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Chunrui Zou,1,2 Frank Li,2,3 Jiwoong Choi,1,4 Babak Haghighi,5 Sanghun Choi,6 Prathish K Rajaraman,1,2 Alejandro P Comellas,7 John D Newell Jnr,8 Chang Hyun Lee,8,9 R Graham Barr,10 Eugene Bleecker,11 Christopher B Cooper,12 David Couper,13 Meilan Han,14 Nadia N Hansel,15 Richard E Kanner,16 Ella A Kazerooni,17 Eric C Kleerup,18 Fernando J Martinez,19 Wanda O’Neal,20 Robert Paine III,16 Stephen I Rennard,21 Benjamin M Smith,22,23 Prescott G Woodruff,24 Eirc A Hoffman,3,7,8 Ching-Long Lin1– 3,8 1Department of Mechanical Engineering, University of Iowa, Iowa City, IA, USA; 2IIHR-Hydroscience & Engineering, University of Iowa, Iowa City, IA, USA; 3Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA; 4Department of Internal Medicine, School of Medicine, University of Kansas, Kansas City, KS, USA; 5Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 6School of Mechanical Engineering, Kyungpook National University, Daegu, Republic of Korea; 7Department of Internal Medicine, University of Iowa, Iowa City, IA, USA; 8Department of Radiology, University of Iowa, Iowa City, IA, USA; 9Department of Radiology, College of Medicine, Seoul National University, Seoul, Republic of Korea; 10Mailman School of Public Health, Columbia University, New York, NY, USA; 11Department of Medicine, The University of Arizona, Tucson, AZ, USA; 12Department of Physiology, UCLA, Los Angeles, CA, USA; 13Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA; 14Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; 15School of Medicine, Johns Hopkins, Baltimore, MD, USA; 16School of Medicine, University of Utah, Salt Lake City, UT, USA; 17Department of Radiology, University of Michigan, Ann Arbor, MI, USA; 18Department of Medicine, UCLA, Los Angeles, CA, USA; 19Weill Cornell Medicine, Cornell University, New York, NY, USA; 20School of Medicine, University of North Carolina, Chapel Hill, NC, USA; 21Department of Internal Medicine, University of Nebraska College of Medicine, Omaha, NE, USA; 22Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; 23Department of Medicine, McGill University Health Centre Research Institute, Montreal, Canada; 24Department of Medicine, University of California at San Francisco, San Francisco, CA, USACorrespondence: Ching-Long Lin 2406 Seamans Center for the Engineering Art and Science, Iowa City, IA, 52242, USATel +1 319 335 5673Email ching-long-lin@uiowa.eduPurpose: 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.Keywords: computed tomography, emphysema, functional small airway disease, longitudinal clustering

Marni Stott-Miller,1 Hana Müllerová,2 Bruce Miller,3 Maggie Tabberer,4 Céline El Baou,5 Tom Keeley,4 Fernando J Martinez,6 Meilan Han,7 Mark Dransfield,8 Nadia N Hansel,9 Christopher B Cooper,10 Prescott Woodruff,11 Victor E Ortega,12 Alejandro P Comellas,13 Robert Paine III,14 Richard E Kanner,14 Wayne Anderson,15 M Bradley Drummond,15 Victor Kim,16 Ruth Tal-Singer,17 Aili L Lazaar3 1GSK R&D, Epidemiology: Value, Evidence and Outcomes, Uxbridge, UK; 2AstraZeneca, Cambridge, UK; 3GSK R&D, Discovery Medicine, Collegeville, PA, USA; 4GSK R&D Patient-Centred Outcomes: Value, Evidence and Outcomes, Uxbridge, UK; 5CEBSTAT Consultancy Ltd, London, UK; 6Cornell Medical College, New York, NY, USA; 7Division of Pulmonary and Critical Care at the University of Michigan, Ann Arbor, MI, USA; 8Children’s of Alabama, Children’s Health Research Unit/University of Alabama, Birmingham, AB, USA; 9Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA; 10David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 11UCSF Department of Medicine, San Francisco, CA, USA; 12Wake Forest School of Medicine, Winston Salem, NC, USA; 13Carver College of Medicine, University of Iowa, Iowa City, IA, USA; 14Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City, UT, USA; 15Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 16Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; 17COPD Foundation, Washington, DC, USACorrespondence: Aili L Lazaar GSK, 1250 S. Collegeville Road, Collegeville, PA 19426-0989, USATel +1 484-923-3730Email Aili.L.Lazaar@gsk.comBackground: 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 FEV1% 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.Keywords: COPD, SGRQ, exacerbation, CAT, cough, phlegm

Christopher B Cooper,1 Robert Paine,2 Jeffrey L Curtis,3,4 Richard E Kanner,2 Carlos H Martinez,3 Catherine A Meldrum,3 Russell Bowler,5 Wanda O’Neal,6 Eric A Hoffman,7 David Couper,6 Miguel Quibrera,6 Gerald Criner,8 Mark T Dransfield,9 MeiLan K Han,3 Nadia N Hansel,10 Jerry A Krishnan,11 Stephen C Lazarus,12 Stephen P Peters,13 R Graham Barr,14 Fernando J Martinez,15 Prescott G Woodruff12 On behalf of the SPIROMICS investigators1Departments of Medicine and Physiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; 2Section of Pulmonary and Critical Care Medicine, Department of Veterans Affairs Medical Center, University of Utah, Salt Lake City, UT, USA; 3Pulmonary and Critical Care Medicine Division, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA; 4Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA; 5National Jewish Health, University of Colorado School of Medicine, Denver, CO, USA; 6University of North Carolina Marisco Lung Institute, Chapel Hill, NC, USA; 7Department of Radiology, University of Iowa, Iowa City, IA, USA; 8Department of Pulmonary and Critical Care Medicine, Temple University, Philadelphia, PA, USA; 9Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; 10Johns Hopkins University School of Medicine, Baltimore, MD, USA; 11Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA; 12Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA; 13Wake Forest School of Medicine, Winston-Salem, NC, USA; 14Department of Medicine, Columbia University Medical Center, New York, NY, USA; 15Joan and Sanford I Weill Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USACorrespondence: Christopher B CooperDepartments of Medicine and Physiology,David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, 37-131 CHS, Los Angeles, CA 90095, USAEmail ccooper@mednet.ucla.eduRationale: 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.Keywords: disability, frailty, exacerbation rate, mortality, SPIROMICS

Panagis Galiatsatos,1 Han Woo,1 Laura M Paulin,2 Amy Kind,3,4 Nirupama Putcha,1 Amanda J Gassett,5 Christopher B Cooper,6 Mark T Dransfield,7 Trisha M Parekh,7 Gabriela R Oates,8 R Graham Barr,9 Alejandro P Comellas,10 Meilan K Han,11 Stephen P Peters,12 Jerry A Krishnan,13 Wassim W Labaki,11 Meredith C McCormack,1 Joel D Kaufman,14 Nadia N Hansel1 1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Pulmonary and Critical Care, Dartmouth Hitchcock Medical Center, Lebanon, NH, USA; 3University of Wisconsin School of Medicine and Public Health, Department of Medicine Health Services and Care Research Program and Division of Geriatrics, Madison, WI, USA; 4Geriatric Research Education and Clinical Center, Wm. S. Middleton Veterans Hospital, Madison, WI, USA; 5Internal Medicine, University of Washington, Seattle, WA, USA; 6Department of Medicine, University of California Los Angeles School of Medicine, Los Angeles, CA, USA; 7Department of Medicine, University of Alabama Birmingham and Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA; 8Department of Medicine, University of Alabama Birmingham, Birmingham, AL, USA; 9Presbyterian Hospital, Columbia University Medical Center, New York, NY, USA; 10Internal Medicine and Pulmonary, University of Iowa, Iowa City, IA, USA; 11Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA; 12Department of Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA; 13Department of Medicine, University of Illinois, Chicago, IL, USA; 14Office of the Dean, University of Washington School of Public Health, Seattle, WA, USACorrespondence: Panagis GaliatsatosJohns Hopkins University School of Medicine, 4940 Eastern Avenue, Asthma and Allergy Building, 4th Floor, Baltimore, MD 21224, USATel +1410 550-0522Fax +1410 550-1094Email panagis@jhmi.eduRationale: Individual socioeconomic status has been shown to influence the outcomes of patients with chronic obstructive pulmonary disease (COPD). However, contextual factors may also play a role. The objective of this study is to evaluate the association between neighborhood socioeconomic disadvantage measured by the area deprivation index (ADI) and COPD-related outcomes.Methods: Residential addresses of SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) subjects with COPD (FEV1/FVC < 0.70) at baseline were geocoded and linked to their respective ADI national ranking score at the census block group level. The associations between the ADI and COPD-related outcomes were evaluated by examining the contrast between participants living in the most-disadvantaged (top quintile) to the least-disadvantaged (bottom quintile) neighborhood. Regression models included adjustment for individual-level demographics, socioeconomic variables (personal income, education), exposures (smoking status, packs per year, occupational exposures), clinical characteristics (FEV1% predicted, body mass index) and neighborhood rural status.Results: A total of 1800 participants were included in the analysis. Participants residing in the most-disadvantaged neighborhoods had 56% higher rate of COPD exacerbation (P< 0.001), 98% higher rate of severe COPD exacerbation (P=0.001), a 1.6 point higher CAT score (P< 0.001), 3.1 points higher SGRQ (P< 0.001), and 24.6 meters less six-minute walk distance (P=0.008) compared with participants who resided in the least disadvantaged neighborhoods.Conclusion: Participants with COPD who reside in more-disadvantaged neighborhoods had worse COPD outcomes compared to those residing in less-disadvantaged neighborhoods. Neighborhood effects were independent of individual-level socioeconomic factors, suggesting that contextual factors could be used to inform intervention strategies targeting high-risk persons with COPD.Keywords: health disparities, COPD, area deprivation index

K Fricke,1,2 H Schneider,1 P Biselli,1,3 NN Hansel,1 ZG Zhang,1,4 MO Sowho,1 L Grote1,5,6 1Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA; 2Department for Pulmonary, Sleep, and Intensive Care Medicine, Helios Klinikum, Wuppertal, Germany; 3Intensive Care Unit, Medical Division, University Hospital, University of Sao Paolo, Sao Paolo, Brazil; 4Department for Geriatrics, Peking University First Hospital, Beijing, China; 5Sleep Disorders Center, Department for Pulmonary Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden; 6Center for Sleep and Wake Disorders, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden Introduction: Patients with COPD have increased respiratory loads and altered blood gases, both of which affect vascular function and sympathetic activity. Sleep, particularly rapid eye movement (REM) sleep, is known to exacerbate hypoxia and respiratory loads. Therefore, we hypothesize that nasal high flow (NHF), which lowers ventilatory loads, reduces sympathetic activity during sleep and that this effect depends on COPD severity. Methods: We performed full polysomnography in COPD patients (n=17; FEV1, 1.6±0.6 L) and in matched controls (n=8). Participants received room air (RA) at baseline and single night treatment with O2 (2 L/min) and NHF (20 L/min) in a random order. Finger pulse wave amplitude (PWA), a measure of vascular sympathetic tone, was assessed by photoplethysmography. Autonomic activation (AA) events were defined as PWA attenuation ≥30% and indexed per hour for sleep stages (AA index [AAI]) at RA, NHF, and O2). Results: In COPD, sleep apnea improved following O2 (REM-apnea hypopnea index [AHI] with RA, O2, and NHF: 18.6±20.9, 12.7±18.1, and 14.4±19.8, respectively; P=0.04 for O2 and P=0.06 for NHF). REM-AAI was reduced only following NHF in COPD patients (AAI-RA, 21.5±18.4 n/h and AAI-NHF, 9.9±6.8 n/h, P=0.02) without changes following O2 (NHF-O2 difference, P=0.01). REM-AAI reduction was associated with lung function expressed as FEV1 and FVC (FEV1: r=-0.59, P=0.001; FEV1/FVC: r=-0.52 and P=0.007). Conclusion: NHF but not elevated oxygenation reduces peripheral vascular sympathetic activity in COPD patients during REM sleep. Sympathetic off-loading by NHF, possibly related to improved breathing mechanics, showed a strong association with COPD severity. Keywords: COPD, sleep, nasal high flow, oxygen therapy, sympathetic activity, pulse wave amplitude

Background: Although outdoor particulate matter (PM) has been linked to mortality and asthma morbidity, the impact of indoor PM on asthma has not been well established. Objective: This study was designed to investigate the effect of in-home PM on asthma morbidity. Methods: For a cohort of 150 asthmatic children (2-6 years of age) from Baltimore, Maryland, a technician deployed environmental monitoring equipment in the children's bedrooms for 3-day intervals at baseline and at 3 and 6 months. Caregivers completed questionnaires and daily diaries during air sampling. Longitudinal data analyses included regression models with generalized estimating equations. Results: Children were primarily African Americans (91%) from lower socioeconomic backgrounds and spent most of their time in the home. Mean (± SD) indoor PM2.5-10 (PM with aerodynamic diameter 2.5-10 µm) and PM2.5 (aerodynamic diameter < 2.5 µm) concentrations were 17.4 ± 21.0 and 40.3 ± 35.4 µg/m3. In adjusted models, 10-µg/m3 increases in indoor PM2.5-10 and PM2.5 were associated with increased incidences of asthma symptoms: 6% [95% confidence interval (CI) , 1 to 12%] and 3% (95% CI, -1 to 7%) , respectively ; symptoms causing children to slow down: 8% (95% CI, 2 to 14%) and 4% (95% CI, 0 to 9%) , respectively ; nocturnal symptoms: 8% (95% CI, 1 to 14%) and 6% (95% CI, 1 to 10%) , respectively ; wheezing that limited speech: 11% (95% CI, 3 to 19%) and 7% (95% CI, 0 to 14%) , respectively ; and use of rescue medication: 6% (95% CI, 1 to 10%) and 4% (95% CI, 1 to 8%) , respectively. Increases of 10 µg/m3 in indoor and ambient PM2.5 were associated with 7% (95% CI, 2 to 11%) and 26% (95% CI, 1 to 52%) increases in exercise-related symptoms, respectively. Conclusions: Among preschool asthmatic children in Baltimore, increases in in-home PM2.5-10 and PM2.5 were associated with respiratory symptoms and rescue medication use. Increases in in-home and ambient PM2.5 were associated with exercise-related symptoms. Although reducing PM outdoors may decrease asthma morbidity, reducing PM indoors, especially in homes of inner-city children, may lead to improved asthma health. [ABSTRACT FROM AUTHOR]

Management of asthma requires attention to environmental exposures both indoors and outdoors. Americans spend most of their time indoors, where they have a greater ability to modify their environment. The indoor environment contains both pollutants (eg, particulate matter, nitrogen dioxide, secondhand smoke, and ozone) and allergens from furred pets, dust mites, cockroaches, rodents, and molds. Indoor particulate matter consists of particles generated from indoor sources such as cooking and cleaning activities, and particles that penetrate from the outdoors. Nitrogen dioxide sources include gas stoves, furnaces, and fireplaces. Indoor particulate matter and nitrogen dioxide are linked to asthma morbidity. The indoor ozone concentration is mainly influenced by the outdoor ozone concentration. The health effects of indoor ozone exposure have not been well studied. In contrast, there is substantial evidence of detrimental health effects from secondhand smoke. Guideline recommendations are not specific for optimizing indoor air quality. The 2007 National Asthma Education and Prevention Program asthma guidelines recommend eliminating indoor smoking and improving the ventilation. Though the guidelines state that there is insufficient evidence to recommend air cleaners, air cleaners and reducing activities that generate indoor pollutants may be sound practical approaches for improving the health of individuals with asthma. The guidelines are more specific about allergen avoidance; they recommend identifying allergens to which the individual is immunoglobin E sensitized and employing a multifaceted, comprehensive strategy to reduce exposure. Outdoor air pollutants that impact asthma include particulate matter, ozone, nitrogen dioxide, and sulfur dioxide, and guidelines recommend that individuals with asthma avoid exertion outdoors when these pollutants are elevated. Outdoor allergens include tree, grass, and weed pollens, which vary in concentration by season. Recommendations to reduce exposure include staying indoors, keeping windows and doors closed, using air conditioning and perhaps high-efficiency particulate arrestor (HEPA) air filters, and thorough daily washing to remove allergens from one's person. [ABSTRACT FROM AUTHOR]

CD4[+] lymphocytes play a key role in asthma pathogenesis, but much remains unknown about the genetic mechanisms that affect disease severity. In this study we sought to investigate global patterns of gene expression in CD4[+] lymphocytes isolated from subjects with severe asthma through the use of microarray technology. CD4[+] lymphocytes were separated from peripheral blood, total RNA was purified, and biotinylated complementary RNA was prepared and hybridized to Affymetrix HU133 chips (Affymetrix, Santa Clara, Calif). Using the robust multi-chip average procedure, we compared the messenger RNA expression profiles of more than 33,000 genes of CD4[+] lymphocytes in subjects with severe (n = 5) and mild (n = 5) asthma. Forty genes had 2-fold mean expression differences or greater. Thirty-seven genes were up-regulated, including transforming growth factor-beta and those involved in T-cell activation, proliferation, and cytoskeletal changes. Three genes were down-regulated, including the T-cell-receptor delta locus. This study demonstrates a method by which CD4[+] lymphocytes can be extracted from blood for the purpose of microarray analysis. Furthermore, we show that T-lymphocytes from the peripheral blood of subjects with severe and mild asthma differ in their gene-expression profiles, supporting the view that asthma is a systemic disease. These differentially expressed genes identify potential molecular targets for preventive and therapeutic options for severe asthma. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVES: Despite curative therapy, mortality remains high for hospitalized patients with tuberculosis (TB) in the United States. The purpose of this study was to describe the characteristics of hospitalized patients with TB and to identify patient characteristics associated with in-hospital mortality. DESIGN, SETTING, AND PATIENTS: Using the 2000 Nationwide Inpatient Sample, representing 20% of US hospital admissions, we identified 2,279 hospital admissions with a primary diagnosis of TB (International Classification of Diseases, ninth revision, codes, 010.xx to 018.xx). MEASUREMENTS AND RESULTS: Mortality was the main outcome measure. Logistic regression analyses were performed including age, gender, race, insurance status, income, Deyo-adapted Charlson comorbidity index (DCI), HIV status, hospital admission source, and hospital characteristics as explanatory variables. A disproportionate number of patients hospitalized with TB were men (64%), nonwhite (72%), lived in areas with median incomes of < $35,000 (50%), and had publicly funded health insurance (49%) or no health insurance (17%). The mortality rate for patients hospitalized for TB was greater than that for non-TB hospital admissions (4.9% vs 2.4%, respectively; p < 0.001). Patients with TB who died during hospitalization were older (mean age, 65.1 vs 49.4 years, respectively; p < 0.001), had greater comorbid illness (DCI, 1.1 vs 0.55, respectively; p < 0.001), required longer hospitalizations (19.9 vs 13.9 days, respectively; p < 0.001), and accumulated substantially higher charges ($79,585 vs $31,610, respectively; p < 0.001) than did patients with TB who were alive at hospital discharge. In a multivariable analysis, older age, comorbid illnesses, and emergency department admissions were independently associated with mortality. The total charges for TB hospitalizations in the United States in 2000 exceeded $385 million. CONCLUSIONS: Despite public health efforts, patients who are hospitalized with TB are frequently admitted through emergency care settings, have a high risk of in-hospital mortality, and incur substantial hospital charges. To improve TB health outcomes, more vigorous clinical management and prevention strategies should especially target older patients and those with comorbid medical conditions. [ABSTRACT FROM AUTHOR]

Rationale: Individuals with chronic obstructive pulmonary disease (COPD) have airflow obstruction and maldistribution of ventilation. For those living at high altitude, any gas exchange abnormality is compounded by reduced partial pressures of inspired oxygen. Objectives: Does residence at higher altitude exposure affect COPD outcomes, including lung function, imaging characteristics, symptoms, health status, functional exercise capacity, exacerbations, and mortality? Methods: From the SPIROMICS (Subpopulation and Intermediate Outcome Measures in COPD Study) cohort, we identified individuals with COPD living below 1,000 ft (305 m) elevation ( n  = 1,367) versus above 4,000 ft (1,219 m) elevation ( n  = 288). Multivariable regression models were used to evaluate associations of exposure to high altitude with COPD-related outcomes. Measurements and Main Results: Living at higher altitude was associated with reduced functional exercise capacity as defined by 6-minute-walk distance (-32.3 m [95% confidence interval, -49.8 to -14.8 m]). There were no differences in patient-reported outcomes as defined by symptoms (COPD Assessment Test and modified Medical Research Council dyspnea scale), or health status (St. George's Respiratory Questionnaire). Higher altitude was not associated with a different rate of FEV 1 decline. Higher altitude was associated with lower odds of severe exacerbations (incidence rate ratio, 0.65 [95% confidence interval, 0.46 to 0.90]). There were no differences in small airway disease, air trapping, or emphysema. In longitudinal analyses, higher altitude was associated with increased mortality (hazard ratio, 1.25 [95% confidence interval, 1.0 to 1.55]); however, this association was no longer significant when accounting for air pollution. Conclusions: Long-term altitude exposure is associated with reduced functional exercise capacity in individuals with COPD, but this did not translate into differences in symptoms or health status. In addition, long-term high-altitude exposure did not affect progression of disease as defined by longitudinal changes in spirometry. Clinical trial registered with www.clinicaltrials.gov (NCT01969344).

Rationale: Serum Immunoglobulin G (IgG) deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD) but it is unclear whether concentrations in the lower end of the normal range still confer risk., Objectives: To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD., Measurements and Main Results: Former and current smokers in SPIROMICS (n=1,497) were studied, n=1,026 with and n=471 at risk for COPD. In a subset (n=1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographics, current smoking, smoking history, FEV 1 % predicted, inhaled corticosteroids, and serum IgA., Results: The 35th percentile (1225 mg/dL in this cohort) of IgG was the best cutoff by Akaike Information Criterion (AIC). Below this, there was increased exacerbation risk (IRR 1.28, 95% CI 1.08-1.51). Among subclasses, IgG1 and IgG2 below 35 th percentile (354 and 105 mg/dL, respectively) were both associated with increased risk of severe exacerbation (IgG1: IRR 1.39, 95% CI 1.06-1.84; IgG2: IRR 1.50, 95% CI 1.14-1.1.97). These associations remained significant when additionally adjusting for history of exacerbations., Conclusions: Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting subtle impairment of humoral immunity may be associated with exacerbations.

Background: Valid, high-resolution estimates of population-level exposure to air pollutants are necessary for accurate estimation of the association between air pollution and the occurrence or exacerbation of adverse health outcomes such as Chronic Obstructive Pulmonary Disease (COPD)., Objectives: We produced fine-scale individual-level estimates of ambient concentrations of multiple air pollutants (fine particulate matter [PM 2.5 ], NO X , NO 2 , and O 3 ) at residences of participants in the Subpopulations and Intermediate Outcomes in COPD Air Pollution (SPIROMICS Air) study, located in seven regions in the US. For PM 2.5 , we additionally integrated modeled estimates of particulate infiltration based on home characteristics and measured total indoor concentrations to provide comprehensive estimates of exposure levels., Methods: To estimate ambient concentrations, we used a hierarchical high-resolution spatiotemporal model that integrates hundreds of geographic covariates and pollutant measurements from regulatory and study-specific monitors, including ones located at participant residences. We modeled infiltration efficiency based on data on house characteristics, home heating and cooling practices, indoor smoke and combustion sources, meteorological factors, and paired indoor-outdoor pollutant measurements, among other indicators., Results: Cross-validated prediction accuracy (R 2 ) for models of ambient concentrations was above 0.80 for most regions and pollutants. Particulate matter infiltration efficiency varied by region, from 0.51 in Winston-Salem to 0.72 in Los Angeles, and ambient-source particles constituted a substantial fraction of total indoor PM 2.5 ., Conclusion: Leveraging well-validated fine-scale approaches for estimating outdoor, ambient-source indoor, and total indoor pollutant concentrations, we can provide comprehensive estimates of short and long-term exposure levels for cohorts undergoing follow-up in multiple different regions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Prescott G Woodruff reports a relationship with AstraZeneca, Sanofi, Regeneron, Roche that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: In chronic obstructive pulmonary disease (COPD), accurately estimating lung function from electronic health record (EHR) data would be beneficial but requires addressing complexities in clinically obtained testing. This study compared analytic methods for estimating rate of forced expiratory volume in one second (FEV 1 ) change from EHR data., Methods: We estimated rate of FEV 1 change in patients with COPD from a single centre who had ≥3 outpatient tests spanning at least 1 year. Estimates were calculated as both an absolute mL/year and a relative %/year using non-regressive (Total Change, Average Change) and regressive (Quantile, RANSAC, Huber) methods. We compared distributions of the estimates across methods focusing on extreme values. Univariate zero-inflated negative binomial regressions tested associations between estimates and all-cause or COPD hospitalisations. Results were validated in an external cohort., Results: Among 1417 participants, median rate of change was approximately -30 mL/year or -2%/year. Non-regressive methods frequently generated erroneous estimates due to outlier first measurements or short intervals between tests. Average change yielded the most extreme estimates (minimum=-3761 mL/year), while regressive methods, and Huber specifically, minimised extreme estimates. Huber, Total Change and Quantile FEV 1 slope estimates were associated with all-cause hospitalisations (Huber incidence rate ratio 0.98, 95% CI 0.97 to 0.99, p<0.001). Huber estimates were also associated with smoking status, comorbidities and prior hospitalisations. Similar results were identified in an external validation cohort., Conclusions: Using EHR data to estimate FEV 1 rate of change is clinically applicable but sensitive to challenges intrinsic to clinically obtained data. While no analytic method will fully overcome these complexities, we identified Huber regression as useful in defining an individual's lung function change using EHR data., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition., Objectives: Accordingly, with National Heart, Lung and Blood Institute support, we initiated the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression., Methods/discussion: SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global initiative for chronic Obstructive Lung Disease (GOLD) groups 0-2 or with preserved ratio-impaired spirometry; and an additional n=40 never-smoker controls. Participants undergo baseline and 3-year follow-up visits, each including high-resolution computed tomography, respiratory oscillometry and spirometry (pre- and postbronchodilator administration), exhaled breath condensate (baseline only), and extensive biospecimen collection, including sputum induction. Symptoms, interim health care utilization, and exacerbations are captured every 6 months via follow-up phone calls. An embedded bronchoscopy substudy involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture., Conclusion: SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis., (JCOPDF © 2024.)

Rationale: Quantifying functional small airways disease (fSAD) requires additional expiratory computed tomography (CT) scan, limiting clinical applicability. Artificial intelligence (AI) could enable fSAD quantification from chest CT scan at total lung capacity (TLC) alone (fSAD TLC )., Objectives: To evaluate an AI model for estimating fSAD TLC and study its clinical associations in chronic obstructive pulmonary disease (COPD)., Methods: We analyzed 2513 participants from the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS). Using a subset ( n = 1055), we developed a generative model to produce virtual expiratory CTs for estimating fSAD TLC in the remaining 1458 SPIROMICS participants. We compared fSAD TLC with dual volume, parametric response mapping fSAD PRM . We investigated univariate and multivariable associations of fSAD TLC with FEV 1 , FEV 1 /FVC, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and FEV 1 decline. The results were validated in a subset ( n = 458) from COPDGene study. Multivariable models were adjusted for age, race, sex, BMI, baseline FEV 1 , smoking pack years, smoking status, and percent emphysema., Measurements and Main Results: Inspiratory fSAD TLC was highly correlated with fSAD PRM in SPIROMICS (Pearson's R = 0.895) and COPDGene (R = 0.897) cohorts. In SPIROMICS, fSAD TLC was associated with FEV 1 (L) (adj.β = -0.034, P < 0.001), FEV 1 /FVC (adj.β = -0.008, P < 0.001), SGRQ (adj.β = 0.243, P < 0.001), and FEV 1 decline (mL / year) (adj.β = -1.156, P < 0.001). fSAD TLC was also associated with FEV 1 (L) (adj.β = -0.032, P < 0.001), FEV 1 /FVC (adj.β = -0.007, P < 0.001), SGRQ (adj.β = 0.190, P = 0.02), and FEV 1 decline (mL / year) (adj.β = -0.866, P = 0.001) in COPDGene. We found fSAD TLC to be more repeatable than fSAD PRM with intraclass correlation of 0.99 (95% CI: 0.98, 0.99) vs. 0.83 (95% CI: 0.76, 0.88)., Conclusions: Inspiratory fSAD TLC captures small airways disease as reliably as fSAD PRM and is associated with FEV 1 decline.

Rationale: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives: To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 μm in aerodynamic diameter (PM 2.5 ), nitrogen oxides (NO x ), nitrogen dioxide (NO 2 ), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between -600 and -250 Hounsfield units), respectively. We assessed for effect modification by MUC5B -promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results: Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism ( P value interaction term for NO x  = 0.04 and PM 2.5  = 0.05) and smoking status ( P value interaction term for NO x  = 0.05; NO 2  = 0.01; and ozone = 0.05). With higher exposure to NO x and PM 2.5 , MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NO x , 2.41; 95% confidence interval [CI], 0.97-6.0; and RR per 4 μg ⋅ m -3 PM 2.5 , 1.43; 95% CI, 0.93-2.2, respectively). With higher exposure to NO 2 , former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0-2.7). Conclusions: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Background: Recent guidelines for spirometry interpretation recommend both race-neutral reference equations and use of z score thresholds to define severity of airflow obstruction., Research Question: How does the transition from race-specific to race-neutral equations impact severity classifications for patients with COPD when using % predicted vs z score thresholds, and do changes in severity correspond to clinical risk?, Study Design and Methods: This retrospective cohort study included Black and White patients with COPD and available spirometry from the Johns Hopkins Health System. Global Lung Function Initiative (GLI) 2012 (race-specific) equations and GLI Global (race-neutral) equations were used to determine FEV 1 % predicted and z score values. Patients were classified as having mild, moderate, or severe disease according to % predicted or z score thresholds. Associations between a change in severity classification from race-specific to race-neutral with COPD exacerbations and all-cause hospitalizations were evaluated using logistic regression., Results: This cohort included 13,324 patients, of whom 9,232 patients (69.3%) were White (mean age, 65.7 years) and 4,092 patients (30.7%) were Black (mean age, 61.1 years). More Black than White patients showed a change in severity classification between approaches when using % predicted thresholds (20.2% vs 6.1%; P < .001), but not with z score thresholds (12.6% vs 12.3%; P = .68). An increased severity classification with a race-neutral approach was associated with increased risk of exacerbation when using z score thresholds (OR, 2.34; 95% CI, 1.51-3.63), but not when using % predicted thresholds (OR, 1.08; 95% CI, 0.61-1.93). A decreased severity classification with a race-neutral approach was associated with lower risk of exacerbation with both % predicted (OR, 0.49; 95% CI, 0.28-0.87) and z score (OR 0.67; 95% CI, 0.50-0.90) thresholds., Interpretation: The proportions of Black and White individuals reclassified were similar with z score thresholds, and changes in severity corresponded to clinical risk with z scores. These results support recent recommendations for use of race-neutral equations and z score thresholds for spirometry interpretation., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Emerging studies suggest that endocrine disrupting chemicals (EDCs) in personal care and other consumer products are linked with various adverse health effects, including respiratory and reproductive effects. Despite Black persons using more personal care products than other demographic groups and having a high asthma burden, little is known regarding their consumer product use patterns and associated EDC exposures., Objective: To examine the association between recent exposure to select EDCs with specific consumer products and behaviors in a cohort of 110 predominantly Black children with asthma, ages 8-17 years, living in Baltimore City, Maryland., Methods: We quantified concentrations of bisphenol A (BPA), bisphenol S (BPS), bisphenol F, two dichlorophenols, four parabens, triclosan, benzophenone-3, and triclocarban in spot urine samples. Questionnaires were used to capture recent (last 24-h) consumer product use and behaviors. Associations between EDCs and consumer product uses/behaviors were assessed using multivariable linear regression, adjusting for age, gender, race/ethnicity, and caregiver income level. Effect estimates were expressed as geometric mean ratios of biomarker concentrations of product-users vs non-users., Results: Increased concentrations to select EDCs were associated with recent use of air freshener (ratios; BPA: 1.9, 95%CI 1.4-2; BPS 1.7, 95%CI 1-2.97; propyl paraben: 3.0, 95%CI 1.6-5.6), scented candles (methyl paraben: 2.6, 95%CI 1.1-6.1), and scented carpet powder (2,5-dichlorophenol: 2.8, 95%CI 1.2-6.3). Additionally, consuming canned food was associated with some increased biomarker concentrations (ratios: BPA: 1.7, 95%CI 1.2-2.4; BPS: 2.1, 95% CI: 1.2-3.6)., Significance: These findings add to the body of evidence suggesting that recent use of select consumer products in Black children contributes to exposure of chemicals of concern and could potentially inform exposure mitigation interventions. Findings have broad potential health implications for pediatric populations and Black children who may face exposure and health disparities., Impact: Little is known about how children's personal care product use and consumer behaviors affect their exposures to endocrine disrupting chemicals (EDCs). This is particularly true for Black children who often experience a disparate exposure burden to many EDCs. This is a significant knowledge gap among children that are uniquely vulnerable to EDCs as they undergo critical windows of growth and development. Our findings show associations between consumer products and EDC exposures in predominantly Black children in low-income settings. Identifying EDC exposure determinants has broad health implications as many of these chemicals have been associated with adverse health risks., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Rationale: Rates of emphysema progression vary in chronic obstructive pulmonary disease (COPD), and the relationships with vascular and airway pathophysiology remain unclear. Objectives: We sought to determine if indices of peripheral (segmental and beyond) pulmonary arterial dilation measured on computed tomography (CT) are associated with a 1-year index of emphysema (EI; percentage of voxels <-950 Hounsfield units) progression. Methods: Five hundred ninety-nine former and never-smokers (Global Initiative for Chronic Obstructive Lung Disease stages 0-3) were evaluated from the SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) cohort: rapid emphysema progressors (RPs; n  = 188, 1-year ΔEI > 1%), nonprogressors ( n  = 301, 1-year ΔEI ± 0.5%), and never-smokers ( n  = 110). Segmental pulmonary arterial cross-sectional areas were standardized to associated airway luminal areas (segmental pulmonary artery-to-airway ratio [PAAR seg ]). Full-inspiratory CT scan-derived total (arteries and veins) pulmonary vascular volume (TPVV) was compared with small vessel volume (radius smaller than 0.75 mm). Ratios of airway to lung volume (an index of dysanapsis and COPD risk) were compared with ratios of TPVV to lung volume. Results: Compared with nonprogressors, RPs exhibited significantly larger PAAR seg (0.73 ± 0.29 vs. 0.67 ± 0.23; P  = 0.001), lower ratios of TPVV to lung volume (3.21 ± 0.42% vs. 3.48 ± 0.38%; P  = 5.0 × 10 -12 ), lower ratios of airway to lung volume (0.031 ± 0.003 vs. 0.034 ± 0.004; P  = 6.1 × 10 -13 ), and larger ratios of small vessel volume to TPVV (37.91 ± 4.26% vs. 35.53 ± 4.89%; P  = 1.9 × 10 -7 ). In adjusted analyses, an increment of 1 standard deviation in PAAR seg was associated with a 98.4% higher rate of severe exacerbations (95% confidence interval, 29-206%; P  = 0.002) and 79.3% higher odds of being in the RP group (95% confidence interval, 24-157%; P  = 0.001). At 2-year follow-up, the CT-defined RP group demonstrated a significant decline in postbronchodilator percentage predicted forced expiratory volume in 1 second. Conclusions: Rapid one-year progression of emphysema was associated with indices indicative of higher peripheral pulmonary vascular resistance and a possible role played by pulmonary vascular-airway dysanapsis.

Background: Omega-3 polyunsaturated fatty acids (PUFAs) have been associated with systemic anti-inflammatory responses. Dietary intake of omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has also been associated with lower chronic obstructive pulmonary disease (COPD) morbidity using self-report food frequency questionnaires., Objective: The objective of this study was to investigate the relationship between measured PUFA intake using plasma EPA+DHA levels and COPD morbidity., Methods: Former smokers with moderate-to-severe COPD living in low-income communities were enrolled in a 6-month prospective cohort study. Participants completed standardized questionnaires, spirometry, and plasma samples at 3-month intervals. Total plasma PUFAs were analyzed using gas chromatography/mass spectrometry for DHA and EPA concentrations. Linear or logistic mixed model regression was used to evaluate EPA+DHA's and COPD morbidity's association, accounting for demographics, lung function, pack years, comorbidities, and neighborhood poverty., Results: A total of 133 plasma EPA+DHA samples from 57 participants were available. Participants exhibited average plasma EPA and DHA levels of 14.7±7.3µg/mL and 40.2±17.2µg/mL, respectively, across the 3 clinic visits. Each standard deviation increase in EPA+DHA levels was associated with 2.7 points lower St George's Respiratory Questionnaire score (95% confidence interval [CI] -5.2, -0.2) and lower odds of moderate exacerbation (odds ratio 0.4; 95% CI 0.2, 0.9), but lacked significant association with the COPD Assessment Test score (95% CI -2.4, 0.8), modified Medical Research Council dyspnea scale (95% CI -02, 0.2), or severe exacerbations (95% CI 0.3, 1.4)., Conclusion: Plasma EPA+DHA levels are associated with better respiratory-specific quality of life and lower odds of moderate exacerbations in patients with moderate-to-severe COPD. Further research is warranted to investigate the efficacy of an omega-3 dietary intervention in the management of COPD morbidities., (JCOPDF © 2024.)

Asthma has striking disparities across ancestral groups, but the molecular underpinning of these differences is poorly understood and minimally studied. A goal of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to understand multi-omic signatures of asthma focusing on populations of African ancestry. RNASeq and DNA methylation data are generated from nasal epithelium including cases (current asthma, N = 253) and controls (never-asthma, N = 283) from 7 different geographic sites to identify differentially expressed genes (DEGs) and gene networks. We identify 389 DEGs; the top DEG, FN1, was downregulated in cases (q = 3.26 × 10 -9 ) and encodes fibronectin which plays a role in wound healing. The top three gene expression modules implicate networks related to immune response (CEACAM5; p = 9.62 × 10 -16 and CPA3; p = 2.39 × 10 -14 ) and wound healing (FN1; p = 7.63 × 10 -9 ). Multi-omic analysis identifies FKBP5, a co-chaperone of glucocorticoid receptor signaling known to be involved in drug response in asthma, where the association between nasal epithelium gene expression is likely regulated by methylation and is associated with increased use of inhaled corticosteroids. This work reveals molecular dysregulation on three axes - increased Th2 inflammation, decreased capacity for wound healing, and impaired drug response - that may play a critical role in asthma within the African Diaspora., (© 2024. The Author(s).)

Introduction: In the USA, minoritised communities (racial and ethnic) have suffered disproportionately from COVID-19 compared with non-Hispanic white communities. In a large cohort of patients hospitalised for COVID-19 in a healthcare system spanning five adult hospitals, we analysed outcomes of patients based on race and ethnicity., Methods: This was a retrospective cohort analysis of patients 18 years or older admitted to five hospitals in the mid-Atlantic area between 4 March 2020 and 27 May 2022 with confirmed COVID-19. Participants were divided into four groups based on their race/ethnicity: non-Hispanic black, non-Hispanic white, Latinx and other. Propensity score weighted generalised linear models were used to assess the association between race/ethnicity and the primary outcome of in-hospital mortality., Results: Of the 9651 participants in the cohort, more than half were aged 18-64 years old (56%) and 51% of the cohort were females. Non-Hispanic white patients had higher mortality (p<0.001) and longer hospital length-of-stay (p<0.001) than Latinx and non-Hispanic black patients., Discussion: In this large multihospital cohort of patients admitted with COVID-19, non-Hispanic black and Hispanic patients did not have worse outcomes than white patients. Such findings likely reflect how the complex range of factors that resulted in a life-threatening and disproportionate impact of incidence on certain vulnerable populations by COVID-19 in the community was offset through admission at well-resourced hospitals and healthcare systems. However, there continues to remain a need for efforts to address the significant pre-existing race and ethnicity inequities highlighted by the COVID-19 pandemic to be better prepared for future public health emergencies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Provider adherence to clinical treatment guidelines in COPD is low. However, for patients to receive guideline-aligned care, providers not only must prescribe guideline-aligned care, but also must communicate that regimen successfully to patients to ensure medication concordance. The rate of medication concordance between patients and providers and its impact on clinical management is unknown in COPD., Research Question: To examine rates of guideline alignment and medication concordance and to identify patient-level factors that place patients at risk for these types of poor disease management outcomes., Study Design and Methods: This study was a secondary data analysis of the Medication Adherence Research in COPD study (2017-2023). Participants were categorized into 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage. Medication regimens were classified as aligned or nonaligned with 2017 GOLD guidelines. Nonaligned regimens were stratified further into overuse and underuse categories. Medication concordance between provider-reported and participant-reported regimens was determined. Factors associated with guideline alignment and medication concordance were evaluated using logistic regression., Results: Of 191 participants, 51% of provider-reported regimens were guideline aligned, with 86% of nonaligned regimens reflecting overuse with an inhaled corticosteroid (ICS). Thirty-eight percent of participants reported different regimens than their providers, of which > 80% reflected participants not reporting medications their providers reported prescribing. Participants did not report long-acting muscarinic antagonists and long-acting beta-agonists at similar rates as ICSs. Greater symptom burden and absence of a pulmonologist on the care team were associated with both guideline misalignment and medication discordance. Cognitive impairment and Black race additionally were associated with medication discordance., Interpretation: Guideline misalignment and medication discordance were common and were driven by overuse of ICSs and unreported medications, respectively. The patient-level factors associated with medication discordance highlight the importance of improving patient-provider communication to improve clinical management in COPD.

Background: Indoor pollutants have been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Elevated biomarkers are associated with ambient pollution exposure, however the association with indoor pollution remains unclear., Methods: Former smokers with spirometry-confirmed COPD were randomized to portable air cleaner or placebo. Indoor particulate matter (PM 2.5 , PM 10 , and ultrafine particles [UFP; PM <0.1 ]) and biomarkers were measured longitudinally at pre-specified intervals and course PM fraction (PM 10-2.5 ) was calculated. Biomarkers were categorized based on associations with biologic mechanisms: inflammation (white blood cell count, interleukin [IL]-6, IL-8, IL-1β, tumor necrosis factor-α, interferon-γ, serum amyloid A), platelet activation (P-selectin, CD40 ligand [CD40L], 11-dehdydro-thromboxane-B2 [11dTxB2]), endothelial dysfunction (Vascular Cell Adhesion Molecule [VCAM]-1, Intercellular Adhesion Molecule [ICAM]-1), and oxidative stress (thiobarbituric acid reactive substances [TBARS], 8-hydroxydeoxyguanosine, 8-isoprostane). Associations between PM concentrations and each biomarker were analyzed using multivariable linear mixed models. An intention-to-treat analysis was performed to evaluate the air cleaner intervention on the biomarker levels longitudinally., Results: Fifty-eight participants were randomized to each group. Finer PM was more strongly associated with higher IL-8 (mean difference per doubling: UFP 13.9% [p = 0.02], PM 2.5 6.8% [p = 0.002], PM 10-2.5 5.0% [p = 0.02]) while interferon-γ was associated with UFP and IL-1β with PM 10-2.5 . UFP and PM 2.5 were associated with elevated levels of the oxidative stress biomarkers TBARS and 8-isoprostane respectively. For platelet activation markers, UFP was associated with higher 11dTxB2 while PM 2.5 was associated with higher P-selectin and CD40L. Pollutants were not associated with biomarkers of endothelial dysfunction. In intention-to-treat analysis there was no association of the air cleaner intervention with any of the biomarkers., Discussion: Among former smokers with COPD, elevated levels of indoor air pollutants, particularly ultrafine particles (PM <0.1 ), were associated with elevated biomarkers of inflammation, platelet activation, and oxidative stress. However, an air cleaner intervention that reduced PM did not significantly reduce biomarker levels., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ashraf Fawzy reports financial support was provided by National Institutes of Health. Nirupama Putcha reports financial support was provided by National Institutes of Health. Nadia N. Hansel reports financial support was provided by National Institutes of Health. Meredith C. McCormack reports financial support was provided by National Institutes of Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Chronic obstructive pulmonary disease (COPD) hospitalizations are a major burden on patients. Diffusing capacity of the lung for carbon monoxide (Dl CO ) is a potential predictor that has not been studied in large cohorts. Objectives: This study used electronic health record data to evaluate whether clinically obtained Dl CO predicts COPD hospitalizations. Methods: We performed time-to-event analyses of individuals with COPD and Dl CO measurements from the Johns Hopkins COPD Precision Medicine Center of Excellence. Cox proportional hazard methods were used to model time from Dl CO measurement to first COPD hospitalization and composite first hospitalization or death, adjusting for age, sex, race, body mass index, smoking status, forced expiratory volume in 1 second (FEV 1 ), history of prior COPD hospitalization, and comorbidities. To identify the utility of including Dl CO in risk models, area under the receiver operating curve (AUC) values were calculated for models with and without Dl CO . Results were externally validated in a separate analogous cohort. Results: Of 2,793 participants, 368 (13%) had a COPD hospitalization within 3 years. In adjusted analyses, for every 10% decrease in Dl CO % predicted, risk of COPD hospitalization increased by 10% (hazard ratio, 1.1; 95% confidence interval, 1.1-1.2; P  < 0.001). Similar associations were observed for COPD hospitalizations or death. The model including demographics, comorbidities, FEV 1 , Dl CO , and prior COPD hospitalizations performed well, with an AUC of 0.85 and an AUC of 0.84 in an external validation cohort. Conclusions: Diffusing capacity is a strong predictor of COPD hospitalizations in a clinical cohort of individuals with COPD, independent of airflow obstruction and prior hospitalizations. These findings support incorporation of Dl CO in risk assessment of patients with COPD.

Objectives: For patients with asthma who remain symptomatic on a medium-dose inhaled corticosteroid/long-acting β2 agonist, addition of a long-acting muscarinic antagonist as a supplementary controller is a recommended option. However, real-world data on the characteristics and treatment patterns of these patients are limited. This study described the demographics and clinical characteristics of new users of single- or multiple-inhaler triple therapy and treatment patterns preceding triple-therapy initiation., Study Design: This retrospective cohort study used medical and pharmacy claims data from the IQVIA PharMetrics Plus database., Methods: The study population comprised adults with asthma with or without chronic obstructive pulmonary disease (COPD) initiating triple therapy with single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI; 100/62.5/25 μg) or multiple-inhaler triple therapy (MITT) between September 18, 2017, and September 30, 2019. Demographics, clinical characteristics, and treatment patterns in the 12 months preceding triple-therapy initiation were described (baseline period)., Results: A total of 12,395 patients were included. Among FF/UMEC/VI initiators with asthma (n = 1301), the mean age was 49.0 years and 59.3% were women. During the baseline period, 81.5% of patients used controller therapy, 94.7% used rescue medications, and 42.0% reported at least 1 asthma-related exacerbation; the annual mean exacerbation rate was 0.96. Similar trends were observed among patients with asthma initiating MITT and patients with comorbid asthma-COPD initiating FF/UMEC/VI or MITT., Conclusion: In real-world practice, triple therapy is often utilized following other asthma controller medication use. High disease burden, as evidenced by substantial use of rescue medications and continued asthma-related exacerbations, suggests that patients may not have achieved adequate asthma control prior to triple-therapy initiation.

Background: Low socioeconomic status (SES) has been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Food insecurity is more common among individuals with low SES and has been associated with poor outcomes in other chronic illnesses, but its impact on COPD has not been studied., Methods: Former smokers with spirometry-confirmed COPD were recruited from low-income areas of Baltimore, Maryland, and followed for 9 months as part of a cohort study of diet and indoor air pollution. Food insecurity and respiratory outcomes, including COPD exacerbations and patient-reported outcomes, were assessed at regular intervals. The association between food insecurity and COPD outcomes was analyzed using generalized linear mixed models. Additional analyses examined the association of COPD morbidity with subdomains of food insecurity and the association of food insecurity with psychological well-being measures., Results: Ninety-nine participants had available data on food insecurity and COPD outcomes. A total of 26.3% of participants were food insecure at 1 or more times during the study. After adjusting for individual SES, neighborhood poverty, and low healthy food access, food insecurity was associated with a higher incidence rate of moderate and severe exacerbations and worse dyspnea, COPD health status, and respiratory-specific quality of life. Subdomains of food insecurity were independently associated with worse patient-reported outcomes. Food insecurity was additionally associated with higher perceived stress., Discussion: Among former smokers with COPD, food insecurity was associated with a higher incidence of exacerbations, worse patient-reported outcomes, and higher perceived stress. Subdomains of food insecurity were independently associated with worse patient-reported outcomes., (JCOPDF © 2024.)

Rationale: The SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) is a prospective cohort study that enrolled 2981 participants with the goal of identifying new chronic obstructive pulmonary disease (COPD) subgroups and intermediate markers of disease progression. Individuals with COPD and obstructive sleep apnea (OSA) experience impaired quality of life and more frequent exacerbations. COPD severity also associates with computed tomography scan-based emphysema and alterations in airway dimensions., Objectives: The objective was to determine whether the combination of lung function and structure influences the risk of OSA among current and former smokers., Methods: Using 2 OSA risk scores, the Berlin Sleep Questionnaire (BSQ), and the DOISNORE50 (Diseases, Observed apnea, Insomnia, Snoring, Neck circumference > 18 inches, Obesity with body mass index [BMI] > 32, R = are you male, Excessive daytime sleepiness, 50 = age ≥ 50) (DIS), 1767 current and former smokers were evaluated for an association of lung structure and function with OSA risk., Measurements and Main Results: The study cohort's mean age was 63 years, BMI was 28 kg/m2, and forced expiratory volume in 1 second (FEV1) was 74.8% predicted. The majority were male (55%), White (77%), former smokers (59%), and had COPD (63%). A high-risk OSA score was reported in 36% and 61% using DIS and BSQ respectively. There was a 9% increased odds of a high-risk DIS score (odds ratio [OR]=1.09, 95% confidence interval [CI]:1.03-1.14) and nominally increased odds of a high-risk BSQ score for every 10% decrease in FEV1 %predicted (OR=1.04, 95%CI: 0.998-1.09). Lung function-OSA risk associations persisted after additionally adjusting for lung structure measurements (%emphysema, %air trapping, parametric response mapping for functional small airways disease, , mean segmental wall area, tracheal %wall area, dysanapsis) for DIS (OR=1.12, 95%CI:1.03-1.22) and BSQ (OR=1.09, 95%CI:1.01-1.18)., Conclusions: Lower lung function independently associates with having high risk for OSA in current and former smokers. Lung structural elements, especially dysanapsis, functional small airways disease, and tracheal %wall area strengthened the effects on OSA risk., (JCOPDF © 2024.)

Rationale: The identification of early chronic obstructive pulmonary disease (COPD) is essential to appropriately counsel patients regarding smoking cessation, provide symptomatic treatment, and eventually develop disease-modifying treatments. Disease severity in COPD is defined using race-specific spirometry equations. These may disadvantage non-White individuals in diagnosis and care. Objectives: Determine the impact of race-specific equations on African American (AA) versus non-Hispanic White individuals. Methods: Cross-sectional analyses of the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) cohort were conducted, comparing non-Hispanic White ( n  = 6,766) and AA ( n  = 3,366) participants for COPD manifestations. Measurements and Main Results: Spirometric classifications using race-specific, multiethnic, and "race-reversed" prediction equations (NHANES [National Health and Nutrition Examination Survey] and Global Lung Function Initiative "Other" and "Global") were compared, as were respiratory symptoms, 6-minute-walk distance, computed tomography imaging, respiratory exacerbations, and St. George's Respiratory Questionnaire. Application of different prediction equations to the cohort resulted in different classifications by stage, with NHANES and Global Lung Function Initiative race-specific equations being minimally different, but race-reversed equations moving AA participants to more severe stages and especially between the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 0 and preserved ratio impaired spirometry groups. Classification using the established NHANES race-specific equations demonstrated that for each of GOLD stages 1-4, AA participants were younger, had fewer pack-years and more current smoking, but had more exacerbations, shorter 6-minute-walk distance, greater dyspnea, and worse BODE (body mass index, airway obstruction, dyspnea, and exercise capacity) scores and St. George's Respiratory Questionnaire scores. Differences were greatest in GOLD stages 1 and 2. Race-reversed equations reclassified 774 AA participants (43%) from GOLD stage 0 to preserved ratio impaired spirometry. Conclusions: Race-specific equations underestimated disease severity among AA participants. These effects were particularly evident in early disease and may result in late detection of COPD.

Rationale: Indoor pollutants have been associated with chronic obstructive pulmonary disease morbidity, but it is unclear whether they contribute to disease progression. Objectives: We aimed to determine whether indoor particulate matter (PM) and nitrogen dioxide (NO 2 ) are associated with lung function decline among current and former smokers. Methods: Of the 2,382 subjects with a history of smoking in SPIROMICS AIR, 1,208 participants had complete information to estimate indoor PM and NO 2 , using individual-based prediction models, in relation to measured spirometry at two or more clinic visits. We used a three-way interaction model between time, pollutant, and smoking status and assessed the indoor pollutant-associated difference in FEV 1 decline separately using a generalized linear mixed model. Measurements and Main Results: Participants had an average rate of FEV 1 decline of 60.3 ml/yr for those currently smoking compared with 35.2 ml/yr for those who quit. The association of indoor PM with FEV 1 decline differed by smoking status. Among former smokers, every 10 μg/m 3 increase in estimated indoor PM was associated with an additional 10 ml/yr decline in FEV 1 ( P  = 0.044). Among current smokers, FEV 1 decline did not differ by indoor PM. The results of indoor NO 2 suggest trends similar to those for PM ⩽2.5 μm in aerodynamic diameter. Conclusions: Former smokers with chronic obstructive pulmonary disease who live in homes with high estimated PM have accelerated lung function loss, and those in homes with low PM have lung function loss similar to normal aging. In-home PM exposure may contribute to variability in lung function decline in people who quit smoking and may be a modifiable exposure.