Publications by authors named "Nadia N Hansel"

222 Publications

Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.

ERJ Open Res 2021 Jul 26;7(3). Epub 2021 Jul 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p<0.001; Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) General Health: p=0.002; SF-36 Physical Health: p<0.001), decreased functional performance (6-min walk distance (6MWD): p<0.001), and severe AECOPD (p=0.01), while polycythaemia was not. Continuous models, however, demonstrated increased morbidity at both ends of the haemoglobin distribution (p<0.01 for mMRC, SGRQ, SF-36 Physical Health, 6MWD, and severe AECOPD). Evaluating interactions, both diffusing capacity and haemoglobin were independently associated with morbidity. We present novel findings that haemoglobin derangements towards either extreme of the observed range are associated with increased morbidity in COPD. Further investigation is necessary to determine whether haemoglobin derangement drives morbidity or merely reflects systemic inflammation, and whether correcting haemoglobin towards the normal range improves morbidity.
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http://dx.doi.org/10.1183/23120541.00068-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311135PMC
July 2021

Metformin use and risk of asthma exacerbation among asthma patients with glycemic dysfunction.

J Allergy Clin Immunol Pract 2021 Jul 19. Epub 2021 Jul 19.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore Maryland. Electronic address:

Background: Diabetes is associated with worse asthma morbidity. Metformin, which treats diabetes, may have a role among patients with asthma and glycemic dysfunction.

Objective: To determine the association between metformin use and asthma exacerbations among patients with diabetes.

Methods: We queried the Johns Hopkins EHR from April 1, 2013 to May 31, 2018. Adults with asthma and diabetes were followed from first hemoglobin A1c (HbA1c) test to an asthma-related systemic corticosteroid prescription, emergency department (ED) visit, or hospitalization. Multivariable Cox models estimated time to each outcome associated with metformin use, modeled as either time-invariant (status at HbA1c testing) or time-dependent (based on fill data). Mediation of results by HbA1c was assessed. Sensitivity analysis was performed by propensity score matching.

Results: The cohort comprised of 1,749 adults with asthma and diabetes. Metformin use at entry was associated with a lower hazard of asthma-related ED visits (adjusted hazard ratio [aHR] 0.40, 95% confidence interval [CI] 0.22-0.75) but not steroid prescription (aHR 0.89; 95% CI 0.70-1.13) or hospitalization (aHR 0.38, 95% CI 0.13-1.12). HbA1c did not mediate the association with ED visits. With metformin exposure modeled as time-dependent, metformin use was additionally associated with lower hazard of asthma-related hospitalization (aHR 0.30, 95% CI 0.09-0.93). Results were consistent within a sub-cohort of 698 metformin users matched 1:1 to non-users by propensity score.

Conclusion: Metformin use, independent of glycemic control and obesity, was associated with lower hazard of asthma-related ED visits and hospitalizations. Metformin may have benefit in patients with asthma and glycemic dysfunction.
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http://dx.doi.org/10.1016/j.jaip.2021.07.007DOI Listing
July 2021

Polycythemia is Associated with Lower Incidence of Severe COPD Exacerbations in the SPIROMICS Study.

Chronic Obstr Pulm Dis 2021 Jul;8(3):326-335

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States.

Secondary polycythemia has long been recognized as a consequence of chronic pulmonary disease and hypoxemia and is associated with lower mortality and fewer hospitalizations among individuals with chronic obstructive pulmonary disease (COPD)-prescribed long-term oxygen therapy. This study investigates the association of polycythemia with COPD severity, phenotypic features, and respiratory exacerbations in a contemporary and representative sample of individuals with COPD. Current and former smokers with COPD (forced expiratory volume in 1 second [FEV] to forced vital capacity [FVC] ratio <70%) without a history of hematologic/oncologic disorders were selected from the SubPopulations and InteRmediate Outcomes Measures In COPD Study (SPIROMICS), a multi-center observational cohort. Participants with polycythemia (hemoglobin ≥15g/dL [females] or ≥17g/dL [males]), were compared to individuals without anemia (hemoglobin ≥12g/dL [females] or ≥13g/dL [males]). Cross-sectional outcomes including percent predicted FEV, respiratory symptoms, quality of life, exercise tolerance, and percentage and distribution of emphysema (voxels<-950 Hounsfield units [HU] at total lung capacity) were evaluated using linear or logistic regression. Longitudinal acute exacerbation of COPD (AECOPD) and severe AECOPD (requiring an emergency department visit or hospitalization) were assessed using zero-inflated negative binomial models. Among 1261 participants, 148 (11.7%) had polycythemia. Average follow-up was 4.2±1.7 years and did not differ by presence of polycythemia. In multivariate analysis, compared to participants with normal hemoglobin, polycythemia was associated with a reduced rate of severe AECOPD (adjusted incidence rate ratio 0.57, 95% CI: 0.33-0.98), lower percent predicted FEV, lower resting oxygen saturation, increased upper to lower lobe ratio of emphysema, and a greater degree of emphysema, though the latter was attenuated after adjusting for lung function. There were no significant differences in total AECOPD, patient-reported outcomes, or exercise tolerance. These findings suggest that polycythemia, while associated with less favorable physiologic parameters, is not independently associated with symptoms, and is associated with fewer severe exacerbations. Future studies should explore the potentially protective role of increased hemoglobin beyond the correction of anemia.
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http://dx.doi.org/10.15326/jcopdf.2021.0216DOI Listing
July 2021

Altered IgA Response to Gut Bacteria Is Associated with Childhood Asthma in Peru.

J Immunol 2021 Jun 30. Epub 2021 Jun 30.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD

Alterations in gut microbiota in early life have been associated with the development of asthma; however, the role of gut bacteria or the IgA response to gut bacteria in school-aged children with asthma is unclear. To address this question, we profiled the microbial populations in fecal and nasal swab samples by 16S rRNA sequencing from 40 asthma and 40 control children aged 9-17 y from Peru. Clinical history and laboratory evaluation of asthma and allergy were obtained. Fecal samples were analyzed by flow cytometry and sorted into IgA and IgA subsets for 16S rRNA sequencing. We found that the fecal or nasal microbial 16S rRNA diversity and frequency of IgA fecal bacteria did not differ between children with or without asthma. However, the α diversity of fecal IgA bacteria was decreased in asthma compared with control. Machine learning analysis of fecal bacterial IgA-enrichment data revealed loss of IgA binding to the , , and taxa in children with asthma compared with controls. In addition, this loss of IgA binding was associated with worse asthma control (Asthma Control Test) and increased odds of severe as opposed to mild to moderate asthma. Thus, despite little to no change in the microbiota, children with asthma exhibit an altered host IgA response to gut bacteria compared with control participants. Notably, the signature of altered IgA responses is loss of IgA binding, in particular to members of spp., which is associated with greater severity of asthma.
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http://dx.doi.org/10.4049/jimmunol.2001296DOI Listing
June 2021

Longitudinal Imaging-Based Clusters in Former Smokers of the COPD Cohort Associate with Clinical Characteristics: The SubPopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS).

Int J Chron Obstruct Pulmon Dis 2021;16:1477-1496. Epub 2021 May 31.

Department of Mechanical Engineering, University of Iowa, Iowa City, IA, USA.

Purpose: Quantitative computed tomography (qCT) imaging-based cluster analysis identified clinically meaningful COPD former-smoker subgroups (clusters) based on cross-sectional data. We aimed to identify progression clusters for former smokers using longitudinal data.

Patients And Methods: We selected 472 former smokers from SPIROMICS with a baseline visit and a one-year follow-up visit. A total of 150 qCT imaging-based variables, comprising 75 variables at baseline and their corresponding progression rates, were derived from the respective inspiration and expiration scans of the two visits. The COPD progression clusters identified were then associated with subject demography, clinical variables and biomarkers.

Results: COPD severities at baseline increased with increasing cluster number. Cluster 1 patients were an obese subgroup with rapid progression of functional small airway disease percentage (fSAD%) and emphysema percentage (Emph%). Cluster 2 exhibited a decrease of fSAD% and Emph%, an increase of tissue fraction at total lung capacity and airway narrowing over one year. Cluster 3 showed rapid expansion of Emph% and an attenuation of fSAD%. Cluster 4 demonstrated severe emphysema and fSAD and significant structural alterations at baseline with rapid progression of fSAD% over one year. Subjects with different progression patterns in the same cross-sectional cluster were identified by longitudinal clustering.

Conclusion: qCT imaging-based metrics at two visits for former smokers allow for the derivation of four statistically stable clusters associated with unique progression patterns and clinical characteristics. Use of baseline variables and their progression rates enables identification of longitudinal clusters, resulting in a refinement of cross-sectional clusters.
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http://dx.doi.org/10.2147/COPD.S301466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178702PMC
July 2021

Airway mucin MUC5AC and MUC5B concentrations and the initiation and progression of chronic obstructive pulmonary disease: an analysis of the SPIROMICS cohort.

Lancet Respir Med 2021 May 28. Epub 2021 May 28.

Marsico Lung Institute/Cystic Fibrosis and Pulmonary Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address:

Background: We previously described the contributions of increased total airway mucin concentrations to the pathogenesis and diagnosis of the chronic bronchitic component of chronic obstructive pulmonary disease (COPD). Here, we investigated the relative contribution of each of the major airway gel-forming mucins, MUC5AC and MUC5B, to the initiation, progression, and early diagnosis of airways disease in COPD.

Methods: SPIROMICS was a multicentre, observational study in patients aged 40-80 years recruited from six clinical sites and additional subsites in the USA. In this analysis, MUC5AC and MUC5B were quantitated by stable isotope-labelled mass spectrometry in induced sputum samples from healthy never-smokers, ever-smokers at risk for COPD, and ever-smokers with COPD. Participants were extensively characterised using results from questionnaires, such as the COPD assessment test (CAT) and St George's Respiratory Questionnaire; quantitative CT, such as residual volume/total lung capacity ratio (RV/TLC) and parametric response mapping-functional small airway disease (PRM-fSAD); and pulmonary function tests, such as FEV, forced vital capacity (FVC), and forced expiratory flow, midexpiratory phase (FEF). Absolute concentrations of both MUC5AC and MUC5B were related to cross-sectional (baseline, initial visit) and 3-year follow-up longitudinal data, including lung function, small airways obstruction, prospective acute exacerbations, and smoking status as primary outcomes. This study is registered with ClinicalTrials.gov (NCT01969344).

Findings: This analysis included 331 participants (mean age 63 years [SEM 9·40]), of whom 40 were healthy never-smokers, 90 were at-risk ever-smokers, and 201 were ever-smokers with COPD. Increased MUC5AC concentrations were more reliably associated with manifestations of COPD than were MUC5B concentrations, including decreased FEV and FEF, and increased prospective exacerbation frequency, RV/TLC, PRM-fSAD, and COPD assessment scores. MUC5AC concentrations were more reactive to cigarette smoke exposure than were MUC5B concentrations. Longitudinal data from 3-year follow-up visits generated a multivariate-adjusted odds ratio for two or more exacerbations of 1·24 (95% CI 1·04-1·47, p=0·015) for individuals with high baseline MUC5AC concentration. Increased MUC5AC, but not MUC5B, concentration at baseline was a significant predictor of FEV, FEV/FVC, FEF, and CAT score decline during the 3-year follow-up. Moreover, current smokers in the at-risk group showed raised MUC5AC concentrations at initial visits and decreased lung function over 3 years. By contrast, former smokers in the at-risk group showed normal MUC5AC concentrations at the initial visit and preserved lung function over 3 years.

Interpretation: These data indicate that increased MUC5AC concentration in the airways might contribute to COPD initiation, progression, exacerbation risk, and overall pathogenesis. Compared with MUC5B, greater relative changes in MUC5AC concentrations were observed as a function of COPD severity, and MUC5AC concentration seems to be an objective biomarker to detect disease in at-risk and pre-COPD individuals. These data suggest that MUC5AC-producing pathways could be potential targets for future therapeutic strategies. Thus, MUC5AC could be a novel biomarker for COPD prognosis and for testing the efficacy of therapeutic agents.

Funding: National Institutes of Health; National Heart, Lung, and Blood Institute.
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http://dx.doi.org/10.1016/S2213-2600(21)00079-5DOI Listing
May 2021

Bronchoalveolar Lavage and Plasma Cathelicidin Response to 25-Hydroxy Vitamin D Supplementation: A Pilot Study.

Chronic Obstr Pulm Dis 2021 Jul;8(3):371-381

Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States.

Introduction: Cathelicidin is a vitamin D-regulated, antimicrobial peptide involved in the innate immune response of the airways. Reduced plasma cathelicidin concentrations are independently associated with worse pulmonary outcomes in current and former smokers. This study aimed to determine whether oral vitamin D supplementation in vitamin D-deficient current smokers increases plasma and bronchoalveolar lavage (BAL) cathelicidin levels.

Methods: Vitamin D-deficient (25-hydroxy vitamin D [25-OH vitamin D] <20 ng/ml) smokers (n=17) underwent collection of plasma and BAL for cathelicidin and 25-OH vitamin D measurements before and after 8 weeks of oral supplementation with 50,000 IU vitamin D3 weekly. Differences between baseline and 8-week levels of cathelicidin and 25-OH vitamin D in blood and BAL were assessed along with correlations between serum 25-OH vitamin D, plasma cathelicidin, and BAL cathelicidin.

Results: At baseline, there was no correlation between BAL and plasma cathelicidin. There was a significant increase in 25-OH vitamin D (median 17.0 to 43.3 ng/mL, <0.001) after 8 weeks of vitamin D supplementation. There was no change in plasma cathelicidin (=0.86), BAL cathelicidin (=0.31), or BAL 25-OH vitamin D (0.89). There was no correlation between serum 25-OH vitamin D and either BAL or plasma cathelicidin post-supplementation.

Conclusions: Oral vitamin D supplementation, while increasing serum 25-OH vitamin D levels, does not increase plasma or BAL cathelicidin levels in vitamin D-deficient, active smokers. The lack of increased BAL cathelicidin may be explained by multiple factors related to dosing, smoking effects, or putative mechanisms of engagement. Future studies are needed to determine the effects of vitamin D supplementation on lung and blood functional activity.
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http://dx.doi.org/10.15326/jcopdf.2021.0220DOI Listing
July 2021

Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment.

Am J Respir Crit Care Med 2021 May 25. Epub 2021 May 25.

Brigham and Women's Hospital, Boston, Massachusetts, United States.

Introduction: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, emphysema, and systemic pathologies. Metformin is beneficial against aging-related diseases, and we hypothesized that it may ameliorate CS-induced pathologies of emphysematous COPD.

Methods: Mice were exposed chronically to CS and fed metformin for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitro were studied. We evaluated the association of metformin use with indices of emphysema progression over five years of follow-up among the COPDGene Study participants. The association of metformin use with percent emphysema and adjusted lung density was estimated with a linear mixed model.

Results: Metformin protected against CS-induced pulmonary inflammation, airspace enlargement, and small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro, and ER stress. The AMPK pathway was central to metformin protective action. Within COPDGene, participants taking metformin compared to those not on it had slower progression of emphysema (-0.92%, CI; -1.7 to -0.14%, p = 0.02) and adjusted lung density decrease (2.2 g/L; 95% CI 0.43 to 4.0 g/L, p = 0.01).

Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury, mitochondrial dysfunction, and UPR-ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.
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http://dx.doi.org/10.1164/rccm.202012-4510OCDOI Listing
May 2021

Emphysema Progression and Lung Function Decline Among Angiotensin Converting Enzyme Inhibitors and Angiotensin-Receptor Blockade Users in the COPDGene Cohort.

Chest 2021 May 21. Epub 2021 May 21.

Division of Pulmonary and Critical Care, Johns Hopkins University, Baltimore, MD.

Background: Attenuation of transforming growth factor β by blocking angiotensin II has been shown to reduce emphysema in a murine model. General population studies have demonstrated that the use of angiotensin converting enzyme inhibitors (ACEis) and angiotensin-receptor blockers (ARBs) is associated with reduction of emphysema progression in former smokers and that the use of ACEis is associated with reduction of FEV progression in current smokers.

Research Question: Is use of ACEi and ARB associated with less progression of emphysema and FEV decline among individuals with COPD or baseline emphysema?

Methods: Former and current smokers from the Genetic Epidemiology of COPD Study who attended baseline and 5-year follow-up visits, did not change smoking status, and underwent chest CT imaging were included. Adjusted linear mixed models were used to evaluate progression of adjusted lung density (ALD), percent emphysema (%total lung volume <-950 Hounsfield units [HU]), 15th percentile of the attenuation histogram (attenuation [in HU] below which 15% of voxels are situated plus 1,000 HU), and lung function decline over 5 years between ACEi and ARB users and nonusers in those with spirometry-confirmed COPD, as well as all participants and those with baseline emphysema. Effect modification by smoking status also was investigated.

Results: Over 5 years of follow-up, compared with nonusers, ACEi and ARB users with COPD showed slower ALD progression (adjusted mean difference [aMD], 1.6; 95% CI, 0.34-2.9). Slowed lung function decline was not observed based on phase 1 medication (aMD of FEV % predicted, 0.83; 95% CI, -0.62 to 2.3), but was when analysis was limited to consistent ACEi and ARB users (aMD of FEV % predicted, 1.9; 95% CI, 0.14-3.6). No effect modification by smoking status was found for radiographic outcomes, and the lung function effect was more pronounced in former smokers. Results were similar among participants with baseline emphysema.

Interpretation: Among participants with spirometry-confirmed COPD or baseline emphysema, ACEi and ARB use was associated with slower progression of emphysema and lung function decline.

Trial Registry: ClinicalTrials.gov; No.: NCT00608764; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.05.007DOI Listing
May 2021

Racial Segregation and Respiratory Outcomes among Urban Black Residents with and at Risk of COPD.

Am J Respir Crit Care Med 2021 May 10. Epub 2021 May 10.

Johns Hopkins University, Medicine, Baltimore, Maryland, United States;

Rationale: Racial residential segregation has been associated with worse health outcomes, but the link with COPD morbidity has not been established.

Objectives: To investigate whether racial residential segregation is associated with COPD morbidity among urban Black adults with or at risk of COPD.

Methods: Racial residential segregation was assessed using isolation index, based on 2010 decennial census and baseline address, for Black former and current smokers in the multi-center SPIROMICS study of adults with or at risk for COPD. We tested the association between isolation index and respiratory symptoms, physiologic outcomes, imaging parameters, and exacerbation risk among urban Black residents, adjusting for established COPD risk factors, including smoking. Additional mediation analysis were conducted for factors that could lie on the pathway between segregation and COPD outcomes, including individual and neighborhood socioeconomic status, comorbidity burden, depression/anxiety, and ambient pollution.

Measurements And Results: Among 515 Black participants, those residing in segregated neighborhoods (i.e., isolation index ≥ 0.6) had worse COPD Assessment Test score (β=2.4, 95%CI, 0.7-4.0), dyspnea (mMRC; β=0.29, 95%CI, 0.10-0.47), quality of life (SGRQ; β=6.1, 95%CI, 2.3-9.9), cough and sputum (MCQ; β=0.8, 95%CI, 0.1-1.5), lower FEV1 % predicted (β=-7.3, 95%CI, -10.9 to -3.6), higher rate of any and severe exacerbations and higher percentage emphysema (β=2.3, 95%CI, 0.7-3.9) and air trapping (β=3.8, 95%CI, 0.6-7.1). Adverse associations attenuated with adjustment for potential mediators but remained robust for several outcomes, including dyspnea, FEV1 % predicted, percent emphysema and air trapping.

Conclusions: Racial residential segregation was adversely associated with COPD morbidity among urban Black participants and supports the hypothesis that racial segregation plays a role in explaining health inequities affecting Black communities.
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http://dx.doi.org/10.1164/rccm.202009-3721OCDOI Listing
May 2021

Disparities in access to food and chronic obstructive pulmonary disease (COPD)-related outcomes: a cross-sectional analysis.

BMC Pulm Med 2021 Apr 27;21(1):139. Epub 2021 Apr 27.

Division of Pulmonary and Critical Care, Johns Hopkins University, 4940 Eastern Avenue, Baltimore, MD, 21224, USA.

Background: Millions of Americans are living in food deserts in the United States, however the role of the local food environment on COPD has not been studied. The aim of this study is to determine the association between food deserts and COPD-related outcomes.

Method: In this cross-sectional analysis we linked data collected from SPIROMICS (SubPopulations and InteRmediate Outcome Measures in COPD Study) between 2010 and 2015 and food desert data, defined as an underserved area that lacks access to affordable healthy foods, from the Food Access Research Atlas. COPD outcomes include percentage of predicted forced expiratory volume in one second (FEV1%), St. George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), 6-min walk distance test (6MWD), exacerbations, and air trapping. We used generalized linear mixed models to evaluate the association between living in food deserts and respiratory outcomes, adjusting for age, gender, race, education, income, marital status, BMI, smoking status, pack years, and urban status RESULTS: Among 2713 participants, 22% lived in food deserts. Participants living in food deserts were less likely to be white and more likely to have a lower income than those who did not live in food deserts. In the adjusted model controlling for demographics and individual income, living in food deserts was associated lower FEV1% (β = - 2.51, P = 0.046), higher air trapping (β = 2.47, P = 0.008), worse SGRQ (β = 3.48, P = 0.001) and CAT (β = 1.20, P = 0.003) scores, and 56% greater odds of severe exacerbations (P = 0.004). Results were consistent when looking at food access alone, regardless of whether participants lived in low income areas.

Conclusions: Findings suggest an independent association between food desert and food access alone with COPD outcomes. Health program planning may benefit from addressing disparities in access to food.
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http://dx.doi.org/10.1186/s12890-021-01485-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077917PMC
April 2021

Association of plasma mitochondrial DNA with COPD severity and progression in the SPIROMICS cohort.

Respir Res 2021 Apr 26;22(1):126. Epub 2021 Apr 26.

Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

Background: There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures.

Methods: P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up.

Results: P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up.

Conclusion: In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies.

Trial Registration:  ClinicalTrials.gov NCT01969344 (SPIROMICS).
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http://dx.doi.org/10.1186/s12931-021-01707-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074408PMC
April 2021

Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.

Genome Med 2021 04 21;13(1):66. Epub 2021 Apr 21.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.

Background: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

Methods: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

Results: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

Conclusions: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.
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http://dx.doi.org/10.1186/s13073-021-00866-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059115PMC
April 2021

E-Cigarettes and Cardiopulmonary Health.

Function (Oxf) 2021 8;2(2):zqab004. Epub 2021 Feb 8.

Dorothy M. Davis Heart and Lung Research Institute, Colleges of Medicine and Nursing, The Ohio State University, Columbus, OH, USA.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.
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http://dx.doi.org/10.1093/function/zqab004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948134PMC
February 2021

The influence of social support on COPD outcomes mediated by depression.

PLoS One 2021 17;16(3):e0245478. Epub 2021 Mar 17.

Johns Hopkins Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Background: The purpose of this study was to explore the association between perceived social support and COPD outcomes and to determine whether the associations are mediated by depressive symptoms.

Methods: Subjects with COPD who were enrolled as part of SPIROMICS were included in this analysis. Questionnaires relating to quality of life, symptom burden, and functional status were administered at annual clinic visits for over a 3 year period. In both cross-sectional and longitudinal analyses, we examined the association of social support as measured by the FACIT-F with COPD outcomes. Cross sectional analyses used multivariable linear or logistic regression, adjusting for covariates. For longitudinal analyses, generalized linear mixed models with random intercepts were used. Models were adjusted with and without depressive symptoms and mediation analyses performed.

Results: Of the 1831 subjects with COPD, 1779 completed the FACIT- F questionnaire. In adjusted cross-sectional analysis without depressive symptoms, higher perceived social support was associated with better quality of life, well-being, 6 minute walk distance, and less dyspnea. When also adjusting for depressive symptoms, all associations between social support and COPD outcomes were attenuated and no longer statistically significant. Mediation analysis suggested that depressive symptoms explained the majority (> = 85%) of the association between social support and measured COPD outcomes. Results of the longitudinal analysis were consistent with the cross-sectional analyses. There was no association between social support and odds of exacerbations.

Conclusion: Higher social support was associated with better COPD outcomes across several measures of morbidity including quality of life, respiratory symptoms, and functional status. In addition, these associations were largely attenuated when accounting for depressive symptoms suggesting that the beneficial association of social support with COPD outcomes may be largely mediated by the association between social support and depression.

Trial Registration: SPIROMICS was approved by Institutional Review Boards at each center and all participants provided written informed consent (clinicaltrials.gov: NCT01969344).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245478PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968645PMC
March 2021

Genome-wide association study of asthma, total IgE, and lung function in a cohort of Peruvian children.

J Allergy Clin Immunol 2021 Mar 10. Epub 2021 Mar 10.

Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Md. Electronic address:

Background: Genetic ancestry plays a role in asthma health disparities.

Objective: Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function.

Methods: A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study.

Results: The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P < .001) and IBS was associated with lower total serum IgE levels (P < .001). NAT was associated with higher FEV percent predicted values (P < .001), whereas IBS was associated with lower FEV values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P = 3.438 × 10) and was independent of an association with the haplotype HLA-DQA1∼HLA-DQB1:04.01∼04.02 (P = 1.55 × 10). For lung function, we identified a locus (rs4410198; P = 5.536 × 10) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P = .005).

Conclusion: This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT.
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http://dx.doi.org/10.1016/j.jaci.2021.02.035DOI Listing
March 2021

Latent traits of lung tissue patterns in former smokers derived by dual channel deep learning in computed tomography images.

Sci Rep 2021 Mar 1;11(1):4916. Epub 2021 Mar 1.

Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and the traditional variables extracted from computed tomography (CT) images may not be sufficient to describe all the topological features of lung tissues in COPD patients. We employed an unsupervised three-dimensional (3D) convolutional autoencoder (CAE)-feature constructor (FC) deep learning network to learn from CT data and derive tissue pattern-clusters jointly. We then applied exploratory factor analysis (EFA) to discover the unobserved latent traits (factors) among pattern-clusters. CT images at total lung capacity (TLC) and residual volume (RV) of 541 former smokers and 59 healthy non-smokers from the cohort of the SubPopulations and Intermediate Outcome Measures in the COPD Study (SPIROMICS) were analyzed. TLC and RV images were registered to calculate the Jacobian (determinant) values for all the voxels in TLC images. 3D Regions of interest (ROIs) with two data channels of CT intensity and Jacobian value were randomly extracted from training images and were fed to the 3D CAE-FC model. 80 pattern-clusters and 7 factors were identified. Factor scores computed for individual subjects were able to predict spirometry-measured pulmonary functions. Two factors which correlated with various emphysema subtypes, parametric response mapping (PRM) metrics, airway variants, and airway tree to lung volume ratio were discriminants of patients across all severity stages. Our findings suggest the potential of developing factor-based surrogate markers for new COPD phenotypes.
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http://dx.doi.org/10.1038/s41598-021-84547-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921389PMC
March 2021

Metformin use and respiratory outcomes in asthma-COPD overlap.

Respir Res 2021 Feb 26;22(1):70. Epub 2021 Feb 26.

Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, 1830 E. Monument St. 5th Floor, Baltimore, MD, 21205, USA.

Background: Metformin is associated with improved respiratory outcomes in asthma; however, metformin in COPD and asthma-COPD overlap (ACO) remains unexplored.

Objective: To determine the association between metformin use and respiratory outcomes in COPD and ACO.

Study Design And Methods: Participants with COPD (FEV1/FVC < 0.70) in the Genetic Epidemiology of COPD study (COPDGene®) were categorized as ACO (n = 510), defined as concurrent physician-diagnosed asthma before age 40 years, or COPD alone (n = 3459). We estimated the association of baseline metformin use with (1) rate of total and severe respiratory exacerbations during follow-up, (2) cross-sectional St. George's Respiratory Questionnaire (SGRQ) score, six-minute walk distance (6MWD), and post-bronchodilator FEV1 percent predicted (FEV1pp), and (3) 5-year change in SGRQ, 6MWD, and FEV1pp. We also examined change in SGRQ, 6MWD and FEV1pp among participants who initiated metformin during follow-up (n = 108) compared to persistent metformin non-users (n = 2080). Analyses were adjusted for sociodemographic factors, medications, and comorbidities.

Results: Among participants with ACO, metformin use was associated with lower rate of total (adjusted incidence rate ratio [aIRR] 0.3; 95% confidence interval [95%CI] 0.11, 0.77) and severe exacerbations (aIRR 0.29; 95%CI 0.10, 0.89). Among participants with COPD alone, there was no association between metformin use with total (aIRR 0.98; 95%CI 0.62, 1.5) or severe exacerbations (aIRR 1.3; 95% CI 0.68, 2.4) (p-interaction < 0.05). Metformin use was associated with lower baseline SGRQ score (adjusted mean difference [aMD] - 2.7; 95%CI - 5.3, - 0.2) overall. Metformin initiation was associated with improved SGRQ score (aMD -10.0; 95% CI - 18.7, - 1.2) among participants with ACO but not COPD alone (p-interaction < 0.05). There was no association between metformin use and 6MWD or FEV1pp in any comparison.

Conclusions: Metformin use was associated with fewer respiratory exacerbations and improved quality of life among individuals with ACO but not COPD alone. Results suggest a potential role for metformin in ACO which requires further prospective study.

Trial Registry: NCT00608764.
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http://dx.doi.org/10.1186/s12931-021-01658-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908718PMC
February 2021

Defining Resilience to Smoking Related Lung Disease: A Modified Delphi Approach from SPIROMICS.

Ann Am Thorac Soc 2021 Feb 25. Epub 2021 Feb 25.

UCSF, Division of Pulmonary and Critical Care Medicine, Department of Medicine and CVRI, San Francisco, California, United States.

Rationale: Diagnosis of chronic obstructive pulmonary disease (COPD) relies on abnormal spirometry. However, spirometry may underestimate the effects of smoking, missing smokers with respiratory disease that have minimal or no airflow obstruction.

Objectives: Develop a multi-dimensional definition of a lung-related "resilient smoker" that is useful in research studies; then identify a resilient smoker subgroup in the SPIROMICS cohort using this definition.

Methods: We performed a three-round modified Delphi survey among a panel of COPD experts to identify and reach a consensus on clinical and radiographic domains to be included in a lung-related resilient smoker definition. Consensus on domains of resilience was defined as ≥80% of experts voting "agree" or "strongly agree" on a 5-point Likert scale. The Delphi-derived definition of resilience was applied to SPIROMICS to identify resilient smokers, whom we then characterized using known biomarkers of COPD.

Results: Consensus was achieved on 6 of 12 diagnostic items which include: cough and sputum production, dyspnea, radiographic measures of emphysema and small airways disease, exacerbations, and decline in FEV1. Although 892 SPIROMICS participants were classified as smokers with preserved lung function by spirometry, only 149 participants (16.7%) qualified as resilient smokers by our definition. Blood biomarker expression of C-reactive protein (CRP) and soluble tumor necrosis receptor factor1A (sTNFRSF1A) was lower in resilient than non-resilient smokers (P=0.02 and P=0.03).

Conclusions: A Delphi-derived consensus definition of resilient smoker identified 83.3% of smokers with preserved spirometry as "non-resilient" based on the presence of adverse effects of smoking on the lung. Resilient smokers were biologically distinct from non-resilient smokers based on CRP measurements. Clinical trial registered with ClinicalTrials.gov (NCT01969344).
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http://dx.doi.org/10.1513/AnnalsATS.202006-757OCDOI Listing
February 2021

Patterns and predictors of air purifier adherence in children with asthma living in low-income, urban households.

J Asthma 2021 Mar 10:1-10. Epub 2021 Mar 10.

Department of Pulmonology and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Objective: Black children and children from low-income communities are disproportionately affected by asthma, attributed partly to pollution exposure. Air purifiers reduce indoor air pollution and improve asthma symptoms in children. In order to implement air purifier interventions, an understanding of patterns of use and potential barriers is necessary.

Methods: In a home intervention study, 127 children with asthma living in Baltimore were randomized to receive two active or two placebo air purifiers. The 16-week study period included: baseline clinic visit, home visit for air purifier installation (active or placebo) with instruction to use the high or turbo settings, and electronic adherence monitoring of air purifiers. Determinants of adherence were identified using linear regression models.

Results: Air purifiers were used 80% of the time, and participants demonstrated adherence to high or turbo settings for 60% of the time. In an adjusted model, season was the major determinant of air purifier adherence, with 21% lower use in the winter ( = 0.025) attributed to the cold draft generated by the machine.

Conclusion: In a clinical trial with electronic adherence monitoring, air purifier use was high and participants were adherent to use of high or turbo settings the majority of the time. Addressing practical barriers to consistent use, such as draft during the winter, in addition to financial barriers may improve air purifier adherence among children with asthma living in low-income, urban households.

Clinical Trials Registry Number: NCT02763917.
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http://dx.doi.org/10.1080/02770903.2021.1893745DOI Listing
March 2021

Lung microbiota associations with clinical features of COPD in the SPIROMICS cohort.

NPJ Biofilms Microbiomes 2021 02 5;7(1):14. Epub 2021 Feb 5.

Division of Pulmonary/Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA.

Chronic obstructive pulmonary disease (COPD) is heterogeneous in development, progression, and phenotypes. Little is known about the lung microbiome, sampled by bronchoscopy, in milder COPD and its relationships to clinical features that reflect disease heterogeneity (lung function, symptom burden, and functional impairment). Using bronchoalveolar lavage fluid collected from 181 never-smokers and ever-smokers with or without COPD (GOLD 0-2) enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we find that lung bacterial composition associates with several clinical features, in particular bronchodilator responsiveness, peak expiratory flow rate, and forced expiratory flow rate between 25 and 75% of FVC (FEF). Measures of symptom burden (COPD Assessment Test) and functional impairment (six-minute walk distance) also associate with disparate lung microbiota composition. Drivers of these relationships include members of the Streptococcus, Prevotella, Veillonella, Staphylococcus, and Pseudomonas genera. Thus, lung microbiota differences may contribute to airway dysfunction and airway disease in milder COPD.
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http://dx.doi.org/10.1038/s41522-021-00185-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865064PMC
February 2021

Ratio of FEV/Slow Vital Capacity of < 0.7 Is Associated With Clinical, Functional, and Radiologic Features of Obstructive Lung Disease in Smokers With Preserved Lung Function.

Chest 2021 Jul 1;160(1):94-103. Epub 2021 Feb 1.

Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC.

Background: Mild expiratory flow limitation may not be recognized using traditional spirometric criteria based on the ratio of FEV/FVC.

Research Question: Does slow vital capacity (SVC) instead of FVC increase the sensitivity of spirometry to identify patients with early or mild obstructive lung disease?

Study Design And Methods: We included 854 current and former smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study cohort with a postbronchodilator FEV/FVC ≥ 0.7 and FEV % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV/FVC, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV/SVC of ≥ 0.7 and 120 with postbronchodilator FEV/SVC < 0.7 at the enrollment. We performed multivariate linear and logistic regression models and negative binomial and interval-censored proportion hazards regression models adjusted for demographics and smoking exposure to examine the association of FEV/SVC < 0.7 with those characteristics and outcomes.

Results: Participants with FEV/SVC < 0.7 were older and had lower FEV and more emphysema than those with FEV/SVC ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV/SVC < 0.7 showed a greater percentage of emphysema by 0.45% (95% CI, 0.09%-0.82%), percentage of gas trapping by 2.52% (95% CI, 0.59%-4.44%), and percentage of functional small airways disease based on parametric response mapping by 2.78% (95% CI, 0.72%-4.83%) at baseline than those with FEV/SVC ≥ 0.7. During a median follow-up time of 1,500 days, an FEV/SVC < 0.7 was not associated with total exacerbations (incident rate ratio [IRR], 1.61; 95% CI, 0.97-2.64), but was associated with severe exacerbations (IRR, 2.60; 95% CI, 1.04-4.89). An FEV/SVC < 0.7 was associated with progression to COPD during a 3-year follow-up even after adjustment for demographics and smoking exposure (hazard ratio, 3.93; 95% CI, 2.71-5.72). We found similar results when we examined the association of prebronchodilator FEV/SVC < 0.7 or FEV/SVC less than the lower limit of normal with chest CT scan features and progression to COPD.

Interpretation: Low FEV to SVC in current and former smokers with normal spirometry results can identify individuals with CT scan features of COPD who are at risk for severe exacerbations and is associated with progression to COPD in the future.

Trial Registry: ClinicalTrials.gov; No.: NCT01969344T4; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.01.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295909PMC
July 2021

Cardiopulmonary Impact of Particulate Air Pollution in High-Risk Populations: JACC State-of-the-Art Review.

J Am Coll Cardiol 2020 12;76(24):2878-2894

Division of Cardiovascular Diseases, Wayne State University, Detroit, Michigan, USA.

Fine particulate air pollution <2.5 μm in diameter (PM) is a major environmental threat to global public health. Multiple national and international medical and governmental organizations have recognized PM as a risk factor for cardiopulmonary diseases. A growing body of evidence indicates that several personal-level approaches that reduce exposures to PM can lead to improvements in health endpoints. Novel and forward-thinking strategies including randomized clinical trials are important to validate key aspects (e.g., feasibility, efficacy, health benefits, risks, burden, costs) of the various protective interventions, in particular among real-world susceptible and vulnerable populations. This paper summarizes the discussions and conclusions from an expert workshop, Reducing the Cardiopulmonary Impact of Particulate Matter Air Pollution in High Risk Populations, held on May 29 to 30, 2019, and convened by the National Institutes of Health, the U.S. Environmental Protection Agency, and the U.S. Centers for Disease Control and Prevention.
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http://dx.doi.org/10.1016/j.jacc.2020.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040922PMC
December 2020

Mucus Plugs and Emphysema in the Pathophysiology of Airflow Obstruction and Hypoxemia in Smokers.

Am J Respir Crit Care Med 2021 04;203(8):957-968

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Utah Hospitals and Clinics, Salt Lake City, Utah.

The relative roles of mucus plugs and emphysema in mechanisms of airflow limitation and hypoxemia in smokers with chronic obstructive pulmonary disease (COPD) are uncertain. To relate image-based measures of mucus plugs and emphysema to measures of airflow obstruction and oxygenation in patients with COPD. We analyzed computed tomographic (CT) lung images and lung function in participants in the Subpopulations and Intermediate Outcome Measures in COPD Study. Radiologists scored mucus plugs on CT lung images, and imaging software automatically quantified emphysema percentage. Unadjusted and adjusted relationships between mucus plug score, emphysema percentage, and lung function were determined using regression. Among 400 smokers, 229 (57%) had mucus plugs and 207 (52%) had emphysema, and subgroups could be identified with mucus-dominant and emphysema-dominant disease. Only 33% of smokers with high mucus plug scores had mucus symptoms. Mucus plug score and emphysema percentage were independently associated with lower values for FEV and peripheral oxygen saturation ( < 0.001). The relationships between mucus plug score and lung function outcomes were strongest in smokers with limited emphysema ( < 0.001). Compared with smokers with low mucus plug scores, those with high scores had worse COPD Assessment Test scores (17.4 ± 7.7 vs. 14.4 ± 13.3), more frequent annual exacerbations (0.75 ± 1.1 vs. 0.43 ± 0.85), and shorter 6-minute-walk distance (329 ± 115 vs. 392 ± 117 m) ( < 0.001). Symptomatically silent mucus plugs are highly prevalent in smokers and independently associate with lung function outcomes. These data provide rationale for targeting patients with mucus-high/emphysema-low COPD in clinical trials of mucoactive treatments.Clinical trial registered with www.clinicaltrials.gov (NCT01969344).
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http://dx.doi.org/10.1164/rccm.202006-2248OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048745PMC
April 2021

Black Carbon Content in Airway Macrophages is Associated with Reduced CD80 Expression and Increased Exacerbations in Former Smokers With COPD.

Chronic Obstr Pulm Dis 2021 Jan;8(1)

Johns Hopkins University, Division of Pulmonary and Critical Care Medicine, Baltimore, Maryland, United States.

Background: Chronic obstructive pulmonary disease (COPD) is characterized by recurrent exacerbations. Macrophages play a critical role in immune response and tissue repair in COPD. Airway macrophages (AM) are exposed to environmental exposures which are retained in the cytoplasmic material. Both biomass and particulate matter have been linked to higher AM black carbon. It is unknown if AM black carbon is associated with COPD morbidity and macrophage phenotype.

Methods: Former smokers with COPD were enrolled and sputum induction was performed to obtain airway macrophages. Macrophages underwent black carbon quantification and flow cytometry phenotyping. Health information was obtained the same day as sputum induction and prospective exacerbations were assessed by monthly telephone calls.

Results: We studied 30 former smokers with COPD who had a mean age of 67 years and mean forced expiratory volume in 1 second (FEV)% predicted of 60.8%. Higher AM black carbon content was associated with increased total exacerbations and severe exacerbations and reduced CD80 expression.

Conclusion: AM black carbon association with respiratory morbidity is largely unexplored and this is the first study to identify association with prospective exacerbations. Macrophages expressed reduced CD80, a surface marker providing costimulatory signals required for development of antigen-specific immune responses. Our findings suggest that reduced CD80 expression is the pathophysiologic mechanism for the association of AM black carbon content and increased exacerbations. Therefore, beyond solely serving as a marker for increased exposures, AM black carbon content may be a predictor of future exacerbations given a macrophage less equipped to respond to an acute infectious exposure.
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http://dx.doi.org/10.15326/jcopdf.2020.0170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047619PMC
January 2021

Defining Chronic Mucus Hypersecretion Using the CAT in the SPIROMICS Cohort.

Int J Chron Obstruct Pulmon Dis 2020 13;15:2467-2476. Epub 2020 Oct 13.

GSK R&D, Discovery Medicine, Collegeville, PA, USA.

Background: Chronic cough and phlegm are frequently reported chronic obstructive pulmonary disease (COPD) symptoms. Prior research classified chronic mucus hypersecretion (CMH) based on the presence of these symptoms for ≥3 months, called chronic bronchitis (CB) if respiratory infection symptoms were present for 1-2 years (Medical Research Council [MRC] definition). We explored whether the COPD Assessment Test (CAT), a simple measure developed for routine clinical use, captures CMH populations and outcomes similarly to MRC and St. George's Respiratory Questionnaire (SGRQ) definitions.

Methods: We identified CMH in the SPIROMICS COPD cohort using (a) MRC definitions, (b) SGRQ questions for cough and phlegm (both as most/several days a week), and (c) CAT cough and phlegm questions. We determined optimal cut-points for CAT items and described exacerbation frequencies for different CMH definitions. Moderate exacerbations required a new prescription for antibiotics/oral corticosteroids or emergency department visit; severe exacerbations required hospitalization. Results were stratified by smoking status.

Results: In a population of 1431 participants (57% male; mean FEV% predicted 61%), 47% and 49% of evaluable participants had SGRQ- or CAT-defined CMH, respectively. A cut-point of ≥2 for cough and phlegm items defined CMH in CAT. Among SGRQ-CMH+ participants, 80% were also defined as CMH+ by the CAT. CMH+ participants were more likely to be current smokers. A higher exacerbation frequency was observed for presence of CMH+ versus CMH- in the year prior to baseline for all CMH definitions; this trend continued across 3 years of follow-up, regardless of smoking status.

Conclusion: Items from the CAT identified SGRQ-defined CMH, a frequent COPD trait that correlated with exacerbation frequency. The CAT is a short, simple questionnaire and a potentially valuable tool for telemedicine or real-world trials. CAT-based CMH is a novel approach for identifying clinically important characteristics in COPD that can be ascertained in these settings.
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http://dx.doi.org/10.2147/COPD.S267002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568676PMC
June 2021

Plasma Cathelicidin is Independently Associated with Reduced Lung Function in COPD: Analysis of the Subpopulations and Intermediate Outcome Measures in COPD Study Cohort.

Chronic Obstr Pulm Dis 2020 Oct;7(4):370-381

Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina, Chapel Hill.

Ratrionale: The antimicrobial peptide cathelicidin, also known in humans as LL-37, is a defensin secreted by immune and airway epithelial cells. Deficiencies in this peptide may contribute to adverse pulmonary outcomes in chronic obstructive pulmonary disease (COPD).

Objectives: Using clinical and biological samples from the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS), we assessed the associations of plasma cathelicidin levels with cross-sectional and longitudinal COPD outcomes.

Methods: A total of 1609 SPIROMICS participants with COPD and available plasma samples were analyzed. Cathelicidin was modeled dichotomously (lowest quartile [< 50 ng/ml] versus highest 75% [≥ 50 ng/ml]) and continuously per 10 ng/ml. Fixed-effect multilevel regression analyses were used to assess associations between cathelicidin and cross-sectional as well as longitudinal lung function. The associations between cathelicidin and participant-reported retrospective and prospective COPD exacerbations were assessed via logistic regression.

Measurements And Main Results: Cathelicidin < 50 ng/ml (N=383) was associated with female sex, black race, and lower body mass index (BMI).At baseline,cathelicidin < 50 ng/ml was independently associated with 3.55% lower % predicted forced expiratory volume in 1 second (FEV)(95% confidence interval [CI] -6.22% to -0.88% predicted; =0.01), while every 10 ng/ml lower cathelicidin was independently associated with 0.65% lower % predicted FEV (95% CI -1.01% to -0.28% predicted; < 0.001). No independent associations with longitudinal lung function decline or participant-reported COPD exacerbations were observed.

Conclusions: Reduced cathelicidin is associated with lower lung function at baseline. Plasma cathelicidin may potentially identify COPD patients at increased risk for more severe lung disease.
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http://dx.doi.org/10.15326/jcopdf.7.4.2020.0142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883905PMC
October 2020

Modeling residential indoor concentrations of PM , NO , NO , and secondhand smoke in the Subpopulations and Intermediate Outcome Measures in COPD (SPIROMICS) Air study.

Indoor Air 2021 May 28;31(3):702-716. Epub 2020 Dec 28.

Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA.

Increased outdoor concentrations of fine particulate matter (PM ) and oxides of nitrogen (NO , NO ) are associated with respiratory and cardiovascular morbidity in adults and children. However, people spend most of their time indoors and this is particularly true for individuals with chronic obstructive pulmonary disease (COPD). Both outdoor and indoor air pollution may accelerate lung function loss in individuals with COPD, but it is not feasible to measure indoor pollutant concentrations in all participants in large cohort studies. We aimed to understand indoor exposures in a cohort of adults (SPIROMICS Air, the SubPopulations and Intermediate Outcome Measures in COPD Study of Air pollution). We developed models for the entire cohort based on monitoring in a subset of homes, to predict mean 2-week-measured concentrations of PM , NO , NO , and nicotine, using home and behavioral questionnaire responses available in the full cohort. Models incorporating socioeconomic, meteorological, behavioral, and residential information together explained about 60% of the variation in indoor concentration of each pollutant. Cross-validated R for best indoor prediction models ranged from 0.43 (NO ) to 0.51 (NO ). Models based on questionnaire responses and estimated outdoor concentrations successfully explained most variation in indoor PM , NO , NO , and nicotine concentrations.
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http://dx.doi.org/10.1111/ina.12760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202242PMC
May 2021

Contribution of Individual and Neighborhood Factors to Racial Disparities in Respiratory Outcomes.

Am J Respir Crit Care Med 2021 04;203(8):987-997

Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.

Black adults have worse health outcomes compared with white adults in certain chronic diseases, including chronic obstructive pulmonary disease (COPD). To determine to what degree disadvantage by individual and neighborhood socioeconomic status (SES) may contribute to racial disparities in COPD outcomes. Individual and neighborhood-scale sociodemographic characteristics were determined in 2,649 current or former adult smokers with and without COPD at recruitment into SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study). We assessed whether racial differences in symptom, functional, and imaging outcomes (St. George's Respiratory Questionnaire, COPD Assessment Test score, modified Medical Research Council dyspnea scale, 6-minute-walk test distance, and computed tomography [CT] scan metrics) and severe exacerbation risk were explained by individual or neighborhood SES. Using generalized linear mixed model regression, we compared respiratory outcomes by race, adjusting for confounders and individual-level and neighborhood-level descriptors of SES both separately and sequentially. After adjusting for COPD risk factors, Black participants had significantly worse respiratory symptoms and quality of life (modified Medical Research Council scale, COPD Assessment Test, and St. George's Respiratory Questionnaire), higher risk of severe exacerbations and higher percentage of emphysema, thicker airways (internal perimeter of 10 mm), and more air trapping on CT metrics compared with white participants. In addition, the association between Black race and respiratory outcomes was attenuated but remained statistically significant after adjusting for individual-level SES, which explained up to 12-35% of racial disparities. Further adjustment showed that neighborhood-level SES explained another 26-54% of the racial disparities in respiratory outcomes. Even after accounting for both individual and neighborhood SES factors, Black individuals continued to have increased severe exacerbation risk and persistently worse CT outcomes (emphysema, air trapping, and airway wall thickness). Disadvantages by individual- and neighborhood-level SES each partly explain disparities in respiratory outcomes between Black individuals and white individuals. Strategies to narrow the gap in SES disadvantages may help to reduce race-related health disparities in COPD; however, further work is needed to identify additional risk factors contributing to persistent disparities.
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http://dx.doi.org/10.1164/rccm.202002-0253OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048743PMC
April 2021

Protective effect of club cell secretory protein (CC-16) on COPD risk and progression: a Mendelian randomisation study.

Thorax 2020 11 24;75(11):934-943. Epub 2020 Aug 24.

Centre for Heart Lung Innovation, St Paul's Hospital, The University of British Columbia, Vancouver, British Columbia, Canada.

Background: The anti-inflammatory pneumoprotein club cell secretory protein-16 (CC-16) is associated with the clinical expression of chronic obstructive pulmonary disease (COPD). We aimed to determine if there is a causal effect of serum CC-16 level on the risk of having COPD and/or its progression using Mendelian randomisation (MR) analysis.

Methods: We performed a genome-wide association meta-analysis for serum CC-16 in two COPD cohorts (Lung Health Study (LHS), n=3850 and ECLIPSE, n=1702). We then used the CC-16-associated single-nucleotide polymorphisms (SNPs) as instrumental variables in MR analysis to identify a causal effect of serum CC-16 on 'COPD risk' (ie, case status in the International COPD Genetics Consortium/UK-Biobank dataset; n=35 735 COPD cases, n=222 076 controls) and 'COPD progression' (ie, annual change in forced expiratory volume in 1 s in LHS and ECLIPSE). We also determined the associations between SNPs associated with CC-16 and gene expression using n=1111 lung tissue samples from the Lung Expression Quantitative Trait Locus Study.

Results: We identified seven SNPs independently associated (p<5×10) with serum CC-16 levels; six of these were novel. MR analysis suggested a protective causal effect of increased serum CC-16 on COPD risk (MR estimate (SE) -0.11 (0.04), p=0.008) and progression (LHS only, MR estimate (SE) 7.40 (3.28), p=0.02). Five of the SNPs were also associated with gene expression in lung tissue (at false discovery rate <0.1) of several genes, including the CC-16-encoding gene .

Conclusion: We have identified several novel genetic variants associated with serum CC-16 level in COPD cohorts. These genetic associations suggest a potential causal effect of serum CC-16 on the risk of having COPD and its progression, the biological basis of which warrants further investigation.
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http://dx.doi.org/10.1136/thoraxjnl-2019-214487DOI Listing
November 2020
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