Publications by authors named "Stephen P Peters"

173 Publications

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

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

NPJ Biofilms Microbiomes 2021 Feb 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

Clinical Outcomes and Health-Care Resource Use Associated With Reslizumab Treatment in Adults With Severe Eosinophilic Asthma in Real-World Practice.

Chest 2020 Dec 14. Epub 2020 Dec 14.

Rutgers University, New Brunswick, NJ.

Background: Reslizumab, an anti-IL-5 monoclonal antibody, is indicated as add-on maintenance treatment for adults with severe eosinophilic asthma.

Research Question: What are the real-world outcomes associated with reslizumab use in patients with severe eosinophilic asthma in a US clinical practice?

Study Design And Methods: In this retrospective study, patient-level data from adults treated with reslizumab were obtained from center- and panel-based medical chart reviews. Eligible patients had available medical records and treatment history for ≥ 6 months before initiation of reslizumab treatment (index date) to ≥ 7 months after reslizumab initiation. The primary outcome was response to reslizumab treatment, based on clinical expert predefined definitions of response. Other outcomes included clinical asthma exacerbations (CAEs), use of maintenance oral corticosteroids (OCS), FEV percent predicted, Asthma Control Test (ACT) score, and health-care resource use (HRU).

Results: Medical charts were obtained for 215 patients. Most patients (58.6%) showed an excellent response, 16.3% showed a clinically meaningful response, 21.9% showed a partial response, and 3.3% were nonresponders or treatment failures. A significant reduction was found in the proportion of patients experiencing a CAE in a 6-month period (from 86.0% to 40.5%; P < .001) and in the mean number of CAEs per patient (2.84 [SD, 2.41] vs 0.94 [SD, 1.86]) after reslizumab initiation. Improvements were observed in FEV percent predicted (65.1% [SD, 20.5%] vs 73.1% [SD, 23.1%]; P < .001) and in ACT scores (13.8 [SD, 4.2] vs 18.6 [SD, 4.0]; P < .001) before to after reslizumab initiation. Among patients using maintenance OCS at baseline, more than half discontinued use of these by approximately 10 months after reslizumab initiation. Significant reductions in asthma-related HRU were observed after reslizumab initiation.

Interpretation: In clinical practice, reslizumab may have been initiated in response to heavy symptom burden and CAEs. Reslizumab was associated with improved clinical and patient-reported outcomes and significant reductions in asthma-related HRU.
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http://dx.doi.org/10.1016/j.chest.2020.11.060DOI Listing
December 2020

Responsiveness to Parenteral Corticosteroids and Lung Function Trajectory in Adults with Moderate to Severe Asthma.

Am J Respir Crit Care Med 2020 Dec 8. Epub 2020 Dec 8.

Brigham and Women's Hospital, 1861, Pulmonary and Critical Care Division, Boston, Massachusetts, United States.

Rationale: It is unclear why select patients with moderate to severe asthma continue to lose lung function despite therapy. We hypothesized that participants with the smallest responses to parenteral corticosteroids have the greatest risk of severe decline in lung function.

Objective: To evaluate corticosteroid response phenotypes as longitudinal predictors of lung decline.

Methods: Adults with in the NHLBI Severe Asthma Research Program (SARP3; (1, 2)) who had undergone a course of intramuscular triamcinolone at baseline and ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV1% predicted. Categories of participant FEV1 slope were defined: severe decline, >2% loss/year; mild decline, >0.5 to 2.0% loss/year; no change, 0.5% loss/year to <1% gain/year; improve, ≥1% gain/year. Regression models were used to develop predictors of severe decline.

Measurements And Main Results: Of 396 participants, 78 had severe decline, 91 had mild decline, 114 had no change, and 113 showed improvement. The triamcinolone-induced difference in the post-bronchodilator FEV1% predicted (tdFEV1; derived by baseline subtraction) was related to the 4-yr change in lung function or slope category in univariable models (p < 0.001). For each 5% decrement in the tdFEV1, there was a 50% increase in the odds of being in the severe decline group (OR 1.5, 95% CI 1.3 to 1.8), when adjusted for baseline FEV1, exacerbation history, blood eosinophils and BMI.

Conclusions: Failure to improve the post-bronchodilator FEV1 after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk of severe decline in lung function.
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http://dx.doi.org/10.1164/rccm.202002-0454OCDOI Listing
December 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

A Risk Prediction Model for Mortality Among Smokers in the COPDGene® Study.

Chronic Obstr Pulm Dis 2020 Oct;7(4):346-361

National Jewish Health, Denver, Colorado.

Background: Risk factor identification is a proven strategy in advancing treatments and preventive therapy for many chronic conditions. Quantifying the impact of those risk factors on health outcomes can consolidate and focus efforts on individuals with specific high-risk profiles. Using multiple risk factors and longitudinal outcomes in 2 independent cohorts, we developed and validated a risk score model to predict mortality in current and former cigarette smokers.

Methods: We obtained extensive data on current and former smokers from the COPD Genetic Epidemiology (COPDGene) study at enrollment. Based on physician input and model goodness-of-fit measures, a subset of variables was selected to fit final Weibull survival models separately for men and women. Coefficients and predictors were translated into a point system, allowing for easy computation of mortality risk scores and probabilities. We then used the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) cohort for external validation of our model.

Results: Of 9867 COPDGene participants with standard baseline data, 17.6% died over 10 years of follow-up, and 9074 of these participants had the full set of baseline predictors (standard plus 6-minute walk distance and computed tomography variables) available for full model fits. The average age of participants in the cohort was 60 for both men and women, and the average predicted 10-year mortality risk was 18% for women and 25% for men. Model time-integrated area under the receiver operating characteristic curve statistics demonstrated good predictive model accuracy (0.797 average), validated in the external cohort (0.756 average). Risk of mortality was impacted most by 6-minute walk distance, forced expiratory volume in 1 second and age, for both men and women.

Conclusions: Current and former smokers exhibited a wide range of mortality risk over a 10- year period. Our models can identify higher risk individuals who can be targeted for interventions to reduce risk of mortality, for participants with or without chronic obstructive pulmonary disease (COPD) using current Global initiative for obstructive Lung Disease (GOLD) criteria.
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http://dx.doi.org/10.15326/jcopdf.7.4.2020.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883903PMC
October 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

Biomarkers of Type 2 Airway Inflammation as Predictors of Loss of Asthma Control During Step-Down Therapy for Well-Controlled Disease: The Long-Acting Beta-Agonist Step-Down Study (LASST).

J Allergy Clin Immunol Pract 2020 Nov - Dec;8(10):3474-3481. Epub 2020 Jul 18.

Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address:

Background: Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking.

Objective: To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down.

Methods: In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator).

Results: Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (<25 parts per billion), those with intermediate (25-50 parts per billion) and high (>50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59-1.78] and 1.29 [95% CI, 0.65-2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers.

Conclusions: In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure.
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http://dx.doi.org/10.1016/j.jaip.2020.06.067DOI Listing
July 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

The Association Between Neighborhood Socioeconomic Disadvantage and Chronic Obstructive Pulmonary Disease.

Int J Chron Obstruct Pulmon Dis 2020 5;15:981-993. Epub 2020 May 5.

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

Rationale: 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 (FEV/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 (FEV% 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.
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http://dx.doi.org/10.2147/COPD.S238933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211318PMC
May 2020

Distinct associations of sputum and oral microbiota with atopic, immunologic, and clinical features in mild asthma.

J Allergy Clin Immunol 2020 Nov 13;146(5):1016-1026. Epub 2020 Apr 13.

Department of Internal Medicine, Division of Pulmonary/Critical Care Medicine, University of Michigan, Ann Arbor, Mich. Electronic address:

Background: Whether microbiome characteristics of induced sputum or oral samples demonstrate unique relationships to features of atopy or mild asthma in adults is unknown.

Objective: We sought to determine sputum and oral microbiota relationships to clinical or immunologic features in mild atopic asthma and the impact on the microbiota of inhaled corticosteroid (ICS) treatment administered to ICS-naive subjects with asthma.

Methods: Bacterial microbiota profiles were analyzed in induced sputum and oral wash samples from 32 subjects with mild atopic asthma before and after inhaled fluticasone treatment, 18 atopic subjects without asthma, and 16 nonatopic healthy subjects in a multicenter study (NCT01537133). Associations with clinical and immunologic features were examined, including markers of atopy, type 2 inflammation, immune cell populations, and cytokines.

Results: Sputum bacterial burden inversely associated with bronchial expression of type 2 (T2)-related genes. Differences in specific sputum microbiota also associated with T2-low asthma phenotype, a subgroup of whom displayed elevations in lung inflammatory mediators and reduced sputum bacterial diversity. Differences in specific oral microbiota were more reflective of atopic status. After ICS treatment of patients with asthma, the compositional structure of sputum microbiota showed greater deviation from baseline in ICS nonresponders than in ICS responders.

Conclusions: Novel associations of sputum and oral microbiota to immunologic features were observed in this cohort of subjects with or without ICS-naive mild asthma. These findings confirm and extend our previous report of reduced bronchial bacterial burden and compositional complexity in subjects with T2-high asthma, with additional identification of a T2-low subgroup with a distinct microbiota-immunologic relationship.
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http://dx.doi.org/10.1016/j.jaci.2020.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554083PMC
November 2020

Implementation of an ICU Recovery Clinic at a Tertiary Care Academic Center.

Crit Care Explor 2019 Aug 9;1(8):e0034. Epub 2019 Aug 9.

Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy, and Immunological Diseases, Wake Forest School of Medicine, Winston-Salem, NC.

Post-ICU clinics may facilitate the care of survivors of critical illness, but there is a paucity of data describing post-ICU clinic implementation. We sought to describe implementation of our ICU recovery clinic, including an assessment of barriers and facilitators to clinic attendance.

Design: Adults admitted to the medical ICU of a large tertiary care academic hospital with shock and/or respiratory failure requiring mechanical ventilation were screened for participation in a newly formed ICU recovery clinic. Participant selection and attendance rates were tracked. Reasons for nonattendance were assessed by phone call in a subset of patients.

Setting: A newly formed ICU recovery clinic of a large tertiary care academic hospital.

Patients: All patients admitted to the medical ICU were screened.

Interventions: ICU recovery clinic appointments were scheduled for all eligible patients. A subset of nonattenders were called to assess reasons for nonattendance.

Measurements And Main Results: Over 2 years, we admitted 5,510 patients to our medical ICU. Three hundred sixty-two were screened into the recovery clinic. One-hundred sixty-six were not scheduled for clinic; major reasons included discharge to hospice/death in the hospital ( = 55) and discharge to a facility ( = 50). One-hundred ninety-six patients were scheduled for a visit and of those, 101 (52%) arrived to clinic. Reasons for nonattendance in a surveyed subset of nonattenders included patient's lack of awareness of the appointment (50%, = 9/18), financial concerns (17%, = 3/18), and transportation difficulty (17%, = 3/18).

Conclusions: ICU recovery clinics may address the needs of survivors of critical illness. Barriers to clinic attendance include high mortality rates, high rates of clinic appointment cancelations and nonattendance, and discharge to locations such as skilled nursing facilities or long-term acute care hospitals. Improved communication to patients about the role of the clinic may facilitate attendance and minimize canceled appointments.
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http://dx.doi.org/10.1097/CCE.0000000000000034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063951PMC
August 2019

genotype identifies glucocorticoid responsiveness in severe asthma.

Proc Natl Acad Sci U S A 2020 01 13;117(4):2187-2193. Epub 2020 Jan 13.

Lerner Research Institute and the Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195;

Asthma resistance to glucocorticoid treatment is a major health problem with unclear etiology. Glucocorticoids inhibit adrenal androgen production. However, androgens have potential benefits in asthma. encodes for 3β-hydroxysteroid dehydrogenase-1 (3β-HSD1), which catalyzes peripheral conversion from adrenal dehydroepiandrosterone (DHEA) to potent androgens and has a germline missense-encoding polymorphism. The adrenal restrictive (1245A) allele limits conversion, whereas the adrenal permissive (1245C) allele increases DHEA metabolism to potent androgens. In the Severe Asthma Research Program (SARP) III cohort, we determined the association between DHEA-sulfate and percentage predicted forced expiratory volume in 1 s (FEVPP). (1245) genotypes were assessed, and association between adrenal restrictive and adrenal permissive alleles and FEVPP in patients with (GC) and without (noGC) daily oral glucocorticoid treatment was determined ( = 318). Validation was performed in a second cohort (SARP I&II; = 184). DHEA-sulfate is associated with FEVPP and is suppressed with GC treatment. GC patients homozygous for the adrenal restrictive genotype have lower FEVPP compared with noGC patients (54.3% vs. 75.1%; < 0.001). In patients with the homozygous adrenal permissive genotype, there was no FEVPP difference in GC vs. noGC patients (73.4% vs. 78.9%; = 0.39). Results were independently confirmed: FEVPP for homozygous adrenal restrictive genotype in GC vs. noGC is 49.8 vs. 63.4 ( < 0.001), and for homozygous adrenal permissive genotype, it is 66.7 vs. 67.7 ( = 0.92). The adrenal restrictive (1245) genotype is associated with GC resistance. This effect appears to be driven by GC suppression of 3β-HSD1 substrate. Our results suggest opportunities for prediction of GC resistance and pharmacologic intervention.
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http://dx.doi.org/10.1073/pnas.1918819117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995013PMC
January 2020

Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis.

Int J Chron Obstruct Pulmon Dis 2019 20;14:2927-2938. Epub 2019 Dec 20.

Department of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Objective: Bronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV (BDR) as a measure reflecting the change in flow and in FVC (BDR) reflecting the change in volume.

Methods: We analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.

Results: A majority of COPD participants exhibited BDR (52.7%). BDR occurred more often in earlier stages of COPD, while BDR occurred more frequently in more advanced disease. When defined by increases in either FEV or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDR was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDR was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV.

Conclusion: With advanced airflow obstruction in COPD, BDR is more prevalent in comparison to BDR and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV, BDR itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.

Clinical Trials Registration: ClinicalTrials.gov: NCT01969344T4.
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http://dx.doi.org/10.2147/COPD.S220164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930016PMC
July 2020

Association of urine mitochondrial DNA with clinical measures of COPD in the SPIROMICS cohort.

JCI Insight 2020 02 13;5(3). Epub 2020 Feb 13.

New York-Presbyterian Hospital, Weill Cornell Medicine, New York, New York, USA.

BACKGROUNDMitochondrial dysfunction, a proposed mechanism of chronic obstructive pulmonary disease (COPD) pathogenesis, is associated with the leakage of mitochondrial DNA (mtDNA), which may be detected extracellularly in various bodily fluids. Despite evidence for the increased prevalence of chronic kidney disease in COPD subjects and for mitochondrial dysfunction in the kidneys of murine COPD models, whether urine mtDNA (u-mtDNA) associates with measures of disease severity in COPD is unknown.METHODSCell-free u-mtDNA, defined as copy number of mitochondrially encoded NADH dehydrogenase-1 (MTND1) gene, was measured by quantitative PCR and normalized to urine creatinine in cell-free urine samples from participants in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Urine albumin/creatinine ratios (UACR) were measured in the same samples. Associations between u-mtDNA, UACR, and clinical disease parameters - including FEV1 % predicted, clinical measures of exercise tolerance, respiratory symptom burden, and chest CT measures of lung structure - were examined.RESULTSU-mtDNA and UACR levels were measured in never smokers (n = 64), smokers without airflow obstruction (n = 109), participants with mild/moderate COPD (n = 142), and participants with severe COPD (n = 168). U-mtDNA was associated with increased respiratory symptom burden, especially among smokers without COPD. Significant sex differences in u-mtDNA levels were observed, with females having higher u-mtDNA levels across all study subgroups. U-mtDNA associated with worse spirometry and CT emphysema in males only and with worse respiratory symptoms in females only. Similar associations were not found with UACR.CONCLUSIONU-mtDNA levels may help to identify distinct clinical phenotypes and underlying pathobiological differences in males versus females with COPD.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov ( NCT01969344).FUNDINGUS NIH, National Heart, Lung and Blood Institute, supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from AstraZeneca/MedImmune, Bayer, Bellerophon Therapeutics, Boehringer-Ingelheim Pharmaceuticals Inc., Chiesi Farmaceutici S.p.A., Forest Research Institute Inc., GlaxoSmithKline, Grifols Therapeutics Inc., Ikaria Inc., Novartis Pharmaceuticals Corporation, Nycomed GmbH, ProterixBio, Regeneron Pharmaceuticals Inc., Sanofi, Sunovion, Takeda Pharmaceutical Company, and Theravance Biopharma and Mylan.
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http://dx.doi.org/10.1172/jci.insight.133984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098791PMC
February 2020

The Effects of Rare Variants on Lung Function and Emphysema in SPIROMICS.

Am J Respir Crit Care Med 2020 03;201(5):540-554

Department of Medicine, University of Arizona, Tucson, Arizona.

The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial. To comprehensively evaluate the effects of rare variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations. DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of . White PI Z heterozygotes confirmed by sequencing (MZ;  = 74) had lower post-bronchodilator FEV ( = 0.007), FEV/FVC ( = 0.003), and greater computed tomography-based emphysema ( = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as V. PI Z-containing compound heterozygotes (ZS/ZV;  = 7) had lower FEV/FVC ( = 0.02) and forced expiratory flow, midexpiratory phase ( = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease ( = 0.007). In this integrative deep sequencing study of with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of variation associated with respiratory disease in at-risk smokers.
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http://dx.doi.org/10.1164/rccm.201904-0769OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047460PMC
March 2020

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

N Engl J Med 2019 09;381(13):1227-1239

From National Jewish Health (M.E.W., R.C., J.T.O.), Denver, and University of Colorado School of Medicine (M.E.W., S.J.S., R.C., F.H., J.T.O.) and Children's Hospital Colorado (S.J.S.), Aurora - all in Colorado; Wake Forest School of Medicine (V.E.O., W.C.M., S.P.P.), Winston-Salem, North Carolina Clinical Research (C.F.L.), Raleigh, and Duke University Medical Center (N.L., L.Q.), Durham - all in North Carolina; Ann and Robert H. Lurie Children's Hospital of Chicago (J.A.P., R.G.R.), University of Illinois at Chicago (J.A.K., H.K.), Rush University Medical Center (J.M.), University of Chicago (E.N., J.S., S. White), and Northwestern University Feinberg School of Medicine (L.J.S.) - all in Chicago; Penn State University (V.C., S.J.K., D.M.), Hershey, and Allegheny General Hospital (D.G.) and University of Pittsburgh Medical Center (S. Wenzel), Pittsburgh - all in Pennsylvania; Nemours Children's Health System, Jacksonville (J.J.L., K.V.B., J.L.), and University of South Florida Morsani College of Medicine, Tampa (J.-C.C.) - both in Florida; University of Arizona Health Sciences, Tucson (E.R.B., M.K., F.M., D.A.M.); Washington University School of Medicine, St. Louis (L.B.B., A.B., M.C.); University of California, San Francisco (UCSF), San Francisco (M.B., M.D.C., S.C.L., D.L.) and UCSF Benioff Children's Hospital, Oakland (M.B., D.L.) - both in California; Brigham and Women's Hospital and Harvard Medical School (J.-C.C., N.G., E.I.) and Boston Children's Hospital (W.P., W.S.) - all in Boston; University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland (J.F.C., K.R.); University of Wisconsin-Madison, Madison (L.D., D.J.J., R.F.L., C.A.S.) and Aurora Sinai Medical Center, Milwaukee (L.S.-V.) - both in Wisconsin; Columbia University Irving Medical Center, New York, (E.D.); Emory University, Atlanta (A.M.F.); and University of New Mexico, Albuquerque (H.R.).

Background: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients.

Methods: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry.

Results: When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age.

Conclusions: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).
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http://dx.doi.org/10.1056/NEJMoa1905560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026584PMC
September 2019

Exacerbation-prone asthma in the context of race and ancestry in Asthma Clinical Research Network trials.

J Allergy Clin Immunol 2019 12 11;144(6):1524-1533. Epub 2019 Sep 11.

Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.

Background: Minority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk.

Objective: We evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations.

Methods: One thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n = 760).

Results: Twenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P = .30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P = .13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P = .74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P = .03]).

Conclusion: Black subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect.
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http://dx.doi.org/10.1016/j.jaci.2019.08.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931257PMC
December 2019

Radiographic lung volumes predict progression to COPD in smokers with preserved spirometry in SPIROMICS.

Eur Respir J 2019 10 31;54(4). Epub 2019 Oct 31.

Dept of Medicine, University of California, San Francisco, CA, USA.

The characteristics that predict progression to overt chronic obstructive pulmonary disease (COPD) in smokers without spirometric airflow obstruction are not clearly defined.We conducted a analysis of 849 current and former smokers (≥20 pack-years) with preserved spirometry from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort who had baseline computed tomography (CT) scans of lungs and serial spirometry. We examined whether CT-derived lung volumes representing air trapping could predict adverse respiratory outcomes and more rapid decline in spirometry to overt COPD using mixed-effect linear modelling.Among these subjects with normal forced expiratory volume in 1 s (FEV) to forced vital capacity (FVC) ratio, CT-measured residual volume (RV) to total lung capacity (TLC) ratio varied widely, from 21% to 59%. Over 2.5±0.7 years of follow-up, subjects with higher RV/TLC had a greater differential rate of decline in FEV/FVC; those in the upper RV/TLC tertile had a 0.66% (95% CI 0.06%-1.27%) faster rate of decline per year compared with those in the lower tertile (p=0.015) regardless of demographics, baseline spirometry, respiratory symptoms score, smoking status (former current) or smoking burden (pack-years). Accordingly, subjects with higher RV/TLC were more likely to develop spirometric COPD (OR 5.7 (95% CI 2.4-13.2) in upper lower RV/TLC tertile; p<0.001). Other CT indices of air trapping showed similar patterns of association with lung function decline; however, when all CT indices of air trapping, emphysema, and airway disease were included in the same model, only RV/TLC retained its significance.Increased air trapping based on radiographic lung volumes predicts accelerated spirometry decline and progression to COPD in smokers without obstruction.
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http://dx.doi.org/10.1183/13993003.02214-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089627PMC
October 2019

Serum amino acid concentrations and clinical outcomes in smokers: SPIROMICS metabolomics study.

Sci Rep 2019 08 6;9(1):11367. Epub 2019 Aug 6.

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

Metabolomics is an emerging science that can inform pathogenic mechanisms behind clinical phenotypes in COPD. We aimed to understand disturbances in the serum metabolome associated with respiratory outcomes in ever-smokers from the SPIROMICS cohort. We measured 27 serum metabolites, mostly amino acids, by H-nuclear magnetic resonance spectroscopy in 157 white ever-smokers with and without COPD. We tested the association between log-transformed metabolite concentrations and one-year incidence of respiratory exacerbations after adjusting for age, sex, current smoking, body mass index, diabetes, inhaled or oral corticosteroid use, study site and clinical predictors of exacerbations, including FEV% predicted and history of exacerbations. The mean age of participants was 53.7 years and 58% had COPD. Lower concentrations of serum amino acids were independently associated with 1-year incidence of respiratory exacerbations, including tryptophan (β = -4.1, 95% CI [-7.0; -1.1], p = 0.007) and the branched-chain amino acids (leucine: β = -6.0, 95% CI [-9.5; -2.4], p = 0.001; isoleucine: β = -5.2, 95% CI [-8.6; -1.8], p = 0.003; valine: β = -4.1, 95% CI [-6.9; -1.4], p = 0.003). Tryptophan concentration was inversely associated with the blood neutrophil-to-lymphocyte ratio (p = 0.03) and the BODE index (p = 0.03). Reduced serum amino acid concentrations in ever-smokers with and without COPD are associated with an increased incidence of respiratory exacerbations.
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http://dx.doi.org/10.1038/s41598-019-47761-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684630PMC
August 2019

Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2019 12;200(11):1402-1413

Division of Pulmonary and Critical Care Medicine.

Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known. To perform a genome-wide association study (GWAS) of ILAs. ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF. Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs ( = 2.6 × 10) and subpleural ILAs ( = 1.6 × 10). We discovered novel genome-wide associations near (rs6886640,  = 3.8 × 10) and (rs73199442,  = 4.8 × 10) with ILAs, and near (rs7744971,  = 4.2 × 10) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPF GWAS loci, five (, , , , and ) were significantly associated ( < 0.05/12) with ILAs. In a GWAS of ILAs in six studies, we confirmed the association with a promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.
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http://dx.doi.org/10.1164/rccm.201903-0511OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884045PMC
December 2019

Structural and Functional Features on Quantitative Chest Computed Tomography in the Korean Asian versus the White American Healthy Non-Smokers.

Korean J Radiol 2019 07;20(7):1236-1245

School of Mechanical Engineering, Kyungpook National University, Daegu, Korea.

Objective: Considering the different prevalence rates of diseases such as asthma and chronic obstructive pulmonary disease in Asians relative to other races, Koreans may have unique airway structure and lung function. This study aimed to investigate unique features of airway structure and lung function based on quantitative computed tomography (QCT)-imaging metrics in the Korean Asian population (Koreans) as compared with the White American population (Whites).

Materials And Methods: QCT data of healthy non-smokers (223 Koreans vs. 70 Whites) were collected, including QCT structural variables of wall thickness (WT) and hydraulic diameter (D) and functional variables of air volume, total air volume change in the lung (ΔV), percent emphysema-like lung (Emph%), and percent functional small airway disease-like lung (fSAD%). Mann-Whitney U tests were performed to compare the two groups.

Results: As compared with Whites, Koreans had smaller volume at inspiration, ΔV between inspiration and expiration ( < 0.001), and Emph% at inspiration ( < 0.001). Especially, Korean females had a decrease of ΔV in the lower lobes ( < 0.001), associated with fSAD% at the lower lobes ( < 0.05). In addition, Koreans had smaller D and WT of the trachea (both, < 0.05), correlated with the forced expiratory volume in 1 second (R = 0.49, 0.39; all < 0.001) and forced vital capacity (R = 0.55, 0.45; all < 0.001).

Conclusion: Koreans had unique features of airway structure and lung function as compared with Whites, and the difference was clearer in female individuals. Discriminating structural and functional features between Koreans and Whites enables exploration of inter-racial differences of pulmonary disease in terms of severity, distribution, and phenotype.
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http://dx.doi.org/10.3348/kjr.2019.0083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609438PMC
July 2019

Preoperative Sleep Questionnaires Identify Medical Emergency Team Activation in Older Adults.

J Am Med Dir Assoc 2019 10 11;20(10):1340-1343.e2. Epub 2019 Jun 11.

Department of Internal Medicine, Section of Pulmonary, Critical Care and Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC.

Patients with obstructive sleep apnea (OSA) have increased postoperative complications that are important for patient safety and healthcare utilization. Questionnaires help identify patients at risk for OSA; however, among older adults who preoperatively self-administered OSA questionnaires, the frequency of postoperative Medical Emergency Team Activation (META), rapid response, code blue, code stroke, is unknown.

Objectives: Identify whether having OSA questionnaires completed by patients is feasible in the preoperative clinic. Determine the frequency of META among older patients at risk for OSA.

Design And Intervention: Cohort of prospective patients independently completed 2 OSA questionnaires in a preoperative clinic, STOP-Bang (SB) and ISNORED (IS). Observers blinded to questionnaire responses recorded incidence of META.

Setting And Participants: Of the 898 consecutive patients approached in the preoperative assessment clinic and surgical navigation center, 575 (64%) consented and completed the questionnaires in <5 minutes and were included in the analysis.

Measures: Sleep questionnaire responses and frequency of inpatient postoperative META.

Results: With an affirmative response to ≥3 questions on either questionnaire, 65% of patients enrolled were at risk for OSA. Of these, 3.1% sustained an META. In patients at risk for OSA, META occurred in 7.6% (SB+) and 7.2% (IS+) vs 2.5% (SB+) and 1.7% (IS+) for low risk. METAs were disproportionately higher among patients aged ≥65 years (6.3% vs 1.7%; P < .018), American Society of Anesthesiologists (ASA) physical status class ≥3, and IS+. All patients with META positively answered ≥3 of 15 components of the 2 questionnaires.

Conclusions/implications: Preoperative, self-administration of SB and IS questionnaires is feasible. Overall, 65% of those with affirmative responses to ≥3 questions were at risk for OSA and associated with a disproportionate number of postoperative META in older patients. Additionally, risk of OSA identified by preoperative sleep questionnaires was associated with postoperative META among older adults. Use of clinical tools and OSA questionnaires may improve preoperative identification of META in this population.
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http://dx.doi.org/10.1016/j.jamda.2019.04.024DOI Listing
October 2019

Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.

N Engl J Med 2019 05 19;380(21):2009-2019. Epub 2019 May 19.

From the Division of Pulmonary and Critical Care Medicine and the Cardiovascular Research Institute (S.C.L., H.A.B., J.V.F., P.G.W.) and the Department of Pediatrics, Epidemiology, and Biostatistics (M.D.C.), University of California, San Francisco, San Francisco; the University of Illinois at Chicago (J.A.K.), the Department of Pediatrics, Rush University Medical Center (J.N.M.), Ann and Robert Lurie Children's Hospital of Chicago (J.A.P.), and Northwestern University, Feinberg School of Medicine (L.S.) - all in Chicago; the Department of Public Health Sciences, Penn State University, Hershey (T.S.K., V.M.C., D.T.M., A.-M.D.), and the University of Pittsburgh Asthma Institute (S.W., F.H.) and Allegheny General Hospital (D.G.), Pittsburgh - all in Pennsylvania; Nemours Children's Hospital, University of Central Florida College of Medicine, Orlando (J.E.L., K.V.B.), and Nemours Children's Health System, Jacksonville (J.E.L., K.V.B.) - both in Florida; the Department of Pediatrics and Medicine, National Jewish Health, Denver (R.C., S.J.S., M.E.W.), and Children's Hospital Colorado, Aurora (R.C., S.J.S., M.E.W.) - both in Colorado; Duke Allergy, Asthma, and Airway Center, Duke University School of Medicine, Durham (N.L., M.K., L.Q.), Wake Forest University School of Medicine, Winston-Salem (A.H., W.M., S.P.P.), and North Carolina Clinical Research, Raleigh (C.L.) - all in North Carolina; the Departments of Pediatrics and Medicine, Washington University in St. Louis School of Medicine, St. Louis (L.B.B., M.C.); Brigham and Women's Hospital and Harvard Medical School (J.C.C., E.I.) and Boston Children's Hospital (W.P.) - all in Boston; Rainbow Babies and Children's Hospital, Cleveland (J.C., R.M., K.R.); the University of Wisconsin, Madison (L.D., D.J., R.F.L., C.A.S.); Columbia University, New York (E.D.); the Department of Pediatrics, Emory University, Atlanta (A.M.F.); and the Arizona Respiratory Center, University of Arizona, Tucson (F.D.M., W.J.M.).

Background: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown.

Methods: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level.

Results: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%).

Conclusions: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).
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http://dx.doi.org/10.1056/NEJMoa1814917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711475PMC
May 2019

Loss of bronchoprotection with ICS plus LABA treatment, β-receptor dynamics, and the effect of alendronate.

J Allergy Clin Immunol 2019 08 11;144(2):416-425.e7. Epub 2019 Mar 11.

Department of Medicine, Brigham and Women's Hospital, Boston, Mass. Electronic address:

Background: Loss of bronchoprotection (LOBP) with a regularly used long-acting β-adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β-adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate.

Objective: We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients.

Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC value.

Results: The mean doubling dose reduction in SPMCh PC value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP.

Conclusion: This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP.
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http://dx.doi.org/10.1016/j.jaci.2019.01.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950766PMC
August 2019

Systemic Markers of Inflammation in Smokers With Symptoms Despite Preserved Spirometry in SPIROMICS.

Chest 2019 05 23;155(5):908-917. Epub 2019 Jan 23.

Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California, San Francisco, San Francisco, CA.

Background: Chronic respiratory symptoms and exacerbation-like events are common among ever-smokers without airflow limitation on spirometry. The pathobiology of respiratory disease in this subgroup remains poorly defined, but may be due to underlying inflammation that overlaps with COPD or asthma. We hypothesized that symptoms, exacerbations, and functional measures of disease severity among smokers with preserved spirometry would be associated with markers of systemic inflammation, similar to what is reported in bone fide COPD, rather than elevated type 2 inflammation, which is often present in asthma.

Methods: We measured inflammatory markers associated with COPD (C-reactive protein [CRP], fibrinogen, soluble tumor necrosis factor receptors [sTNFRSF1A and sTNFRSF1B], and blood/sputum neutrophils) and type 2 inflammation (IgE and blood/sputum eosinophils) in smokers with preserved spirometry (postbronchodilator FEV/FVC ≥ 0.70) from the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). We evaluated the relationship of these markers with respiratory symptom burden (dichotomized by a COPD assessment test score cutoff of 10, diagnosis of chronic bronchitis), exacerbations, 6-minute walk distance, and lung function on the basis of FEV.

Results: CRP was associated with increased symptom burden (on the basis of COPD assessment test score and diagnosis of chronic bronchitis) and a greater number of exacerbations in the year before study enrollment. sTNFRSF1A was associated with symptom burden on the basis of COPD assessment test score. CRP and sTNFRSF1A levels negatively correlated with 6-minute walk distance. IgE and eosinophils were not associated with these outcomes.

Conclusions: Markers of inflammation including CRP and sTNFRSF1A are enriched among symptomatic smokers with preserved spirometry, suggesting an overlap with the underlying pathophysiology of COPD.
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http://dx.doi.org/10.1016/j.chest.2018.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533449PMC
May 2019