AERIFY-1/2: two phase 3, randomised, controlled trials of itepekimab in former smokers with moderate-to-severe COPD.

Background: Accumulating data implicate interleukin (IL)-33, a proinflammatory cytokine released locally upon epithelial cell damage, in the pathogenesis of COPD. In a phase 2 study, itepekimab, a human monoclonal antibody against IL-33, reduced exacerbations and improved lung function in a subgroup analysis of former smokers with COPD with an acceptable safety profile. Methods: The study designs of AERIFY-1 and AERIFY-2 are described in this article. Discussion: The primary objective of AERIFY-1/2 (NCT04701983/NCT04751487), two phase 3 randomised, double-blind, placebo-controlled trials, is to assess the efficacy and safety of itepekimab versus placebo in a population of former smokers with moderate-to-severe COPD over up to 52 weeks. An additional secondary population of current smokers are being enrolled in AERIFY-2. These two studies will enrol patients (aged 40-85 years) with COPD and chronic bronchitis who had ≥2 moderate or ≥ 1 severe exacerbations within the previous year despite standard-of-care triple or double background therapy. All participants are required to have ≥10-pack-year smoking history, and ≥6 months since smoking cessation for former smokers. The primary end-point is the annualised rate of moderate or severe acute exacerbation of COPD. Secondary end-points include change from baseline in pre- and post-bronchodilator forced expiratory volume in 1 s, and annualised frequency of severe exacerbations. Symptomatic end-points include Evaluating Respiratory Symptoms in COPD and St. George's Respiratory Questionnaire, safety and anti-drug antibody responses.

Deep Learning Estimation of Small Airways Disease from Inspiratory Chest CT is Associated with FEV1 Decline in COPD.

Rationale: Quantifying functional small airways disease (fSAD) requires additional expiratory computed tomography (CT) scan, limiting clinical applicability. Artificial intelligence (AI) could enable fSAD quantification from chest CT scan at total lung capacity (TLC) alone (fSADTLC). Objectives: To evaluate an AI model for estimating fSADTLC and study its clinical associations in chronic obstructive pulmonary disease (COPD). Methods: We analyzed 2513 participants from the SubPopulations and InteRmediate Outcome Measures in COPD Study (SPIROMICS). Using a subset (n = 1055), we developed a generative model to produce virtual expiratory CTs for estimating fSADTLC in the remaining 1458 SPIROMICS participants. We compared fSADTLC with dual volume, parametric response mapping fSADPRM. We investigated univariate and multivariable associations of fSADTLC with FEV1, FEV1/FVC, six-minute walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and FEV1 decline. The results were validated in a subset (n = 458) from COPDGene study. Multivariable models were adjusted for age, race, sex, BMI, baseline FEV1, smoking pack years, smoking status, and percent emphysema. Measurements and Main Results: Inspiratory fSADTLC was highly correlated with fSADPRM in SPIROMICS (Pearson's R = 0.895) and COPDGene (R = 0.897) cohorts. In SPIROMICS, fSADTLC was associated with FEV1 (L) (adj.ß = -0.034, P < 0.001), FEV1/FVC (adj.ß = -0.008, P < 0.001), SGRQ (adj.ß = 0.243, P < 0.001), and FEV1 decline (mL / year) (adj.ß = -1.156, P < 0.001). fSADTLC was also associated with FEV1 (L) (adj.ß = -0.032, P < 0.001), FEV1/FVC (adj.ß = -0.007, P < 0.001), SGRQ (adj.ß = 0.190, P = 0.02), and FEV1 decline (mL / year) (adj.ß = -0.866, P = 0.001) in COPDGene. We found fSADTLC to be more repeatable than fSADPRM with intraclass correlation of 0.99 (95% CI: 0.98, 0.99) vs. 0.83 (95% CI: 0.76, 0.88). Conclusions: Inspiratory fSADTLC captures small airways disease as reliably as fSADPRM and is associated with FEV1 decline.

Temporal Exploration of COPD Phenotypes: Insights from the COPDGene and SPIROMICS Cohorts.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) exhibits considerable progression heterogeneity. We hypothesized that elastic principal graph analysis (EPGA) would identify distinct clinical phenotypes and their longitudinal relationships. METHODS: Cross-sectional data from 8,972 tobacco-exposed COPDGene participants, with and without COPD, were used to train a model with EPGA, using thirty clinical, physiologic and CT features. Principal component analysis (PCA) was used to reduce data dimensionality to six principal components. An elastic principal tree was fitted to the reduced space. 4,585 participants from COPDGene Phase 2 were used to test longitudinal trajectories. 2,652 participants from SPIROMICS tested external reproducibility. RESULTS: Our analysis used cross-sectional data to create an elastic principal tree, where the concept of time is represented by distance on the tree. Six clinically distinct tree segments were identified that differed by lung function, symptoms, and CT features: 1) Subclinical (SC); 2) Parenchymal Abnormality (PA); 3) Chronic Bronchitis (CB); 4) Emphysema Male (EM); 5) Emphysema Female (EF); and 6) Severe Airways (SA) disease. Cross-sectional SPIROMICS data confirmed similar groupings. 5-year data from COPDGene mapped longitudinal changes onto the tree. 29% of patients changed segment during follow-up; longitudinal trajectories confirmed a net flow of patients along the tree, from SC towards Emphysema, although alternative trajectories were noted, through airway disease predominant phenotypes, CB and SA. CONCLUSION: This novel analytic methodology provides an approach to defining longitudinal phenotypic trajectories using cross sectional data. These insights are clinically relevant and could facilitate precision therapy and future trials to modify disease progression.

Development and initial validation of a disease-specific instrument to measure health-related quality of life in hypersensitivity pneumonitis.

Rationale and objective: Disease-specific health-related quality of life (HRQOL) instruments enable us to capture domains that are most relevant to specific patient populations and are useful when a more individualised approach to patient assessment is desired. In this study, we assessed the validity and reliability of the first instrument specifically developed to measure HRQOL in hypersensitivity pneumonitis (HP). Methods: A 39-item HP-HRQOL instrument and several anchors were collected from a cohort of patients with HP. Exploratory factor analysis and item reduction were utilised to construct a shortened version of the instrument. Several validity and reliability analyses were conducted on this version of the HP-HRQOL. Measurements and main results: 59 patients with HP completed the study. The revised HP-HRQOL instrument comprises 15 items composing two factors (domains): 1) impacts on daily life; and 2) mental wellbeing. Internal consistency reliability was strong for Factor 1 (Cronbach's α=0.94, 95% CI 0.92-0.96) and Factor 2 (Cronbach's α=0.89, 95% CI 0.85-0.94). Test-retest reliability was strong (ICC 0.94, 95% CI 0.89-0.97). The HP-HRQOL strongly correlated with other validated patient-reported outcome measures and moderately correlated with % predicted forced vital capacity. The HP-HRQOL distinguished between those with different severities of HP as determined by lung function and supplemental oxygen use. Conclusions: The HP-HRQOL, the first patient-reported outcome instrument specific to adults with HP, possesses strong validity and reliability characteristics for measuring disease-specific HRQOL and distinguishes among patients with different severities of disease.

Multimorbidities in COPD are Associated With Increased Exacerbations and Health Care Resource Utilization in Real-World Patients from a U.S. Database.

Background: Patients with chronic obstructive pulmonary disease (COPD) often develop other morbidities, suggesting a systemic component to this disease. This retrospective noninterventional cohort study investigated relationships between multimorbidities in COPD and their impact on COPD exacerbations and COPD-related health care resource utilization (HCRU) using real-world evidence from Optum's de-identified Clinformatics® Data Mart Database. Methods: Demographic and clinical characteristics were assessed. Overall comorbidity burden and proportion of individuals with gastroesophageal reflux disease (GERD), diabetes, or osteoporosis/osteopenia were compared in age-matched COPD versus non-COPD cohorts using descriptive statistics. COPD exacerbations and COPD-related HCRU (hospitalizations and emergency department visits) were compared between age-matched cohorts of COPD patients with and without specific common morbidities (GERD, diabetes, and osteoporosis/osteopenia). Additional weight-matching was performed for matched cohorts of COPD patients with and without diabetes, and with and without osteoporosis/osteopenia. The follow-up period was 5 years. Results: Age-matched cohorts with and without COPD each comprised 158,106 patients. Morbidities were more common in the COPD cohort than the cohort without COPD (GERD: 44.9% versus 27.8%; diabetes: 40.8% versus 31.1%; osteoporosis/osteopenia: 18.8% versus 14.1%, respectively). Compared with matched cohorts with COPD only, cohorts of COPD patients with either GERD, diabetes, or osteoporosis/osteopenia experienced increased risk of severe exacerbations (odds ratio [OR]=1.819, OR=1.119, and OR=1.373, respectively), moderate exacerbations (OR=1.699, OR=1.102, and OR=1.322, respectively), or any exacerbations (OR=1.848, OR=1.099, and OR=1.384, respectively, p<0.001 for all comparisons) and increased risk of COPD-related HCRU (emergency department visits: OR=1.983, OR=1.098, and OR=1.343, respectively; hospitalization visits: OR=2.222, OR=1.26, and OR=1.368, respectively; p<0.001 for all comparisons). Conclusion: These real-world data confirm that GERD, diabetes, and osteoporosis are common morbidities in patients with COPD and, moreover, that they affect frequency of exacerbation and HCRU. Determining and addressing the mechanisms behind the systemic effects of COPD may be beneficial for COPD patients and may also help reduce COPD exacerbations.

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

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

Dynamic and prognostic proteomic associations with FEV1 decline in chronic obstructive pulmonary disease.

Rationale: Identification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need. Objective: Identify prognostic and dynamic plasma protein biomarkers of COPD progression. Methods: We 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 Results: The 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. Conclusion: We 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.

RIOK2 transcriptionally regulates TRiC and dyskerin complexes to prevent telomere shortening.

Telomere shortening is a prominent hallmark of aging and is emerging as a characteristic feature of Myelodysplastic Syndromes (MDS) and Idiopathic Pulmonary Fibrosis (IPF). Optimal telomerase activity prevents progressive shortening of telomeres that triggers DNA damage responses. However, the upstream regulation of telomerase holoenzyme components remains poorly defined. Here, we identify RIOK2, a master regulator of human blood cell development, as a critical transcription factor for telomere maintenance. Mechanistically, loss of RIOK2 or its DNA-binding/transactivation properties downregulates mRNA expression of both TRiC and dyskerin complex subunits that impairs telomerase activity, thereby causing telomere shortening. We further show that RIOK2 expression is diminished in aged individuals and IPF patients, and it strongly correlates with shortened telomeres in MDS patient-derived bone marrow cells. Importantly, ectopic expression of RIOK2 alleviates telomere shortening in IPF patient-derived primary lung fibroblasts. Hence, increasing RIOK2 levels prevents telomere shortening, thus offering therapeutic strategies for telomere biology disorders.

Effect of Triple Therapy on Cardiovascular and Severe Cardiopulmonary Events in COPD: A Post-hoc Analysis of a Randomized, Double-Blind, Phase 3 Clinical Trial (ETHOS).

Rationale: Chronic obstructive pulmonary disease (COPD) is associated with increased risk of cardiovascular and cardiopulmonary events. In the Phase III, 52-week ETHOS trial (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) reduced rates of moderate/severe exacerbations and all-cause mortality versus dual therapy with glycopyrrolate/formoterol fumarate (GFF) or budesonide/formoterol fumarate (BFF). However, the effect of BGF on cardiovascular events versus GFF remains unevaluated. Further, the effect of BGF on time to first severe exacerbation has not been reported. Objective: Assess the effects of BGF 320/18/9.6 µg (BGF 320) and other ICS-containing arms on cardiovascular and severe cardiopulmonary endpoints versus GFF in patients with COPD from ETHOS. Methods: Patients with moderate-to-very severe COPD and a history of exacerbations were randomized to twice-daily BGF 320, BGF 160/18/9.6 µg, BFF 320/9.6 µg, or GFF 18/9.6 µg (GFF). Time to first severe COPD exacerbation was a pre-specified endpoint; post-hoc cardiovascular and severe cardiopulmonary endpoints included time to first major adverse cardiac event (MACE), time to first cardiovascular adverse event (AE) of special interest (CVAESI), time to first cardiac AE, and time to the composite endpoint of first severe cardiopulmonary event. Measurements and Main Results: BGF 320 reduced the rate of first occurrence (hazard ratio [95% confidence interval]) of cardiovascular and severe cardiopulmonary events versus GFF, including for CVAESI (0.63 [0.48, 0.82]), cardiac AE (0.60 [0.48, 0.76]), and severe cardiopulmonary event (0.80 [0.67, 0.95]). Conclusions: BGF had a benefit on cardiovascular endpoints and severe cardiopulmonary events versus GFF in patients with moderate-to-very severe COPD.

COPD Exacerbations Before and During COVID-19 in France, Germany, Italy, the UK and the US.

Background: Exacerbations of chronic obstructive pulmonary disease (COPD) were reported less frequently during the COVID-19 pandemic. We report real-world data on COPD exacerbation rates before and during this pandemic. Methods: Exacerbation patterns were analysed using electronic medical records or claims data of patients with COPD before (2017-2019) and during the COVID-19 pandemic (2020 through early 2022) in France, Germany, Italy, the United Kingdom and the United States. Data from each country were analysed separately. The proportions of patients with COPD receiving maintenance treatment were also estimated. Results: The proportion of patients with exacerbations fell 45-78% across five countries in 2020 versus 2019. Exacerbation rates in most countries were reduced by >50% in 2020 compared with 2019. The proportions of patients with an exacerbation increased in most countries in 2021. Across each country, seasonal exacerbation increases seen during autumn and winter in pre-pandemic years were absent during the first year of the pandemic. The percentage of patients filling COPD prescriptions across each country increased by 4.53-22.13% in 2019 to 9.94-34.17% in 2021. Conclusion: Early, steep declines in exacerbation rates occurred in 2020 versus 2019 across all five countries and were accompanied by a loss of the seasonal pattern of exacerbation.

Association of Ground Glass Opacities with Systemic Inflammation and Progression of Emphysema.

RATIONAL: Ground glass opacities (GGO) in the absence of interstitial lung disease are understudied. OBJECTIVE: To assess the association of GGO with white blood cells (WBCs) and progression of quantified chest CT emphysema. METHODS: We analyzed data of participants in the Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS). Chest radiologists and pulmonologists labeled regions of the lung as GGO and adaptive multiple feature method (AMFM) trained the computer to assign those labels to image voxels and quantify the volume of the lung with GGO (%GGOAMFM). We used multivariable linear regression, zero-inflated negative binomial, and proportional hazards regression models to assess the association of %GGOAMFM with WBC, changes in %emphysema, and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: Among 2,714 participants, 1,680 had COPD and 1,034 had normal spirometry. Among COPD participants, based on the multivariable analysis, current smoking and chronic productive cough was associated with higher %GGOAMFM. Higher %GGOAMFM was cross-sectionally associated with higher WBCs and neutrophils levels. Higher %GGOAMFM per interquartile range at visit 1 (baseline) was associated with an increase in emphysema at one-year follow visit by 11.7% (Relative increase; 95%CI 7.5-16.1%;P<0.001). We found no association between %GGOAMFM and one-year FEV1 decline but %GGOAMFM was associated with exacerbations and all-cause mortality during a median follow-up time of 1,544 days (Interquartile Interval=1,118-2,059). Among normal spirometry participants, we found similar results except that %GGOAMFM was associated with progression to COPD at one-year follow-up. CONCLUSIONS: Our findings suggest that GGOAMFM is associated with increased systemic inflammation and emphysema progression.

Biological Age, Chronological Age, and Survival in Pulmonary Fibrosis: A Causal Mediation Analysis.

Rationale: Accelerated biological aging has been implicated in the development of interstitial lung disease (ILD) and other diseases of aging but remains poorly understood. Objectives: To identify plasma proteins that mediate the relationship between chronological age and survival association in patients with ILD. Methods: Causal mediation analysis was performed to identify plasma proteins that mediated the chronological age-survival relationship in an idiopathic pulmonary fibrosis discovery cohort. Proteins mediating this relationship after adjustment for false discovery were advanced for testing in an independent ILD validation cohort and explored in a chronic obstructive pulmonary disease cohort. A proteomic-based measure of biological age was constructed and survival analysis performed, assessing the impact of biological age and peripheral blood telomere length on the chronological age-survival relationship. Measurements and Main Results: Twenty-two proteins mediated the chronological age-survival relationship after adjustment for false discovery in the idiopathic pulmonary fibrosis discovery cohort (n = 874), with 19 remaining significant mediators of this relationship in the ILD validation cohort (n = 983) and one mediating this relationship in the chronic obstructive pulmonary disease cohort. Latent transforming growth factor-ß binding protein 2 and ectodysplasin A2 receptor showed the strongest mediation across cohorts. A proteomic measure of biological age completely attenuated the chronological age-survival association and better discriminated survival than chronological age. Results were robust to adjustment for peripheral blood telomere length, which did not mediate the chronological age-survival relationship. Conclusions: Molecular measures of aging completely mediate the relationship between chronological age and survival, suggesting that chronological age has no direct effect on ILD survival.

Molecular Endotypes of Idiopathic Pulmonary Fibrosis: A Latent Class Analysis of Two Multicenter Observational Cohorts.

Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. Although antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objectives: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery (n = 875) and validation (n = 347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naive to antifibrotic therapy at the time of biomarker measurement (n = 555). Measurements and Main Results: LCA independently identified two latent classes in both cohorts (P < 0.0001). WFDC2 (WAP four-disulfide core domain protein 2) was the most important determinant of class membership across cohorts. Membership in class 2 was characterized by higher biomarker concentrations and a higher risk of death or transplant (discovery, hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.64-2.48; P < 0.001; validation, HR, 1.95; 95% CI, 1.34-2.82; P < 0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (P = 0.030 for interaction), with a favorable antifibrotic response in class 2 (HR, 0.64; 95% CI, 0.45-0.93; P = 0.018) but not in class 1 (HR, 1.19; 95% CI, 0.77-1.84; P = 0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and responses to antifibrotic therapy. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials.

Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in COPDGene.

RATIONALE: Quantitative interstitial abnormalities (QIA) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIA and its role in the QIA-outcome relationship is unknown. OBJECTIVES: To quantify radiographic pulmonary vasculopathy in quantitative interstitial abnormalities (QIA) and determine if this vasculopathy mediates the QIA-outcome relationship. METHODS: Ever-smokers with QIA, outcome, and pulmonary vascular mediator data were identified from the COPDGene cohort. CT-based vascular mediators were: right ventricle-to-left ventricle ratio (RV/LV), pulmonary artery-to-aorta ratio (PA/Ao), and pre-acinar intraparenchymal arterial dilation (PA volume 5-20mm2 in cross-sectional area, normalized to total arterial volume). Outcomes were: six-minute walk distance (6MWD) and modified Medical Council Research Council (mMRC) Dyspnea score ≥2. Adjusted causal mediation analyses were used to determine if the pulmonary vasculature mediated the QIA effect on outcomes. Associations of pre-acinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. MAIN RESULTS: Among 8,200 participants, QIA burden correlated positively with vascular damage measures including pre-acinar arterial dilation. Pre-acinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6MWD (56.2-100%, p<0.001). PA/Ao was a weak mediator and RV/LV was a suppressor. Similar results were observed in the QIA-mMRC relationship. Pre-acinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels including angiopoietin-2 and NT-proBNP. CONCLUSIONS: Parenchymal quantitative interstitial abnormalities (QIA) deleteriously impact outcomes primarily through pulmonary vasculopathy. Pre-acinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIA.

Computational Deconvolution of Cell Type-Specific Gene Expression in COPD and IPF Lungs Reveals Disease Severity Associations.

RATIONALE: Chronic 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. METHODS: We 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. RESULTS: The 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. CONCLUSION: Utilization 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.

Air Pollution Exposure and Interstitial Lung Features in SPIROMICS Participants with Chronic Obstructive Pulmonary Disease.

Rationale: It is unknown whether air pollution is associated with radiographic features of interstitial lung disease in individuals with chronic obstructive pulmonary disease (COPD). Objectives: To determine whether air pollution increases the prevalence of interstitial lung abnormalities (ILA) or percent high-attenuation areas (HAA) on computed tomography (CT) in individuals with a heavy smoking history and COPD. Methods: We performed a cross-sectional study of SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study), focused on current or former smokers with COPD. Ten-year exposure to particulate matter ⩽2.5 µm in aerodynamic diameter (PM2.5), nitrogen oxides (NOx), nitrogen dioxide (NO2), and ozone before enrollment CT (completed between 2010 and 2015) were estimated with validated spatiotemporal models at residential addresses. We applied adjusted multivariable modified Poisson regression and linear regression to investigate associations between pollution exposure and relative risk (RR) of ILA or increased percent HAA (between -600 and -250 Hounsfield units), respectively. We assessed for effect modification by MUC5B-promoter polymorphism (variant allele carriers GT or TT vs. GG at rs3705950), smoking status, sex, and percent emphysema. Results: Among 1,272 participants with COPD assessed for HAA, 424 were current smokers, and 249 were carriers of the variant MUC5B allele. A total of 519 participants were assessed for ILA. We found no association between pollution exposure and ILA or HAA. Associations between pollutant exposures and risk of ILA were modified by the presence of MUC5B polymorphism (P value interaction term for NOx = 0.04 and PM2.5 = 0.05) and smoking status (P value interaction term for NOx = 0.05; NO2 = 0.01; and ozone = 0.05). With higher exposure to NOx and PM2.5, MUC5B variant carriers had an increased risk of ILA (RR per 26 ppb NOx, 2.41; 95% confidence interval [CI], 0.97-6.0; and RR per 4 µg ⋅ m-3 PM2.5, 1.43; 95% CI, 0.93-2.2, respectively). With higher exposure to NO2, former smokers had an increased risk of ILA (RR per 10 ppb, 1.64; 95% CI, 1.0-2.7). Conclusions: Exposure to ambient air pollution was not associated with interstitial features on CT in this population of heavy smokers with COPD. MUC5B modified the association between pollution and ILA, suggesting that gene-environment interactions may influence prevalence of interstitial lung features in COPD.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.