: The OSIRIS study.

INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is a long-term sequel to pulmonary embolism (PE) whose incidence varies according to different published studies. We have carried out this study to determine its incidence within 2 years after index pulmonary embolism and to study limitations to an early diagnosis. MATERIAL AND METHODS: OSIRIS is a multicentre, longitudinal cohort study. Patients were followed for 3, 6, 12, and 24 months after pulmonary embolism using a structured three-step algorithm. A physician-centered questionnaire at least one positive response in a screening proceeded to the second step, transthoracic echocardiography. The third step consisted of ventilation/perfusion lung scintigraphy and right heart catheterisation. A transthoracic echocardiography was performed in patients without positive response in the screening questionnaire after 2 years. CTEPH diagnosis required haemodynamic confirmation by right heart catheterisation and mismatched perfusion defects on lung scintigraphy. RESULTS: A total of 1191 patients were enrolled in 18 Spanish hospitals. Cumulative CTEPH incidence after 2-years PE was: 2.49 % (95 % CI: 1.68-3.56) and the incidence rate of CTEPH was 1.1 cases per 1000 person-months (95 % CI: 0.725; 1.60). The CTEPH algorithm presented a lack of adherence of 29 %; patient and physician preferences posed barriers to the triage algorithm The screening questionnaire, in patients who completed the follow-up, shows a specificity of 91.3 % (89.0-93.2 %) and negative predictive value of 99.4 % (98.4-99.8 %).. CONCLUSIONS: OSIRIS provides practiced clinical based data on the chronic thromboembolic pulmonary hypertension incidence and identified barriers to the implementation of a 3-step triage algorithm for its detection. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT03134898.

Treatment of COVID-19 during the Acute Phase in Hospitalized Patients Decreases Post-Acute Sequelae of COVID-19.

BACKGROUND: The post-acute sequelae of SARS-CoV-2 (PASC) infection have caused a significant impact on our health system, but there is limited evidence of approved drugs focused on its prevention. Our objective was to identify risk factors that can determine the presence of PASC, with special attention to the treatment received in the acute phase, and to describe the profile of persistent symptoms in a multidisciplinary Post-Coronavirus Disease-19 (COVID-19) Unit. METHODS: This one-year prospective observational study included patients following an acute COVID-19 infection, irrespective of whether they required hospital admission. A standardized symptom questionnaire and blood sampling were performed at the first follow-up visit, and demographic and clinical electronic data were collected. We compared subjects with PASC with those who had fully recovered. Multivariate logistic regression was performed to identify factors associated with PASC in hospitalized patients, and Kaplan-Meier curves were used to assess duration of symptoms according to disease severity and treatments received in the acute phase. RESULTS: 1966 patients were evaluated; 1081 had mild disease, 542 moderate and 343 severe; around one third of the subjects had PASC, and were more frequently female, with obesity, asthma, and eosinophilia during acute COVID-19 disease. Patients who received treatment with dexamethasone and remdesivir during the course of the acute illness showed a lower median duration of symptoms, compared with those who received none of these treatments. CONCLUSION: Treatment with dexamethasone and/or remdesivir may be useful to reduce the impact of PASC secondary to SARS-CoV-2 infection. In addition, we identified female gender, obesity, asthma, and disease severity as risk factors for having PASC.

Nitrosative and Oxidative Stress, Reduced Antioxidant Capacity, and Fiber Type Switch in Iron-Deficient COPD Patients: Analysis of Muscle and Systemic Compartments.

We hypothesized that a rise in the levels of oxidative/nitrosative stress markers and a decline in antioxidants might take place in systemic and muscle compartments of chronic obstructive pulmonary disease (COPD) patients with non-anemic iron deficiency. In COPD patients with/without iron depletion (n = 20/group), markers of oxidative/nitrosative stress and antioxidants were determined in blood and vastus lateralis (biopsies, muscle fiber phenotype). Iron metabolism, exercise, and limb muscle strength were assessed in all patients. In iron-deficient COPD compared to non-iron deficient patients, oxidative (lipofuscin) and nitrosative stress levels were greater in muscle and blood compartments and proportions of fast-twitch fibers, whereas levels of mitochondrial superoxide dismutase (SOD) and Trolox equivalent antioxidant capacity (TEAC) decreased. In severe COPD, nitrosative stress and reduced antioxidant capacity were demonstrated in vastus lateralis and systemic compartments of iron-deficient patients. The slow- to fast-twitch muscle fiber switch towards a less resistant phenotype was significantly more prominent in muscles of these patients. Iron deficiency is associated with a specific pattern of nitrosative and oxidative stress and reduced antioxidant capacity in severe COPD irrespective of quadriceps muscle function. In clinical settings, parameters of iron metabolism and content should be routinely quantify given its implications in redox balance and exercise tolerance.

Iron Depletion in Systemic and Muscle Compartments Defines a Specific Phenotype of Severe COPD in Female and Male Patients: Implications in Exercise Tolerance.

We hypothesized that iron content and regulatory factors, which may be involved in exercise tolerance, are differentially expressed in systemic and muscle compartments in iron deficient severe chronic obstructive pulmonary disease (COPD) patients. In the vastus lateralis and blood of severe COPD patients with/without iron depletion, iron content and regulators, exercise capacity, and muscle function were evaluated in 40 severe COPD patients: non-iron deficiency (NID) and iron deficiency (ID) (20 patients/group). In ID compared to NID patients, exercise capacity, muscle iron and ferritin content, serum transferrin saturation, hepcidin-25, and hemojuvelin decreased, while serum transferrin and soluble transferrin receptor and muscle IRP-1 and IRP-2 increased. Among all COPD, a significant positive correlation was detected between FEV1 and serum transferrin saturation. In ID patients, significant positive correlations were detected between serum ferritin, hepcidin, and muscle iron content and exercise tolerance and between muscle IRP-2 and serum ferritin and hepcidin levels. In ID severe COPD patients, iron content and its regulators are differentially expressed. A potential crosstalk between systemic and muscle compartments was observed in the ID patients. Lung function and exercise capacity were associated with several markers of iron metabolism regulation. Iron status should be included in the overall assessment of COPD patients given its implications in their exercise performance.

Intravenous Iron Replacement Improves Exercise Tolerance in COPD: A Single-Blind Randomized Trial

Introduction: Iron deficiency affects exercise capacity because of the critical role iron plays in the optimal functioning of skeletal muscle metabolism. We hypothesized that intravenous iron may improve exercise tolerance, quality of life (QoL), and daily physical activity (DPA) in patients with chronic obstructive pulmonary disease (COPD). Methods: This was a placebo-controlled, single-blind, parallel-group, randomized clinical trial. Iron deficiency was defined as a ferritin level<100ng/mL or a ferritin level between 100 and 299ng/mL with a transferrin saturation<20%, with or without mild anaemia. Patients were randomized at a 2:1 ratio to receive intravenous ferric carboxymaltose or placebo. The primary objective was to investigate whether intravenous iron replacement improved endurance time from baseline by at least 33%. The secondary objectives were to evaluate impact on QoL using the COPD Assessment Test (CAT) and on DPA by accelerometry. Results: We included 66 patients, 44 (66.7%) in the intervention group and 22 (33.3%) in the placebo group. Among patients receiving ferric carboxymaltose, 23 (52.3%) achieved the primary endpoint compared to 4 (18.2%) in the placebo group [p=0.009; relative risk 3.12, (95% CI, 1.19–8.12)]. CAT score decreased −3 (−6.0–1.3) points from baseline in the intervention group (p=0.007), in contrast to placebo group [−1 (−4.0–2.3) points, p=0.236] with no differences in DPA and adverse events in both groups. Conclusions: Iron replacement improved exercise capacity and QoL in stable COPD patients with iron deficiency. The treatment was well tolerated. (AU)

Predictors and changes of physical activity in idiopathic pulmonary fibrosis.

BACKGROUND: Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival. METHODS: PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established. RESULTS: Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI ≥ 25 kg/m2 and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009]. CONCLUSION: Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis.

The Effect of Borderline Pulmonary Hypertension on Survival in Chronic Lung Disease.

BACKGROUND: The impact of the new "borderline" hemodynamic class for pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP], 21-24 mm Hg and pulmonary vascular resistance, [PVR], ≥3 wood units, [WU]) in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) is unclear. OBJECTIVES: The aim of this study was to assess the effect of borderline PH (BLPH) on survival in COPD and ILD patients. METHOD: Survival was analyzed from retrospective data from 317 patients in 12 centers (Italy, Spain, UK) comparing four hemodynamic groups: the absence of PH (NoPH; mPAP <21 mm Hg or 21-24 mm Hg and PVR <3 WU), BLPH (mPAP 21-24 mm Hg and PVR ≥3 WU), mild-moderate PH (MPH; mPAP 25-35 mm Hg and cardiac index [CI] ≥2 L/min/m2), and severe PH (SPH; mPAP ≥35 mm Hg or mPAP ≥25 mm Hg and CI <2 L/min/m2). RESULTS: BLPH affected 14% of patients; hemodynamic severity did not predict survival when COPD and ILD patients were analyzed together. However, survival in the ILD cohort for any PH level was worse than in NoPH (3-year survival: NoPH 58%, BLPH 32%, MPH 28%, SPH 33%, p = 0.002). In the COPD cohort, only SPH had reduced survival compared to the other groups (3-year survival: NoPH 82%, BLPH 86%, MPH 87%, SPH 57%, p = 0.005). The mortality risk correlated significantly with mPAP in ILD (hazard ratio [HR]: 2.776, 95% CI: 2.057-3.748, p < 0.001) and notably less in COPD patients (HR: 1.015, 95% CI: 1.003-1.027, p = 0.0146). CONCLUSIONS: In ILD, any level of PH portends worse survival, while in COPD, only SPH presents a worse outcome.

Respuesta a «Ausencia de efectos clínicos destacables del SARS-CoV-2 sobre la afinidad de la hemoglobina por el O2 en pacientes con COVID-19» / Reply to «Absence of Relevant Clinical Effects of SARS-CoV-2 on the Affinity of Hemoglobin for O2 in Patients with COVID-19»

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[Translated article] Reply to “Absence of Relevant Clinical Effects of SARS-CoV-2 on the Affinity of Hemoglobin for O2 in Patients With COVID-19” / Respuesta a «Ausencia de efectos clínicos destacables del SARS-CoV-2 sobre la afinidad de la hemoglobina por el O2 en pacientes con COVID-19»

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Intravenous Iron Replacement Improves Exercise Tolerance in COPD: A Single-Blind Randomized Trial.

INTRODUCTION: Iron deficiency affects exercise capacity because of the critical role iron plays in the optimal functioning of skeletal muscle metabolism. We hypothesized that intravenous iron may improve exercise tolerance, quality of life (QoL), and daily physical activity (DPA) in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a placebo-controlled, single-blind, parallel-group, randomized clinical trial. Iron deficiency was defined as a ferritin level<100ng/mL or a ferritin level between 100 and 299ng/mL with a transferrin saturation<20%, with or without mild anaemia. Patients were randomized at a 2:1 ratio to receive intravenous ferric carboxymaltose or placebo. The primary objective was to investigate whether intravenous iron replacement improved endurance time from baseline by at least 33%. The secondary objectives were to evaluate impact on QoL using the COPD Assessment Test (CAT) and on DPA by accelerometry. RESULTS: We included 66 patients, 44 (66.7%) in the intervention group and 22 (33.3%) in the placebo group. Among patients receiving ferric carboxymaltose, 23 (52.3%) achieved the primary endpoint compared to 4 (18.2%) in the placebo group [p=0.009; relative risk 3.12, (95% CI, 1.19-8.12)]. CAT score decreased -3 (-6.0-1.3) points from baseline in the intervention group (p=0.007), in contrast to placebo group [-1 (-4.0-2.3) points, p=0.236] with no differences in DPA and adverse events in both groups. CONCLUSIONS: Iron replacement improved exercise capacity and QoL in stable COPD patients with iron deficiency. The treatment was well tolerated. CLINICAL TRIAL REGISTRATION: EudraCT 2016-001238-89.

Roles of the physical environment in health-related quality of life in patients with chronic obstructive pulmonary disease.

RATIONALE: Many clinical and psychological factors are known to influence the health-related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD). However, research on whether environmental factors, such as air pollution, noise, temperature, and blue/green spaces also influence HRQL in COPD has not been systematically investigated. OBJECTIVE: To assess the relationship between air pollution, road traffic noise, temperature, and distance to blue/green spaces and respiratory-specific HRQL in COPD. METHODS: We used cross-sectional data from a multicenter study in 407 stable mild-to-very severe COPD patients from Barcelona (Catalonia). Patients answered the COPD Assessment Test (CAT) and Clinical COPD Questionnaire (CCQ). Individual residential exposure to air pollutants (nitrogen dioxide [NO2] and particulate matters of varying aerodynamic diameters [PM2.5, PM10, and PM2.5absorbance]), road traffic noise (Lden), and land surface temperature were estimated using long-term averages from land-use regression models, 24-h noise maps, and land surface temperature maps, respectively. We measured residential distances to blue/green spaces from the Urban Atlas. We used mixed-effect negative binomial (for CAT) and linear (for CCQ) regression models, adjusted for potential confounders, with a random effect by center. RESULTS: Of those patients, 85 % were male and had a mean (SD) age of 69 (9) years, CAT score of 12 (7), CCQ-total score of 1.4 (1.0), and post-bronchodilator forced expiratory volume in 1 s (FEV1) of 57 (18) %predicted. We found that NO2 and PM2.5absorbance were associated with worsened CAT and CCQ-mental scores, e.g., 0.15-unit change in CAT score [regression coefficient (ß) = 0.15; 95 % confidence interval (CI) = 0.03, 0.26] per interquartile range in NO2 [13.7 µg/m3]. Greater distances to blue/green spaces were associated with worsened CCQ-mental scores [0.08; 0.002, 0.15]. CONCLUSIONS: Our study showed that increased air pollution, particularly NO2 and PM2.5absorbance and greater distances to blue/green spaces negatively influence HRQL in COPD patients. These findings have important implications for the WHO promotion to develop healthy cities for our future.