Respiratory Research

RationaleIdentification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need. ObjectiveIdentify prognostic and dynamic plasma protein biomarkers of COPD progression. MethodsWe measured plasma proteins using SomaScan from two COPD-enriched cohorts, the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene), and one population-based cohort, Multi-Ethnic Study of Atherosclerosis (MESA) Lung. Using SPIROMICS as a discovery cohort, linear mixed models identified baseline proteins that predicted future change in FEV1 (prognostic model) and proteins whose expression changed with change in lung function (dynamic model). Findings were replicated in COPDGene and MESA-Lung. Using the COPD-enriched cohorts, Gene Set Enrichment Analysis (GSEA) identified proteins shared between COPDGene and SPIROMICS. Metascape identified significant associated pathways. Measurements and Main ResultsThe prognostic model found 7 significant proteins in common (p < 0.05) among all 3 cohorts. After applying false discovery rate (adjusted p < 0.2), leptin remained significant in all three cohorts and growth hormone receptor remained significant in the two COPD cohorts. Elevated baseline levels of leptin and growth hormone receptor were associated with slower rate of decline in FEV1. Twelve proteins were nominally but not FDR significant in the dynamic model and all were distinct from the prognostic model. Metascape identified several immune related pathways unique to prognostic and dynamic proteins. ConclusionWe identified leptin as the most reproducible COPD progression biomarker. The difference between prognostic and dynamic proteins suggests disease activity signatures may be different from prognosis signatures.

BackgroundCigarette smoking has a significant impact on global health. Although cessation has positive health benefits, some molecular changes to intercellular communications may persist in the lung. In this study we created a framework to generate hypotheses by predicting altered cell-cell communication in smoker lungs using single-cell and spatial transcriptomic data. MethodsWe integrated publicly available lung single-cell transcriptomic data with spatial transcriptomic data from never-smoker and current-smoker lung tissue samples to create spatial transcriptomic data at virtual single-cell resolution by mapping individual cells from our lung scRNA-seq atlas to spots in the spatial transcriptomic data. Cell-cell communications altered in smoking were identified using the virtual single-cell transcriptomic data. ResultsWe identified pathways altered in the three current-smoker samples compared with the three never-smoker samples, including the up-regulated collagen pathway. We observed increased collagen pathway activity involving the ligands COL1A1 and COL1A2 in adventitial fibroblasts and decreased activity involving COL1A2 and COL6A3 in pericytes and myofibroblasts, respectively. We also identified other pathways with structural (e.g. Fibronectin-1), immune-related (e.g. MHC-II), growth factor (e.g. Pleiotrophin) and immunophilin (e.g. Cyclophilin A) roles. ConclusionsIn this study we inferred spatially proximal cell-cell communication between interacting cell types from spatial transcriptomics at virtual single-cell resolution to identify lung intercellular signaling altered in smoking. Our findings further implicate several pathways previously identified, and provide additional molecular context to inform future functional experiments and therapeutic avenues to mitigate pathogenic effects of smoking.

BackgroundChronic obstructive pulmonary disease (COPD) is a complex disorder with a high degree of interindividual variability. Gastrointestinal dysfunction is common in COPD patients and has been proposed to influence the clinical progression of the disease. Using the presence of bile acid(s) (BA) in bronchoalveolar lavage fluid (BAL) as a marker of gastric aspiration, we evaluated the relationships between BAs, clinical outcomes, and bacterial lung colonisation. MethodsWe used BAL specimens from a cohort of COPD patients and healthy controls. Bile acids were profiled and quantified in BAL supernatants using mass spectrometry. Microbial DNA was extracted from BAL cell pellets and quantified using qPCR. We profiled the BAL microbiota using an amplicon sequencing approach targeting the V3-V4 region of the 16S rRNA gene. ResultsDetection of BAs in BAL was more likely at earliest clinical stages of COPD and was independent of the degree of airway obstruction. BAL specimens with BAs demonstrated higher bacterial biomass and lower diversity. Likewise, the odds of recovering bacterial cultures from BAL were higher if BAs were also detected. Detection of BAs in BAL was not associated with either inflammatory markers or clinical outcomes. We also observed different bacterial community types in BAL, which were associated with different clinical groups, levels of inflammatory markers, and the degree of airway obstruction. ConclusionDetection of BAs in BAL was associated with different parameters of airway ecology. Further studies are needed to evaluate whether BAs in BAL can be used to stratify patients and for predicting disease progression trajectories.

RationaleWhile many studies have examined gene expression in lung tissue, the gene regulatory processes underlying emphysema are still not well understood. Finding efficient non-imaging screening methods and disease-modifying therapies has been challenging, but knowledge of the transcriptomic features of emphysema may help in this effort. ObjectivesOur goals were to identify emphysema-associated biological pathways through transcriptomic analysis of bulk lung tissue, to determine the lung cell types in which these emphysema-associated pathways are altered, and to detect unique and overlapping transcriptomic signatures in blood and lung. MethodsUsing RNA-sequencing data from 456 samples in the Lung Tissue Research Consortium and 2,370 blood samples from the COPDGene study, we examined the transcriptomic features of computed tomography quantified emphysema. We also queried lung single-cell RNA-sequencing data to identify cell types showing COPD-associated differential expression of the emphysema pathways found in the bulk analyses. Measurements and Main ResultsIn the lung, 1,055 differentially expressed genes and 29 dysregulated pathways were significantly associated with emphysema. We observed alternative splicing of genes regulating NF-{kappa}B and cell adhesion and increased activity in the TGF-{beta} and FoxO signaling pathways. Multiple lung cell types displayed dysregulation of epithelial barrier function pathways, and an imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages was detected. Lung tissue and blood samples shared 251 differentially expressed genes and two pathways (oxidative phosphorylation and ribosomal function). ConclusionsThis study identified emphysema-related changes in gene expression and alternative splicing, cell-type specific dysregulated pathways, and instances of shared pathway dysregulation between blood and lung. AT A GLANCE COMMENTARYO_ST_ABSScientific Knowledge on the SubjectC_ST_ABSPrior studies have investigated the transcriptomic characteristics of emphysema and its associated biological pathways. However, less is known about alternative splicing mechanisms and cell-type specific transcriptional patterns in emphysema. Additionally, a comparison between dysregulated genes and pathways in blood and lung tissues is needed to better understand the utility of non-invasive diagnostic and prognostic tools for emphysema. What This Study Adds to the FieldUsing lung samples from the Lung Tissue Research Consortium (LTRC) and blood samples from the COPDGene study, we performed differential gene and alternative splicing association analyses for CT-quantified emphysema. We then queried a previously published lung tissue single-cell RNA-sequencing atlas of COPD patients and controls to determine lung cell-type specific expression patterns of the biological pathways identified from the bulk analyses. We demonstrated that multiple pathways, including oxidative phosphorylation and ribosomal function processes, were enriched in both blood and lung tissues. We also observed that in COPD, oxidative phosphorylation was downregulated in pro-inflammatory (M1) macrophages and upregulated in anti-inflammatory (M2) macrophages. Additionally, other immunity-related cell types, including plasma cells, natural killer cells, and T lymphocytes, were linked to epithelial barrier function, such as the Rap1, adherens junction, and TGF-{beta} signaling pathways.

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are phenotypically divergent disorders arising from similar exposures (including cigarette smoke). Differences in DNA methylation may drive the exposed lung towards COPD vs. IPF. To characterize differential methylation in COPD and IPF lung tissue relative to controls, we conducted epigenome-wide association studies of COPD and IPF in lung tissue from the Lung Tissue Research Consortium (N=1029), adjusting for age, sex, smoke exposure, ancestry, estimated cell type composition, and plate. "Switch probes" were defined as CpGs differentially methylated in COPD vs. control and IPF vs. control in opposite directions. Gaussian graphical models were used to mine network properties of switch probes. Differential methylation of genes related to COPD/IPF in the literature was assessed. Switch probe methylation was compared with previously reported gene expression to identify multi-omic switches. We found 13,313 CpGs were associated with COPD and 43,359 with IPF (3,163 overlapping). We identified 1,091 switch CpGs enriched for endocytosis, glycosphingolipid biosynthesis, and pathways in cancer. 24 genes exhibited multi-omic switch behavior, many related to lipid metabolism (ACSL1; FASN; LPCAT1; MED27; NCOR2). LPCAT1 is of particular interest due to its role in maintaining phosphatidylcholine, the majority component of surfactant. Further related to surfactant, we observed strong divergent methylation and expression of ATP11A, which facilitates endocytosis of surfactant lipids. CONCLUSIONS Our findings suggest multi-omic switch-like regulation may underlie differential COPD/IPF etiology. Future investigation of LPCAT1 and ATP11A could provide new mechanistic understanding and therapeutic avenues.

Epigenetic dysregulation, particularly DNA methylation variations, is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Ten-eleven translocation (TET) proteins (TET1, TET2, and TET3) regulate DNA methylation and gene transcription. Impaired TET1 expression was previously associated with airway inflammation and asthma. Here we investigated TET gene associations with COPD severity. We found that reduced TET1 expression in peripheral blood mononuclear cells was associated with higher sputum and blood neutrophil counts, decreased lung function and increased disease severity in patients. These findings support a potential protective role and warrant further mechanistic investigations into the actions of TET1 in COPD.

RationaleChronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are debilitating diseases associated with divergent histopathological changes in the lungs. At present, due to cost and technical limitations, profiling cell types is not practical in large epidemiology cohorts (n>1000). Here, we used computational deconvolution to identify cell types in COPD and IPF lungs whose abundances and cell type-specific gene expression are associated with disease diagnosis and severity. MethodsWe analyzed lung tissue RNA-seq data from 1026 subjects (COPD, n=465; IPF, n=213; control, n=348) from the Lung Tissue Research Consortium. We performed RNA-seq deconvolution, querying thirty-eight discrete cell-type varieties in the lungs. We tested whether deconvoluted cell-type abundance and cell type-specific gene expression were associated with disease severity. ResultsThe abundance score of twenty cell types significantly differed between IPF and control lungs. In IPF subjects, eleven and nine cell types were significantly associated with forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO), respectively. Aberrant basaloid cells, a rare cells found in fibrotic lungs, were associated with worse FVC and DLCO in IPF subjects, indicating that this aberrant epithelial population increased with disease severity. Alveolar type 1 and vascular endothelial (VE) capillary A were decreased in COPD lungs compared to controls. An increase in macrophages and classical monocytes was associated with lower DLCO in IPF and COPD subjects. In both diseases, lower non-classical monocytes and VE capillary A cells were associated with increased disease severity. Alveolar type 2 cells and alveolar macrophages had the highest number of genes with cell type-specific differential expression by disease severity in COPD and IPF. In IPF, genes implicated in the pathogenesis of IPF, such as matrix metallopeptidase 7, growth differentiation factor 15, and eph receptor B2, were associated with disease severity in a cell type-specific manner. ConclusionUtilization of RNA-seq deconvolution enabled us to pinpoint cell types present in the lungs that are associated with the severity of COPD and IPF. This knowledge offers valuable insight into the alterations within tissues in more advanced illness, ultimately providing a better understanding of the underlying pathological processes that drive disease progression.

BackgroundChronic obstructive pulmonary disease (COPD) is the third leading cause of global mortality. Emerging evidence suggests the oral microbiome may contribute to COPD progression, though causal relationships remain elusive. MethodsUsing bidirectional Mendelian randomization (MR) on East Asian genome-wide association study (GWAS) summary data, we assessed causal links between oral microbial taxa and COPD risk. Subsequently, hub genes in COPD bulk RNA sequencing data were identified by integrating the Protein-Protein Interaction (PPI) network with machine learning, followed by target validation using single-cell RNA sequencing, immune infiltration analysis, and molecular docking. ResultsForward MR identified 43 taxa associated with COPD, primarily from genera such as Fusobacterium, Prevotella, and Streptococcus. Reverse MR detected 73 taxa affected by COPD, mainly involving Campylobacter_A, Rothia, and Streptococcus. Through the PPI network, machine learning screening, and multi-omics analysis validation, MPDZ emerged as a key hub gene, upregulated in Ciliated and Endothelial cells during early stages of COPD and linked to immune dysregulation. Molecular docking revealed six candidate drugs with strong binding affinity to MPDZ. ConclusionOur study provides insights for the development of personalized treatment strategies for COPD and offers preliminary candidate targets and drugs for future drug development.

BackgroundBronchiectasis is an increasingly recognized structural complication among patients with chronic obstructive pulmonary disease (COPD), yet evidence from Bangladesh remains limited. This study aimed to determine the prevalence, clinical characteristics, radiological patterns, and associated factors of bronchiectasis among COPD patients in tertiary-level hospitals. MethodsA cross-sectional study was conducted among 129 COPD patients regardless of age distribution, all are met GOLD criteria and underwent high-resolution computed tomography (HRCT). Data on sociodemographic, behavioral, clinical, radiological, laboratory, and quality-of-life characteristics were analyzed using descriptive statistics, chi-square tests, t-tests, correlation analyses, and binary logistic regression. ResultsBronchiectasis was detected in 73.6% of COPD patients, with cylindrical bronchiectasis being the most common subtype (48.4%). Patients with bronchiectasis had a significantly longer duration of COPD (7.58 {+/-} 3.36 years vs. 2.51 {+/-} 1.67 years; p < 0.001) and more frequent symptoms, including chronic cough (72.1%), purulent sputum (34.9%), and higher dyspnea grades. Mucus plugging showed a perfect association with bronchiectasis (p = 0.001). Significant predictors of bronchiectasis included rural residence (AOR 5.82; 95% CI 1.34-25.29) and smoking habit (AOR 3.69; 95% CI 1.01-13.49). A weak but significant negative correlation was found between serum albumin and CRP (r = -0.211; p = 0.016), indicating systemic inflammation, while smoking duration was negatively correlated with FEV{square} (r = -0.174; p = 0.048). Quality of life was markedly impaired, with over 70% reporting poor or fair status. ConclusionBronchiectasis is highly prevalent among COPD patients in Bangladesh and is associated with longer disease duration, greater symptom burden, functional impairment, structural lung abnormalities, and poor quality of life. Rural residence, smoking, and mucus plugging emerged as key determinants. Early HRCT-based screening, phenotype-specific management, reduction of biomass and tobacco exposure, and improved rural respiratory care are essential to mitigate disease progression and improve outcomes.

Interstitial lung disease (ILD) encompasses multiple pulmonary disorders characterized by damaged pulmonary tissue caused by a sequence of inflammation and fibrosis. While much is known about ILD-associated changes within the parenchyma and the pathophysiological processes underpinning the disruption of pulmonary dynamics and gas exchange, less is known about ILD-associated changes of luminal area within the large conducting airways. We aimed to investigate whether luminal area of the large conducting airways is different between patients with ILD and healthy controls. In a retrospective case-control study, luminal areas of seven large conducting airways were measured using three-dimensional reconstructions of computed tomography imaging. Patients with ILD (N=82; 54% female) were compared to control subjects matched for age, sex, and height. Univariate ANOVA tests or Kruskal-Wallis tests were used to analyze group and sex differences. Patients with ILD had greater large conducting airway luminal areas than control subjects for measured large conducting airways, including the trachea (296{+/-}73 vs. 247{+/-}65 mm2, P<0.001), right main bronchus (214{+/-}59 vs. 161{+/-}46 mm2, P<0.001), bronchus intermediate (123{+/-}32 vs. 94{+/-}28 mm2, P<0.001), right upper lobe (81{+/-}22 vs. 61{+/-}20 mm2, P<0.001), left main bronchus (151{+/-}41 vs. 119{+/-}35 mm2, P<0.001), left lower lobe (71{+/-}22 vs. 48{+/-}15 mm2, P<0.001), and left upper lobe (86{+/-}21 vs. 68{+/-}22 mm2, P<0.001). Among patients with ILD, males had 17-34% greater luminal areas (normalized to height) than females depending on the airway segment (all P<0.05). NEW & NOTEWORTHYThis study provides evidence that interstitial lung disease (ILD) is associated with greater large conducting airway luminal area, even if matched for key characteristics (age, sex, and height). Consistent with observations in health, adult males with ILD had greater height-normalized large conducting luminal areas than adult females with ILD.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with varying degrees of airway wall thickening, chronic bronchitis, and emphysema. A better understanding of the underlying pathology is needed to improve the personalized treatment of the disease and identify new therapeutic targets. Available data from 56 COPD patients included in the GLUCOLD study were used (61.1{+/-}7.7 years, 89% male, and FEV1 of 62.5{+/-}8.9% predicted). Clinical characterization was performed including bronchoscopy and collection of bronchial biopsies at baseline. RNA from bronchial biopsies was sequenced and used for unsupervised clustering, using a 98 COPD gene signature previously identified in bronchial brushes comparing patients with COPD to non-COPD controls. Next, we assessed differences in the clinical expression of COPD, lung function decline, inflammatory cell counts, and gene expression between clusters. Validation was performed in an independent dataset. We identified two clusters: CAGE1 (n=39) and CAGE2 (n=17). CAGE2 patients had higher percentage of sputum lymphocytes, and more CD4+ and CD8+ T-cell counts in their bronchial biopsies. In addition, their FEV1 improved less in response to 30-months treatment with inhaled corticosteroids (ICS) (change in FEV1- CAGE1: +24.4mL; CAGE2: -29.1mL; p-value=0.048), and they experienced a faster decline in their lung function follow-up (CAGE1: -44.0mL/year; CAGE2: -69.9mL/year; p-value=0.002). Gene expression analysis showed more activation of T- and B-cell immune responses in CAGE2. We identified a new COPD endotype, CAGE2, characterized by ICS unresponsiveness and faster lung function decline. Additionally, we show a different pathobiology in CAGE2 with more activation of T- and B-cell immune responses.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia of unknown etiology often leading to respiratory failure. Over half of IPF patients present with discordant features of usual interstitial pneumonia on high-resolution computed tomography at diagnosis which warrants surgical lung biopsy to exclude the possibility of other interstitial lung diseases (ILDs). Therefore, there is a need for non-invasive biomarkers for expediting the differential diagnosis of IPF. MethodsUsing mass spectrometry, we performed proteomic analysis of plasma extracellular vesicles (EVs) in a cohort of subjects with IPF, chronic hypersensitivity pneumonitis, nonspecific interstitial pneumonitis, and healthy subjects (HS). A five-protein signature was identified by lasso regression and was validated in an independent cohort using ELISA. We evaluated the concordance between plasma EV proteome and the lung transcriptome data. Lastly, we compared the molecular pathways overrepresented in IPF by differentially expressed proteins and transcripts from EVs and lung tissues, respectively. ResultsThe five-protein signature derived from mass spectrometry data showed area under the receiver operating characteristic curve of 0.915 (95%CI: 0.819-1.011) and 0.958 (95%CI: 0.882-1.034) for differentiating IPF from other ILDs and from HS, respectively. We also found that the EV protein expression profiles mirrored their corresponding mRNA expressions in IPF lungs. Further, we observed an overlap in the EV proteome- and lung mRNA-associated molecular pathways. ConclusionsWe discovered a plasma EV-based protein signature for differential diagnosis of IPF and validated this signature in an independent cohort. The signature needs to be tested in large prospective cohorts to establish its clinical utility.

IntroductionEicosanoids are bioactive lipids with roles in airway remodeling, smooth muscle hypertrophy, emphysema and pulmonary fibrosis via inflammatory pathways. Specific eicosanoids have been associated with diseases like asthma and pulmonary fibrosis, yet their broader associations with lung function remain unclear. We investigated associations of eicosanoids and related metabolites with early changes in lung function and structure. MethodsWe comprehensively profiled >250 eicosanoids and eicosanoid-related metabolites using directed non-targeted mass spectrometry in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study with independent validation in the Framingham Heart Study (FHS). We performed cross-sectional analysis of associations between metabolites and lung function as assessed by spirometry and quantitative computed tomography (CT) measures. ResultsAmong 3384 MESA Lung participants (mean age 63{+/-}10 years, 51% women), 51 metabolites were associated with lung function (22 with % predicted FEV1, 18 with % predicted FVC, and 25 with FEV1/FVC), with 24 validated in FHS. Of these, 27 were associated with obstructive physiology, including linoleic acid derivatives (9-HODE) and other long-chain fatty acids (LCFAs, hydroxyhexadecanoic and hydroxyoctadecanoic acids) associated with higher odds. Fourteen metabolites were associated with restrictive physiology, including LTB3 and its analog associated with lower odds, and omega-3 fatty acids (EPA, stearidonic acid) associated with higher odds. ConclusionsSpecific eicosanoids and eicosanoid-related metabolites including linoleic acid derivatives and LCFAs were associated with obstructive, and leukotrienes and omega-3 fatty acids with restrictive physiology. These findings highlight bioactive lipids involved in pro- and anti-inflammatory pathways as potential influencers of lung function and may be future therapeutic targets. Take Home MessageWe identified eicosanoid metabolites associated with pulmonary function testing measurements and several that are associated with altered odds of obstructive and restrictive lung physiologies in a cohort MESA participants, with validation in FHS.

RationalePulmonary innate immune cells play a central role in the initiation and perpetuation of chronic obstructive pulmonary disease (COPD), however the precise mechanisms that orchestrate the development and severity of COPD are poorly understood. ObjectivesWe hypothesized that the recently described family of innate lymphoid cells (ILCs) play an important role in COPD. MethodsSubjects with COPD and healthy controls were clinically evaluated, and their sputum samples were assessed by flow cytometry. A mouse model of spontaneous COPD [genetically deficient in surfactant protein-D (SP-D-/-)] and ozone (O3) exposure were used to examine the mechanism by which lack of functional SP-D may skew ILC2s to produce IL-17A in combination with IL-5 and IL-13, leading to a mixed inflammatory profile and more severe disease. Measurements and Main ResultsCOPD was characterized by poor spirometry, sputum inflammation, and the emergence of sputum GATA3+ ILCs (ILC2s), but not T-bet+ ILCs (ILC1s) nor ROR{gamma}t+ ILCs (ILC3s). COPD subjects with elevated sputum ILC2s (the ILC2high group) had worse spirometry and sputum neutrophilia and eosinophilia than healthy and ILC2low subjects. This was associated with the presence of dual-positive IL-5+IL-17A+ and IL-13+IL-17A+ ILCs and nonfunctional SP-D in the sputum in ILC2high subjects. SP-D-/- mice showed spontaneous airway neutrophilia. Lack of SP-D in the mouse lung licensed ILC2s to produce IL-17A, which was dose-dependently inhibited by recombinant SP-D. SP-D-/- mice showed enhanced susceptibility to O3-induced airway neutrophilia, which was associated with the emergence of inflammatory IL-13+IL-17A+ ILCs. ConclusionsWe report that the presence of sputum ILC2s predicts the severity of COPD, and unravel a novel pathway of IL-17A plasticity in lung ILC2s, prevented by the immunomodulatory protein SP-D.

Background: Our group previously reported that lung cancer (LC) screening history results and subsequent timing of diagnosis are associated with significant differences in survival outcomes. As a follow-up study, we sought to develop novel personalized risk models that considered screening history for incidence cancers, interval LCs, and prevalence LCs. Methods: Using data from the CT-arm of the NLST, four independent case-control analyses were conducted to develop parsimonious risk models. Controls (n=26,038) were those never diagnosed with LC. The four LC case groups were 270 prevalence LCs, 44 interval LCs, 206 screen-detected LCs (SDLCs) that had a baseline positive screen, and 164 SDLCs that had a baseline negative screen. For each case-control analysis, univariable analyses identified statistically significant covariates from 48 variables and then significant covariates were included into a stepwise backward selection approach to identify a model with the most informative covariates. Results: For prevalence LCs, the model (AUC=0.711) included age, pack-years smoked, BMI, smoking status, smoking onset age, personal history of cancer, family history of LC, alcohol consumption, and milling occupation. For interval LCs, the model (AUC=0.734) included age, smoking status, smoking onset age, cigar smoking, marital status, and asbestos occupation. For baseline positive SDLCs, the model (AUC=0.685) included age, pack-years smoked, BMI, emphysema, chemicals/plastics exposure, and milling occupation. For baseline negative SDLCs, the model (AUC=0.701) included age, pack-years smoked, BMI, smoking status, emphysema, sarcoidosis, and sandblasting occupation. Conclusions: Besides smoking and age, which are inclusion criteria for screening, these models identified other important risk factors which could be used to provide personalized LC risk assessment and screening management.

RationaleIndividuals homozygous for the Alpha-1 Antitrypsin (AAT) Z allele (Pi*ZZ) exhibit heterogeneity in COPD risk. COPD occurrence in non-smokers with AAT deficiency (AATD) suggests inflammatory processes may contribute to COPD risk independently of smoking. We hypothesized that inflammatory protein biomarkers in non-AATD COPD are associated with moderate-to-severe COPD in AATD individuals, after accounting for clinical factors. MethodsParticipants from the COPDGene (Pi*MM) and AAT Genetic Modifier Study (Pi*ZZ) were included. Proteins associated with FEV1/FVC were identified, adjusting for confounders and familial relatedness. Lung-specific protein-protein interaction (PPI) networks were constructed. Proteins associated with AAT augmentation therapy were identified, and drug repurposing analyses performed. A protein risk score (protRS) was developed in COPDGene and validated in AAT GMS using AUC analysis. Machine learning ranked proteomic predictors, adjusting for age, sex, and smoking history. ResultsAmong 4,446 Pi*MM and 352 Pi*ZZ individuals, sixteen blood proteins were associated with airflow obstruction, fourteen of which were highly expressed in lung. PPI networks implicated regulation of immune system function, cytokine and interleukin signaling, and matrix metalloproteinases. Eleven proteins, including IL4R, were linked to augmentation therapy. Drug repurposing identified antibiotics, thyroid medications, hormone therapies, and antihistamines as potential AATD treatments. Adding protRS improved COPD prediction in AAT GMS (AUC 0.86 vs. 0.80, p = 0.0001). AGER was the top-ranked protein predictor of COPD. ConclusionsSixteen proteins are associated with COPD and inflammatory processes that predict airflow obstruction in AATD after accounting for age and smoking. Immune activation and inflammation are modulators of COPD risk in AATD.

BackgroundFractional exhaled nitric oxide (FeNO) is used to differentiate asthma inflammatory phenotypes and guide its management. However, data on FeNO reference values in a representative adult population is limited. ObjectiveTo derive reference values and determinants of FeNO in a representative adult population. MethodsThe West Sweden Asthma Study is a clinical-epidemiological population- representative study of randomly selected adults in Western Sweden. From this cohort, 943 subjects participated in comprehensive clinical investigations, including skin prick testing (SPT), specific immunoglobulin E (sIgE) analysis, and FeNO measurement. Clinical allergy was defined as co-occurrence of atopy (positivity to SPT or sIgE) and self-reported allergic symptoms to the same allergen family. FeNO levels were analysed in relation to the presence or absence of clinical allergy, asthma, and other factors. ResultsThe 95th percentile of FeNO ranged from 34 to 52 parts per billion (ppb) in the entire sample (N=943), and from 26 to 37 ppb among individuals without clinical allergy, asthma, or chronic obstructive pulmonary disease (COPD) (n=587), depending on age. Sex, smoking, clinical allergy, atopy, asthma, and hypertension influenced FeNO levels, meanwhile, age, asthma, clinical allergy, and reversibility- related variables were significant determinants of FeNO levels. ConclusionThe 95th percentile (upper normal limit) for FeNO ranges from 34 to 52 ppb overall, and from 26 to 37 ppb in those without clinical allergy, asthma, or COPD, depending on age. These findings provide a guide for interpreting FeNO in the general population and in asthma and COPD clinics.

BackgroundChronic obstructive pulmonary disease (COPD) exhibits marked heterogeneity in lung function decline, mortality, exacerbations, and other disease-related outcomes. Omic risk scores (ORS) estimate the cumulative contribution of omics, such as the transcriptome, proteome, and metabolome, to a particular trait. This study evaluates the predictive value of ORS for COPD-related traits in both smoking-enriched and general population cohorts. MethodsORS were developed and tested in 3,339 participants of Genetic Epidemiology of COPD (COPDGene) with blood RNA-sequencing, proteomic, and metabolomic. Single- and multi-omic risk scores were trained 24 cross-sectional and five longitudinal traits using 80% of the data, focusing on disease severity, exacerbations, and traits from spirometry and computed tomography scans. Multivariable models were used to test ORS associations with outcomes in remaining COPDGene participants and externally validated in SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS) (n = 2,177) and Multi-Ethnic Study of Atherosclerosis (MESA) (n = 1,000). ResultsIn the COPDGene testing set, 69 of 72 single-omic ORS showed significant associations with 24 cross-sectional traits (adjusted p-value < 0{middle dot}05). One of 15 longitudinal ORS was associated with changes in trait values between COPDGene visits. Significant associations were observed for all 38 cross-sectional ORS tested in SPIROMICS and for 16 of 24 in MESA. Proteomic and metabolomic risk scores generally displayed stronger associations than transcriptomic scores. DiscussionBlood-based ORS can predict cross-sectional and future COPD-related traits in both smoking-enriched and general population cohorts.

BackgroundTo examine the prevalence and characteristics of PRISm among Chinese individuals, as well as its association with future mortality and cardiovascular (CVD) outcomes. MethodsThis was a substudy of the Prospective Urban Rural Epidemiology (PURE) study, which recruited 40,279 individuals aged 35-70 years from 115 urban and rural communities in 12 provinces across China between 2005 and 2009. At baseline, participants were categorized into subgroups based on PRISm, airflow obstruction (AO), and normal spirometry. Follow-up was conducted every three years to obtain information on major cardiovascular events and mortality. Cox frailty proportional hazard regression was used to estimate the hazard ratios (HR) and 95% confidence interval (95%CI). ResultsThe baseline prevalence rates of PRISm, AO and normal spirometry were 29.3%, 8.5%, and 62.2% respectively. Over a median follow-up period of 11.9 years, 2,214 deaths, with 773 attributed to CVD, and 3,507 major CVD events were observed. After adjusting for potential confounders, individuals with PRISm, comparing to those with normal spirometry, exhibited significantly elevated risks of all-cause mortality (HR 1.42, 95%CI [1.29, 1.58]), CVD mortality (HR 1.35, 95%CI [1.14, 1.60]), major CVD events (HR 1.16, 95%CI [1.07, 1.25]), myocardial infarction (HR 1.34, 95%CI [1.15,1.56]), and heart failure (HR 2.02, 95%CI [1.46, 2.79]). ConclusionsPRISm, a frequently observed result in spirometry among the general Chinese population, exhibits a substantial association with long-term all-cause mortality, CVD mortality, major CVD events. Further investigation is warranted to comprehensively compared the underlying pathophysiologic connection between PRISm and CVD as well as mortality. What is already known on this topicPRISm is considered a transient state with higher transition rates to both normal and obstructive spirometry, often indicating progression to COPD, which is associated with increased respiratory symptoms, diminished quality of life, and a higher risk of cardiovascular events and all-cause mortality. Given the limited understanding of PRISm, there are several studies on the association between PRISm and health outcomes have been carried out in different populations since the concept of PRISm was introduced in 2014. Longitudinal studies based on population cohorts such as COPDGene, UK Biobank, Rotterdam, and NHLBI have shown that PRISm is associated with an increased risk of all-cause mortality and adverse cardiovascular outcomes, with similar results found in a study based on a Japanese population. Lung function differs substantially between races and regions. Most of the existing PRISm-related studies are based on populations in developed countries such as Europe and the United States, and the conclusions of these studies should not be directly generalized to East Asian populations, including China. Currently, there is only two studies based on a Japanese and Korean aimed at exploring the relationship between PRISm and all-cause mortality and adverse cardiovascular outcomes, but the sample size of these study is relatively small, and the statistical power of the conclusions is relatively limited. What this study addsThis is the first longitudinal study examining the association of PRISm with the risk for all-cause mortality and adverse cardiovascular outcomes in a general Chinese population. The results showed that the prevalence of PRISm in the general Chinese population is 29.3%, which is significantly higher than previous studies. Compared to individuals with normal spirometry, the population with baseline PRISm had a significantly increased risk of all-cause mortality, CVD mortality, myocardial infarction (MI), and heart failure (HF), and showed a trend towards higher risk than those with baseline airflow obstruction (AO, although no statistically significant difference was observed). How this study might affect research, practice or policyOur findings support that the early prevention, diagnosis, and intervention of PRISm may offer an important strategy to alleviating the high CVD burden in China.

BackgroundWhile low body mass index (BMI) is associated with emphysema and obesity is associated with airway disease in chronic obstructive pulmonary disease (COPD), the underlying mechanisms are unclear. MethodsWe aggregated genetic variants from population-based genome-wide association studies to generate a polygenic score of BMI (PGSBMI). We calculated this score for participants from COPD-enriched and community-based cohorts and examined associations with automated quantification and visual interpretation of computed tomographic emphysema and airway wall thickness (AWT). We summarized the results using meta-analysis. ResultsIn the random-effects meta-analyses combining results of all cohorts (n=16,349), a standard deviation increase of the PGSBMI was associated with less emphysema as quantified by log-transformed percent of low attenuation areas [&le;] 950 Hounsfield units ({beta}= -0.062, p<0.0001) and 15th percentile value of lung density histogram ({beta}=2.27, p<0.0001), and increased AWT as quantified by the square root of wall area of a 10-mm lumen perimeter airway ({beta}=0.016, p=0.0006) and mean segmental bronchial wall area percent ({beta}=0.26, p=0.0013). For imaging characteristics assessed by visual interpretation, a higher PGSBMI was associated with reduced emphysema in both COPD-enriched cohorts (OR for a higher severity grade=0.89, p=0.0080) and in the community-based Framingham Heart Study (OR for the presence of emphysema=0.82, p=0.0034), and a higher risk of airway wall thickening in the COPDGene study (OR=1.17, p=0.0023). ConclusionsIn individuals with and without COPD, a higher body mass index polygenic risk is associated with both quantitative and visual decreased emphysema and increased AWT, suggesting genetic determinants of BMI affect both emphysema and airway wall thickening.