Publications by authors named "Prescott G Woodruff"

182 Publications

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

Chronic Obstr Pulm Dis 2021 Jun 30. Epub 2021 Jun 30.

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

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

Update in Adult Asthma 2020.

Am J Respir Crit Care Med 2021 Jun 28. Epub 2021 Jun 28.

UCSF, 8785, Division of Pulmonary and Critical Care Medicine, Department of Medicine and CVRI, San Francisco, California, United States;

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http://dx.doi.org/10.1164/rccm.202103-0552UPDOI Listing
June 2021

Metabolome subtyping of severe bronchiolitis in infancy and risk of childhood asthma.

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

Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Mass.

Background: Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition.

Objectives: We sought to identify biologically distinct subgroups based on the metabolome signatures (metabotypes) in infants with severe bronchiolitis and to examine the longitudinal relationships of metabotypes with asthma development.

Methods: In a multicenter prospective cohort study of infants (age, <12 months) hospitalized for bronchiolitis, the nasopharyngeal airway metabolome was profiled at hospitalization. Using a clustering approach, this study identified mutually exclusive metabotypes. This study also examined their longitudinal association with the risk of developing asthma by 5 years of age.

Results: Of 918 infants hospitalized for bronchiolitis (median age, 3 months), this study identified 5 distinct metabotypes-characterized by their nasopharyngeal metabolome profile: A, glycerophosphocholine-high; B, amino acid-high, polyunsaturated fatty acid-low; C, amino acid-high, glycerophospholipid-low; D, glycerophospholipid-high; and E, mixed. Compared with infants with metabotype A (who clinically resembled "classic" bronchiolitis), infants with metabotype B had a significantly higher risk for developing asthma (23% vs 41%; adjusted odds ratio, 2.22; 95% CI, 1.07-4.69). The pathway analysis showed that metabotype B had enriched amino acid (eg, methionine, histidine, glutathione) and α-linolenic/linoleic acid metabolism pathways (false discovery rate, <5 × 10 for all). Finally, the transcriptome analysis revealed that infants with metabotype B had upregulated IFN-α and IL-6/JAK/STAT3 pathways and downregulated fatty acid metabolism pathways (false discovery rate, <0.05 for both).

Conclusions: In this multicenter prospective cohort study of infants with severe bronchiolitis, the clustering analysis of metabolome data identified biologically distinct metabotypes, including a metabotype characterized by high inflammatory amino acids and low polyunsaturated fatty acids that is at significantly increased risk for developing asthma.
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http://dx.doi.org/10.1016/j.jaci.2021.05.036DOI Listing
June 2021

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD.

Respir Res 2021 Apr 27;22(1):127. Epub 2021 Apr 27.

Research and Development, GlaxoSmithKline, Collegeville, PA, USA.

Background: Soluble receptor for advanced glycation end products (sRAGE) is a proposed emphysema and airflow obstruction biomarker; however, previous publications have shown inconsistent associations and only one study has investigate the association between sRAGE and emphysema. No cohorts have examined the association between sRAGE and progressive decline of lung function. There have also been no evaluation of assay compatibility, receiver operating characteristics, and little examination of the effect of genetic variability in non-white population. This manuscript addresses these deficiencies and introduces novel data from Pittsburgh COPD SCCOR and as well as novel work on airflow obstruction. A meta-analysis is used to quantify sRAGE associations with clinical phenotypes.

Methods: sRAGE was measured in four independent longitudinal cohorts on different analytic assays: COPDGene (n = 1443); SPIROMICS (n = 1623); ECLIPSE (n = 2349); Pittsburgh COPD SCCOR (n = 399). We constructed adjusted linear mixed models to determine associations of sRAGE with baseline and follow up forced expiratory volume at one second (FEV) and emphysema by quantitative high-resolution CT lung density at the 15th percentile (adjusted for total lung capacity).

Results: Lower plasma or serum sRAGE values were associated with a COPD diagnosis (P < 0.001), reduced FEV (P < 0.001), and emphysema severity (P < 0.001). In an inverse-variance weighted meta-analysis, one SD lower log-transformed sRAGE was associated with 105 ± 22 mL lower FEV and 4.14 ± 0.55 g/L lower adjusted lung density. After adjusting for covariates, lower sRAGE at baseline was associated with greater FEV decline and emphysema progression only in the ECLIPSE cohort. Non-Hispanic white subjects carrying the rs2070600 minor allele (A) and non-Hispanic African Americans carrying the rs2071288 minor allele (A) had lower sRAGE measurements compare to those with the major allele, but their emphysema-sRAGE regression slopes were similar.

Conclusions: Lower blood sRAGE is associated with more severe airflow obstruction and emphysema, but associations with progression are inconsistent in the cohorts analyzed. In these cohorts, genotype influenced sRAGE measurements and strengthened variance modelling. Thus, genotype should be included in sRAGE evaluations.
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http://dx.doi.org/10.1186/s12931-021-01686-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076883PMC
April 2021

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Age-Dependent Associations Between 25-Hydroxy Vitamin D Levels and COPD Symptoms: Analysis of SPIROMICS.

Chronic Obstr Pulm Dis 2021 Apr;8(2):277-291

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

Introduction: Age and vitamin D levels may affect symptom burden in chronic obstructive pulmonary disease (COPD). We used the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) to determine independent associations between vitamin D levels and COPD symptoms in different age strata.

Methods: Serum 25-hydroxy (OH)-vitamin D levels were modeled continuously and categorically (<20 ng/ml versus ≥20 ng/ml). Stratifying by age group (middle-age: 40-64 years old and older: >65 years old), multivariable modeling was performed to identify relationships between 25-OH-vitamin D levels and the COPD Assessment Test (CAT), the modified Medical Research Council score (mMRC), the St George's Respiratory Questionnaire (SGRQ) total and subdomain scores, the Veterans' Specific Activity Questionnaire, and the 6-minute walk test distance.

Results: InIn the middle-aged group, each 5 ng/ml higher 25-OH-vitamin D level was independently associated with more favorable CAT score (-0.35 [-0.67 to -0.03], =0.03), total SGRQ (-0.91 [-1.65 to -0.17]; =0.02), and the SGRQ subdomains (Symptoms:-1.07 [-1.96 to -0.18], =0.02; Impact: -0.77 [-1.53 to -0.003], =0.049; Activity: -1.07 [-1.96 to -0.18], =0.02). These associations persisted after the addition of comorbidity score, reported vitamin D supplementation, outdoor time, or season of blood draw to models. No associations were observed between 25-OH-vitamin D levels and symptom scores in the older age group.

Discussion: When controlled for clinically relevant covariates, higher 25-OH-vitamin D levels are associated with more favorable respiratory-specific symptoms and quality-of-life assessments in middle-age but not older COPD individuals. Study of the role of vitamin D supplementation in the symptom burden of younger COPD patients is needed.
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http://dx.doi.org/10.15326/jcopdf.2020.0180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237982PMC
April 2021

Impaired antibacterial immune signaling and changes in the lung microbiome precede secondary bacterial pneumonia in COVID-19.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

Secondary bacterial infections, including ventilator-associated pneumonia (VAP), lead to worse clinical outcomes and increased mortality following viral respiratory infections. Critically ill patients with coronavirus disease 2019 (COVID-19) face an elevated risk of VAP, although susceptibility varies widely. Because mechanisms underlying VAP predisposition remained unknown, we assessed lower respiratory tract host immune responses and microbiome dynamics in 36 patients, including 28 COVID-19 patients, 15 of whom developed VAP, and eight critically ill controls. We employed a combination of tracheal aspirate bulk and single cell RNA sequencing (scRNA-seq). Two days before VAP onset, a lower respiratory transcriptional signature of bacterial infection was observed, characterized by increased expression of neutrophil degranulation, toll-like receptor and cytokine signaling pathways. When assessed at an earlier time point following endotracheal intubation, more than two weeks prior to VAP onset, we observed a striking early impairment in antibacterial innate and adaptive immune signaling that markedly differed from COVID-19 patients who did not develop VAP. scRNA-seq further demonstrated suppressed immune signaling across monocytes/macrophages, neutrophils and T cells. While viral load did not differ at an early post-intubation timepoint, impaired SARS-CoV-2 clearance and persistent interferon signaling characterized the patients who later developed VAP. Longitudinal metatranscriptomic analysis revealed disruption of lung microbiome community composition in patients who developed VAP, providing a connection between dysregulated immune signaling and outgrowth of opportunistic pathogens. Together, these findings demonstrate that COVID-19 patients who develop VAP have impaired antibacterial immune defense weeks before secondary infection onset.

One Sentence Summary: COVID-19 patients with secondary bacterial pneumonia have impaired immune signaling and lung microbiome changes weeks before onset.
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http://dx.doi.org/10.1101/2021.03.23.21253487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010763PMC
March 2021

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

medRxiv 2021 Mar 20. Epub 2021 Mar 20.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.
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http://dx.doi.org/10.1101/2021.03.19.21253986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987050PMC
March 2021

Longitudinal single-cell epitope and RNA-sequencing reveals the immunological impact of type 1 interferon autoantibodies in critical COVID-19.

bioRxiv 2021 Mar 10. Epub 2021 Mar 10.

Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.
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http://dx.doi.org/10.1101/2021.03.09.434529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987018PMC
March 2021

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

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

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

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

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

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

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

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

Epithelial miR-141 regulates IL-13-induced airway mucus production.

JCI Insight 2021 Mar 8;6(5). Epub 2021 Mar 8.

Department of Medicine, Division of Pulmonary and Critical Care Medicine.

IL-13-induced goblet cell metaplasia contributes to airway remodeling and pathological mucus hypersecretion in asthma. miRNAs are potent modulators of cellular responses, but their role in mucus regulation is largely unexplored. We hypothesized that airway epithelial miRNAs play roles in IL-13-induced mucus regulation. miR-141 is highly expressed in human and mouse airway epithelium, is altered in bronchial brushings from asthmatic subjects at baseline, and is induced shortly after airway allergen exposure. We established a CRISPR/Cas9-based protocol to target miR-141 in primary human bronchial epithelial cells that were differentiated at air-liquid-interface, and goblet cell hyperplasia was induced by IL-13 stimulation. miR-141 disruption resulted in decreased goblet cell frequency, intracellular MUC5AC, and total secreted mucus. These effects correlated with a reduction in a goblet cell gene expression signature and enrichment of a basal cell gene expression signature defined by single cell RNA sequencing. Furthermore, intranasal administration of a sequence-specific mmu-miR-141-3p inhibitor in mice decreased Aspergillus-induced secreted mucus and mucus-producing cells in the lung and reduced airway hyperresponsiveness without affecting cellular inflammation. In conclusion, we have identified a miRNA that regulates pathological airway mucus production and is amenable to therapeutic manipulation through an inhaled route.
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http://dx.doi.org/10.1172/jci.insight.139019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021117PMC
March 2021

The type 2 asthma mediator IL-13 inhibits SARS-CoV-2 infection of bronchial epithelium.

bioRxiv 2021 Feb 25. Epub 2021 Feb 25.

Rationale: Asthma is associated with chronic changes in the airway epithelium, a key target of SARS-CoV-2. Many epithelial changes are driven by the type 2 cytokine IL-13, but the effects of IL-13 on SARS-CoV-2 infection are unknown.

Objectives: We sought to discover how IL-13 and other cytokines affect expression of genes encoding SARS-CoV-2-associated host proteins in human bronchial epithelial cells (HBECs) and determine whether IL-13 stimulation alters susceptibility to SARS-CoV-2 infection.

Methods: We used bulk and single cell RNA-seq to identify cytokine-induced changes in SARS-CoV-2-associated gene expression in HBECs. We related these to gene expression changes in airway epithelium from individuals with mild-moderate asthma and chronic obstructive pulmonary disease (COPD). We analyzed effects of IL-13 on SARS-CoV-2 infection of HBECs.

Measurements And Main Results: Transcripts encoding 332 of 342 (97%) SARS-CoV-2-associated proteins were detected in HBECs (≥1 RPM in 50% samples). 41 (12%) of these mRNAs were regulated by IL-13 (>1.5-fold change, FDR < 0.05). Many IL-13-regulated SARS-CoV-2-associated genes were also altered in type 2 high asthma and COPD. IL-13 pretreatment reduced viral RNA recovered from SARS-CoV-2 infected cells and decreased dsRNA, a marker of viral replication, to below the limit of detection in our assay. Mucus also inhibited viral infection.

Conclusions: IL-13 markedly reduces susceptibility of HBECs to SARS-CoV-2 infection through mechanisms that likely differ from those activated by type I interferons. Our findings may help explain reports of relatively low prevalence of asthma in patients diagnosed with COVID-19 and could lead to new strategies for reducing SARS-CoV-2 infection.
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http://dx.doi.org/10.1101/2021.02.25.432762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924269PMC
February 2021

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

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

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

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

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

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

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

Global absence and targeting of protective immune states in severe COVID-19.

Nature 2021 03 25;591(7848):124-130. Epub 2021 Jan 25.

Department of Pathology, University of California San Francisco, San Francisco, CA, USA.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs) across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.
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http://dx.doi.org/10.1038/s41586-021-03234-7DOI Listing
March 2021

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

Am J Respir Crit Care Med 2021 04;203(7):841-852

Divisions of Pulmonary and Critical Care and of Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard University, Boston, Massachusetts.

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 undergoing a severe decline in lung function. To evaluate corticosteroid-response phenotypes as longitudinal predictors of lung decline. Adults within the NHLBI SARP III (Severe Asthma Research Program III) who had undergone a course of intramuscular triamcinolone at baseline and at ≥2 annual follow-up visits were evaluated. Longitudinal slopes were calculated for each participant's post-bronchodilator FEV% predicted. Categories of participant FEV slope were defined: severe decline, >2% loss/yr; mild decline, >0.5-2.0% loss/yr; no change, 0.5% loss/yr to <1% gain/yr; and improvement, ≥1% gain/yr. Regression models were used to develop predictors of severe decline. 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 FEV% predicted (derived by baseline subtraction) was related to the 4-year change in lung function or slope category in univariable models ( < 0.001). For each 5% decrement in the triamcinolone-induced difference the FEV1% predicted, there was a 50% increase in the odds of being in the severe decline group (odds ratio, 1.5; 95% confidence interval, 1.3-1.8), when adjusted for baseline FEV, exacerbation history, blood eosinophils and body mass index. Failure to improve the post-bronchodilator FEV after a challenge with parenteral corticosteroids is an evoked biomarker for patients at risk for a severe decline in lung function.
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http://dx.doi.org/10.1164/rccm.202002-0454OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017577PMC
April 2021

Current smoking with or without chronic bronchitis is independently associated with goblet cell hyperplasia in healthy smokers and COPD subjects.

Sci Rep 2020 11 18;10(1):20133. Epub 2020 Nov 18.

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

COPD, chronic bronchitis (CB) and active smoking have all been associated with goblet cell hyperplasia (GCH) in small studies. Active smoking is strongly associated with CB, but there is a disconnect between CB clinical symptoms and pathology. Chronic cough and sputum production poorly correlate with the presence of GCH or COPD. We hypothesized that the primary determinant of GCH in ever smokers with or without airflow obstruction is active smoking. Goblet Cell Density (GCD) was measured in 71 current or former smokers [32 subjects without COPD and 39 COPD subjects]. Endobronchial mucosal biopsies were stained with Periodic Acid Schiff-Alcian Blue, and GCD was measured as number of goblet cells/mm basement membrane. GCD was divided into tertiles based on log transformed values. LogGCD was greater in current smokers compared to former smokers. Those with classically defined CB or SGRQ defined CB had a greater log GCD compared to those without CB. Current smoking was independently associated with tertile 3 (high logGCD) whereas CB was not in multivariable regression when adjusting for lung function and demographics. These results suggest that GCH is induced by active smoke exposure and does not necessarily correlate with the clinical symptoms of CB.
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http://dx.doi.org/10.1038/s41598-020-77229-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674445PMC
November 2020

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

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

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

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

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

bioRxiv 2020 Oct 29. Epub 2020 Oct 29.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a whole-blood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferon-stimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and auto-directed antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.

One Sentence Summary: In severe COVID-19 patients, the immune system fails to generate cells that define mild disease; antibodies in their serum actively prevents the successful production of those cells.
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http://dx.doi.org/10.1101/2020.10.28.359935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605559PMC
October 2020

Global Absence and Targeting of Protective Immune States in Severe COVID-19.

Res Sq 2020 Oct 28. Epub 2020 Oct 28.

Division of Pulmonary and Critical Care Medicine, Department of Medicine and the Cardiovascular Research Institute, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, CA 94143-0511, USA.

While SARS-CoV-2 infection has pleiotropic and systemic effects in some patients, many others experience milder symptoms. We sought a holistic understanding of the severe/mild distinction in COVID-19 pathology, and its origins. We performed a wholeblood preserving single-cell analysis protocol to integrate contributions from all major cell types including neutrophils, monocytes, platelets, lymphocytes and the contents of serum. Patients with mild COVID-19 disease display a coordinated pattern of interferonstimulated gene (ISG) expression across every cell population and these cells are systemically absent in patients with severe disease. Severe COVID-19 patients also paradoxically produce very high anti-SARS-CoV-2 antibody titers and have lower viral load as compared to mild disease. Examination of the serum from severe patients demonstrates that they uniquely produce antibodies with multiple patterns of specificity against interferon-stimulated cells and that those antibodies functionally block the production of the mild disease-associated ISG-expressing cells. Overzealous and autodirected antibody responses pit the immune system against itself in many COVID-19 patients and this defines targets for immunotherapies to allow immune systems to provide viral defense.
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http://dx.doi.org/10.21203/rs.3.rs-97042/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605560PMC
October 2020

A randomized, placebo-controlled trial evaluating effects of lebrikizumab on airway eosinophilic inflammation and remodelling in uncontrolled asthma (CLAVIER).

Clin Exp Allergy 2020 12 4;50(12):1342-1351. Epub 2020 Oct 4.

San Francisco Medical Center, University of California, San Francisco, CA, USA.

Background: The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling.

Objective: To report safety and efficacy results from enrolled participants with available data from CLAVIER.

Methods: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double-blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre-specified primary end-point was relative change in airway subepithelial eosinophils per mm of basement membrane (cells/mm ). Pre-specified secondary and exploratory outcomes included change in IL-13-associated biomarkers and measures of airway remodelling.

Results: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm in response to lebrikizumab (95% CI, -82.5%, 97.5%). As previously observed, FEV increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, -32.9%, -10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies.

Conclusions & Clinical Relevance: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre-specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL-13 in airway pathobiology and suggest that neutralization of IL-13 may reduce asthmatic airway remodelling.

Clinical Trial Registration: NCT02099656.
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http://dx.doi.org/10.1111/cea.13731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756263PMC
December 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
June 2021

Genetic analyses identify GSDMB associated with asthma severity, exacerbations, and antiviral pathways.

J Allergy Clin Immunol 2021 Mar 11;147(3):894-909. Epub 2020 Aug 11.

Division of Genetics, Genomics and Precision Medicine, Department of Medicine, University of Arizona, Tucson, Ariz.

Background: The Chr17q12-21.2 region is the strongest and most consistently associated region with asthma susceptibility. The functional genes or single nucleotide polymorphisms (SNPs) are not obvious due to linkage disequilibrium.

Objectives: We sought to comprehensively investigate whole-genome sequence and RNA sequence from human bronchial epithelial cells to dissect functional genes/SNPs for asthma severity in the Severe Asthma Research Program.

Methods: Expression quantitative trait loci analysis (n = 114), correlation analysis (n = 156) of gene expression and asthma phenotypes, and pathway analysis were performed in bronchial epithelial cells and replicated. Genetic association for asthma severity (426 severe vs 531 nonsevere asthma) and longitudinal asthma exacerbations (n = 273) was performed.

Results: Multiple SNPs in gasdermin B (GSDMB) associated with asthma severity (odds ratio, >1.25) and longitudinal asthma exacerbations (P < .05). Expression quantitative trait loci analyses identified multiple SNPs associated with expression levels of post-GPI attachment to proteins 3, GSDMB, or gasdermin A (3.1 × 10 
Conclusions: By using a unique set of gene expression data from lung cells obtained using bronchoscopy from comprehensively characterized subjects with asthma, we show that SNPs in GSDMB associated with asthma severity, exacerbations, and GSDMB expression levels. Furthermore, its expression levels correlated with asthma exacerbations and antiviral pathways. Thus, GSDMB is a functional gene for both asthma susceptibility and severity.
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http://dx.doi.org/10.1016/j.jaci.2020.07.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876167PMC
March 2021

T-bet Expression in Peripheral Th17.0 Cells Is Associated With Pulmonary Function Changes in Sarcoidosis.

Front Immunol 2020 22;11:1129. Epub 2020 Jul 22.

Division of Pulmonary and Critical Care, University of California, San Francisco, San Francisco, CA, United States.

Interferon-gamma (IFN-γ) is a key mediator of sarcoidosis-related granulomatous inflammation. Previous findings of IFN-γ-producing Th17 cells in bronchoalveolar lavage fluid from sarcoidosis patients invokes the transition of Th17.0 cells to Th17.1 cells in the disease's pathogenesis. Since the T-bet transcription factor is crucial for this transition, the goal of this study was to determine if T-bet expression in Th17.0 cells reflects the extent of granulomatous inflammation in sarcoidosis patients as assessed by clinical outcomes. Using a case-control study design, we identified two groups of sarcoidosis subjects (total = 43) with pulmonary function tests (PFTs) that either (1) changed (increased or decreased) longitudinally or (2) were stable. We used flow cytometry to measure the transcription factors T-bet and RORγt in Th1, Th17.0, and Th17.1 cell subsets defined by CCR6, CCR4 and CXCR3 in blood samples. We compared the percentages of T-bet cells in RORγtTh17.0 cells (defined as CCR6CCR4CXCR3) based on subjects' PFT group. We also assessed the relationship between the direction of change in PFTs with the changes in %T-bet frequencies using mixed effects modeling. We found that T-bet expression in subjects' RORγtTh17.0 cells varied based on clinical outcome. The T-bet percentage of RORγtTh17.0 cells was higher in the cases (subject group with PFT changes) as compared to controls (stable group) (27 vs. 16%, = 0.0040). In comparisons before and after subjects' PFT changes, the T-bet frequency of RORγtTh17.0 cells increased or decreased in the opposite direction of the PFT change. The percentage of these T-bet cells was also higher in those with greater numbers of involved organs. Serum levels of interferon-γ-induced chemokines, CXCL9, CXCL10, and CXCL11, and whole blood gene expression of IFN-γ-related genes including , and were independently positively associated with the T-bet frequencies of RORγtTh17.0 cells. These data suggest that expression of T-bet in Th17.0 cells could reflect the extent of granulomatous inflammation in sarcoidosis patients because they represent a transition state leading to the Th17.1 cell phenotype. These findings indicate that Th17 plasticity may be part of the disease paradigm.
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http://dx.doi.org/10.3389/fimmu.2020.01129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387715PMC
April 2021

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

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

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

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

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

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

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

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

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

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

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

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

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

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