Publications by authors named "Nadia Hansel"

228 Publications

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 to 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 Feb 1. 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 to 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 to FVC ratio of ≥ 0.7 and FEV % predicted of ≥ 80% at enrollment. We compared baseline characteristics, chest CT scan features, exacerbations, and progression to COPD (postbronchodilator FEV to FVC ratio, < 0.7) during the follow-up period between 734 participants with postbronchodilator FEV to SVC ratio of ≥ 0.7 and 120 with postbronchodilator FEV to SVC ratio of < 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 to SVC ratio of < 0.7 with those characteristics and outcomes.

Results: Participants with FEV to SVC ratio of < 0.7 were older and had lower FEV and more emphysema than those with FEV to SVC ratio of ≥ 0.7. In adjusted analysis, individuals with postbronchodilator FEV to SVC ratio of < 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 to SVC ratio of ≥ 0.7. During a median follow-up time of 1,500 days, an FEV to SVC ratio of < 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 to SVC ratio of < 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 to SVC ratio of < 0.7 or FEV to SVC ratio of less than the lower limit of normal with chest CT scan features and progression to COPD.

Interpretation: Low FEV to SVC ratio 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
February 2021

The Lung Health Ambassador Program: A Community-Engagement Initiative Focusing on Pulmonary-Related Health Issues and Disparities Regarding Tobacco Use.

Int J Environ Res Public Health 2020 12 22;18(1). Epub 2020 Dec 22.

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21224, USA.

Educational campaigns have the potential to inform at risk populations about key issues relevant to lung health and to facilitate active engagement promoting healthy behaviors and risk prevention. We developed a community-based educational campaign called the Lung Health Ambassador Program (LHAP) with a goal of engaging youth and empowering them to be advocates for pulmonary health in their community. To evaluate the process outcomes and feasibility of the inaugural LHAP (2018-2019 academic year), with a specific aim to impact tobacco policy in the state of Maryland. Outcomes regarding feasibility included assessment of number of schools reached, number of students and healthcare professionals participating, and types of projects developed by participating students to impact modifiable risk factors for lung health. The courses for the LHAP were five 1 h sessions implemented at days and times identified by the community. The topics of the LHAP focused on lung anatomy, pulmonary diseases affecting school aged youth, tobacco use and prevalence, and air pollution (both indoor and outdoor). The fifth class discussed ways in which the students could impact lung health (e.g., policy and advocacy) and mitigate pulmonary disparities. The LHAP was implemented at two elementary/middle schools, one high school, and two recreation centers within an urban metropolitan region. A total of 268 youths participated in the LHAP (age ranging from 11 to 18), whereby 72 (26.9%) were Hispanic/Latino and 110 (41.0%) were African American. Of the participating students, 240 wrote letters to local politicians to advocate for policies that would raise the legal age of acquiring tobacco products to 21. As for healthcare professionals, 18 academic faculty members participated in implementing the LHAP: 8 physicians and faculty staff and 10 nurses. The LHAP is a community-based program that provides education and training in advocacy with a goal of teaching about and, ultimately, reducing respiratory health disparities. The results from the first year demonstrate that the program is feasible, with success demonstrated in completing educational modules and engaging students. Next steps will include strategies to ensure sustainability and scalability to increase the reach of this program.
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http://dx.doi.org/10.3390/ijerph18010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792622PMC
December 2020

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
October 2020

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
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

Novel Respiratory Disability Score Predicts COPD Exacerbations and Mortality in the SPIROMICS Cohort.

Int J Chron Obstruct Pulmon Dis 2020 4;15:1887-1898. Epub 2020 Aug 4.

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Rationale: Some COPD patients develop extreme breathlessness, decreased exercise capacity and poor health status yet respiratory disability is poorly characterized as a distinct phenotype.

Objective: To define respiratory disability in COPD based on available functional measures and to determine associations with risk for exacerbations and death.

Methods: We analyzed baseline data from a multi-center observational study (SPIROMICS). This analysis includes 2332 participants (472 with severe COPD, 991 with mild/moderate COPD, 726 smokers without airflow obstruction and 143 non-smoking controls).

Measurements: We defined respiratory disability by ≥4 of 7 criteria: mMRC dyspnea scale ≥3; Veterans Specific Activity Questionnaire <5; 6-minute walking distance <250 m; St George's Respiratory Questionnaire activity domain >60; COPD Assessment Test >20; fatigue (FACIT-F Trial Outcome Index) <50; SF-12 <20.

Results: Using these criteria, respiratory disability was identified in 315 (13.5%) participants (52.1% female). Frequencies were severe COPD 34.5%; mild-moderate COPD 11.2%; smokers without obstruction 5.2% and never-smokers 2.1%. Compared with others, participants with disability had more emphysema (13.2 vs. 6.6%) and air-trapping (37.0 vs. 21.6%) on HRCT (P<0.0001). Using principal components analysis to derive a disability score, two factors explained 71% of variance, and a cut point -1.0 reliably identified disability. This disability score independently predicted future exacerbations (ß=0.34; CI 0.12, 0.64; P=0.003) and death (HR 2.97; CI 1.54, 5.75; P=0.001). Thus, participants with disability by this criterion had almost three times greater mortality compared to those without disability.

Conclusion: Our novel SPIROMICS respiratory disability score in COPD was associated with worse airflow obstruction as well as airway wall thickening, lung parenchymal destruction and certain inflammatory biomarkers. The disability score also proved to be an independent predictor of future exacerbations and death. These findings validate disability as an important phenotype in the spectrum of COPD.
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http://dx.doi.org/10.2147/COPD.S250191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417644PMC
August 2020

Exposure to bisphenols and asthma morbidity among low-income urban children with asthma.

J Allergy Clin Immunol 2021 Feb 28;147(2):577-586.e7. Epub 2020 Jul 28.

School of Medicine, Johns Hopkins University, Baltimore, Md; Dell Medical School, University of Texas, Austin, Tex.

Background: Bisphenol A (BPA) has been linked with pediatric asthma development and allergic airway inflammation in animal models. Whether exposure to BPA or its structural analogs bisphenol S (BPS) and bisphenol F (BPF) is associated with asthma morbidity remains unknown.

Objective: We examined associations between bisphenols and morbidity due to pediatric asthma.

Methods: We quantified concentrations of BPA, BPS, and BPF in 660 urine samples from 148 predominantly low-income, African American children (aged 5-17 years) with established asthma. We used biobanked biospecimens and data on symptoms, health care utilization, and pulmonary function and inflammation that were collected every 3 months over the course of a year. We used generalized estimating equations to examine associations between concentrations or detection of urinary bisphenols and morbidity outcomes and assessed heterogeneity of associations by sex.

Results: We observed consistent positive associations between BPA exposure and measures of asthma morbidity. For example, we observed increased odds of general symptom days (adjusted odds ratio [aOR] = 1.40 [95% C = 1.02-1.92]), maximal symptom days (aOR = 1.36 [95% CI = 1.00-1.83]), and emergency department visits (aOR = 2.12 [95% CI =1.28-3.51]) per 10-fold increase in BPA concentration. We also observed evidence of sexually dimorphic effects; BPA concentrations were associated with increased odds of symptom days and health care utilization only among boys. Findings regarding BPS and BPF did not consistently point to associations with asthma symptoms or health care utilization.

Conclusion: We found evidence to suggest that BPA exposure in a predominantly low-income, minority pediatric cohort is associated with asthma morbidity and that associations may differ by sex. Our findings support additional studies, given the high pediatric asthma burden and widespread exposure to BPA in the United States.
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http://dx.doi.org/10.1016/j.jaci.2020.05.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855247PMC
February 2021

Risk Factors for Physical Inactivity Among Children With and Without Asthma Living in Peri-Urban Communities of Lima, Peru.

J Phys Act Health 2020 Jul 14:1-7. Epub 2020 Jul 14.

Background: The authors sought to examine physical activity patterns among children with and without asthma in 2 peri-urban communities in Lima, Peru, to identify socioeconomic and demographic risk factors for physical inactivity and examine the relationship between asthma and physical activity.

Methods: The authors measured mean steps per day in 114 children (49 with asthma and 65 without) using pedometers worn over a 1-week period. They also used the 3-day physical activity recall to determine the most common activities carried out by children.

Results: The authors found that 84.2% of the children did not meet the daily international physical activity recommendations. Girls took significantly fewer mean steps per day as compared with boys (2258 fewer steps, 95% confidence interval, 1042-3474), but no other factors, including asthma status, showed significant differences in the mean daily steps. Mean daily steps were positively associated with higher socioeconomic status among girls, and current asthma had a larger inverse effect on daily steps in boys when compared with girls.

Conclusion: Physical activity levels were below recommended guidelines in all children. There is a need for policy and neighborhood-level interventions to address low physical activity levels among Peruvian youth. Special focus should be given to increasing the physical activity levels in girls.
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http://dx.doi.org/10.1123/jpah.2019-0553DOI Listing
July 2020

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts.

Lancet Respir Med 2020 07;8(7):696-708

Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.

Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.

Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.

Funding: US National Institutes of Health, Wellcome Trust.
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http://dx.doi.org/10.1016/S2213-2600(20)30101-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429152PMC
July 2020

Proposal for smoke-free public housing: a systematic review of attitudes and preferences from residents of multi-unit housing.

J Public Health Policy 2020 Dec;41(4):496-514

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, Asthma & Allergy Building, 4th Floor, Baltimore, MD, 21224, USA.

A policy proposal to ban public housing smoking indoors has received support, but it is unclear how certain affected groups, specifically smokers in housing units, perceive such a policy. To review the literature on attitudes and perceptions of housing unit tenants towards an indoor smoke-free housing policy, using various databases, we searched articles for attitudes towards smoking ban enforcement in housing units. We identified fourteen articles. Non-smokers heavily favored indoor policies and current smokers heavily opposed them. Current smokers represented a substantial minority in the reviewed articles, resulting in overall outcomes of the surveys driven by non-smokers. Studies investigating attitudes about housing smoking bans largely represent the views of non-smokers and lack data about barriers and concerns of tenants who do not support a smoke-free policy. Future studies should investigate if such a discrepancy impacts the efficacy of smoke-free housing policies.
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http://dx.doi.org/10.1057/s41271-020-00236-zDOI Listing
December 2020

Increased airway iron parameters and risk for exacerbation in COPD: an analysis from SPIROMICS.

Sci Rep 2020 06 29;10(1):10562. Epub 2020 Jun 29.

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

Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195). BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV % predicted and exacerbation frequency. Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV % predicted as clinical covariates. BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers. BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively. Similar associations were not observed with plasma ferritin. Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals.
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http://dx.doi.org/10.1038/s41598-020-67047-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324559PMC
June 2020

Association of Dysanapsis With Chronic Obstructive Pulmonary Disease Among Older Adults.

JAMA 2020 06;323(22):2268-2280

Department of Medicine, Columbia University Medical Center, New York, New York.

Importance: Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD), yet much of COPD risk remains unexplained.

Objective: To determine whether dysanapsis, a mismatch of airway tree caliber to lung size, assessed by computed tomography (CT), is associated with incident COPD among older adults and lung function decline in COPD.

Design, Setting, And Participants: A retrospective cohort study of 2 community-based samples: the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study, which involved 2531 participants (6 US sites, 2010-2018) and the Canadian Cohort of Obstructive Lung Disease (CanCOLD), which involved 1272 participants (9 Canadian sites, 2010-2018), and a case-control study of COPD: the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS), which involved 2726 participants (12 US sites, 2011-2016).

Exposures: Dysanapsis was quantified on CT as the geometric mean of airway lumen diameters measured at 19 standard anatomic locations divided by the cube root of lung volume (airway to lung ratio).

Main Outcomes And Measures: Primary outcome was COPD defined by postbronchodilator ratio of forced expired volume in the first second to vital capacity (FEV1:FVC) less than 0.70 with respiratory symptoms. Secondary outcome was longitudinal lung function. All analyses were adjusted for demographics and standard COPD risk factors (primary and secondhand tobacco smoke exposures, occupational and environmental pollutants, and asthma).

Results: In the MESA Lung sample (mean [SD] age, 69 years [9 years]; 1334 women [52.7%]), 237 of 2531 participants (9.4%) had prevalent COPD, the mean (SD) airway to lung ratio was 0.033 (0.004), and the mean (SD) FEV1 decline was -33 mL/y (31 mL/y). Of 2294 MESA Lung participants without prevalent COPD, 98 (4.3%) had incident COPD at a median of 6.2 years. Compared with participants in the highest quartile of airway to lung ratio, those in the lowest had a significantly higher COPD incidence (9.8 vs 1.2 cases per 1000 person-years; rate ratio [RR], 8.12; 95% CI, 3.81 to 17.27; rate difference, 8.6 cases per 1000 person-years; 95% CI, 7.1 to 9.2; P < .001) but no significant difference in FEV1 decline (-31 vs -33 mL/y; difference, 2 mL/y; 95% CI, -2 to 5; P = .30). Among CanCOLD participants (mean [SD] age, 67 years [10 years]; 564 women [44.3%]), 113 of 752 (15.0%) had incident COPD at a median of 3.1 years and the mean (SD) FEV1 decline was -36 mL/y (75 mL/y). The COPD incidence in the lowest airway to lung quartile was significantly higher than in the highest quartile (80.6 vs 24.2 cases per 1000 person-years; RR, 3.33; 95% CI, 1.89 to 5.85; rate difference, 56.4 cases per 1000 person-years; 95% CI, 38.0 to 66.8; P<.001), but the FEV1 decline did not differ significantly (-34 vs -36 mL/y; difference, 1 mL/y; 95% CI, -15 to 16; P=.97). Among 1206 SPIROMICS participants (mean [SD] age, 65 years [8 years]; 542 women [44.9%]) with COPD who were followed up for a median 2.1 years, those in the lowest airway to lung ratio quartile had a mean FEV1 decline of -37 mL/y (15 mL/y), which did not differ significantly from the decline in MESA Lung participants (P = .98), whereas those in highest quartile had significantly faster decline than participants in MESA Lung (-55 mL/y [16 mL/y ]; difference, -17 mL/y; 95% CI, -32 to -3; P = .004).

Conclusions And Relevance: Among older adults, dysanapsis was significantly associated with COPD, with lower airway tree caliber relative to lung size associated with greater COPD risk. Dysanapsis appears to be a risk factor associated with COPD.
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http://dx.doi.org/10.1001/jama.2020.6918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284296PMC
June 2020

Clinical Phenotypes of Atopy and Asthma in COPD: A Meta-analysis of SPIROMICS and COPDGene.

Chest 2020 12 23;158(6):2333-2345. Epub 2020 May 23.

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

Background: Little is known about the concordance of atopy with asthma COPD overlap. Among individuals with COPD, a better understanding of the phenotypes characterized by asthma overlap and atopy is needed to better target therapies.

Research Question: What is the overlap between atopy and asthma status among individuals with COPD, and how are categories defined by the presence of atopy and asthma status associated with clinical and radiologic phenotypes and outcomes in the Genetic Epidemiology of COPD Study (COPDGene) and Subpopulation and Intermediate Outcome Measures in COPD Study (SPIROMICS)?

Study Design And Methods: Four hundred three individuals with COPD from SPIROMICS and 696 individuals from COPDGene with data about specific IgEs to 10 common allergens and mixes (simultaneous assessment of combination of allergens in similar category) were included. Comparison groups were defined by atopic and asthma status (neither, atopy alone, atopic asthma, nonatopic asthma, with atopy defined as any positive specific IgE (≥0.35 KU/L) to any of the 10 allergens or mixes and asthma defined as self-report of doctor-diagnosed current asthma). Multivariable regression analyses (linear, logistic, and zero inflated negative binomial where appropriate) adjusted for age, sex, race, lung function, smoking status, pack-years smoked, and use of inhaled corticosteroids were used to determine characteristics of groups and relationship with outcomes (exacerbations, clinical outcomes, CT metrics) separately in COPDGene and SPIROMICS, and then adjusted results were combined using meta-analysis.

Results: The prevalence of atopy was 35% and 36% in COPD subjects from SPIROMICS and COPDGene, respectively, and less than 50% overlap was seen between atopic status with asthma in both cohorts. In meta-analysis, individuals with nonatopic asthma had the most impaired symptom scores (effect size for St. George's Respiratory Questionnaire total score, 4.2; 95% CI, 0.4-7.9; effect size for COPD Assessment Test score, 2.8; 95% CI, 0.089-5.4), highest risk for exacerbations (incidence rate ratio, 1.41; 95% CI, 1.05-1.88) compared with the group without atopy or asthma. Those with atopy and atopic asthma were not at increased risk for adverse outcomes.

Interpretation: Asthma and atopy had incomplete overlap among former and current smokers with COPD in COPDGene and SPIROMICS. Nonatopic asthma was associated with adverse outcomes and exacerbation risk in COPD, whereas groups having atopy alone and atopic asthma had less risk.
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http://dx.doi.org/10.1016/j.chest.2020.04.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768932PMC
December 2020