Curtis, Jeffrey L.

Abstract Rationale Mismatch of airway to lung size has been implicated in chronic obstructive pulmonary disease (COPD) pathophysiology, whether arising from disproportioned growth or from acquired pathologies over the life course. Lower airway-to-lung ratio (ALR), assessed reproducibly via computed tomography (CT) as the mean airway lumen diameters (trachea-to-subsegments) divided by the cubed root of lung volume, is associated with COPD risk and mortality (all-cause, respiratory, cardiovascular, lung cancer). We sought to characterize the airway biology associated with lower ALR by profiling bronchial gene expression across current and former smokers. Methods We leveraged clinical, radiologic, and bronchial epithelial RNA sequencing data from the SPIROMICS (SubPopulations and Intermediate Outcomes Measures in COPD Study) Phase 1 Bronchoscopy Sub-study (n = 161). To analyze transcriptional differential expression (DE) between participants based on CT-assessed ALR, we utilized DESeq2 and then identified impacted pathways by Ingenuity Pathway Analysis (IPA). Generating cell-type transcriptional signatures from lung and blood single cell sequencing atlases, we also assessed association of ALR with differences in airway cellular composition. Results Across all ever-smokers, after adjustment for age, sex, height, COPD status, smoking status, and pack-years, n = 1,324 genes from airway epithelial samples exhibited DE at a false discovery rate (FDR) <0.2. Per IPA, enriched pathways associated with lower ALR included neutrophilic degranulation and macrophage activity. In cell type analysis, lower ALR was associated with higher signatures of macrophages, neutrophils, dendritic cells, and B cells, and lower ciliated and club cell signatures. When we repeated DE analysis using the same covariate adjustments plus an interaction term for ALR and smoking, n = 713 DE genes were identified at FDR <0.2; the association of DE with lower ALR was overwhelmingly in current rather than former smokers (3699 vs. 2 genes). By pathway and cell type analyses, the association between lower ALR and heightened inflammation (greater macrophage and neutrophil signaling) and epithelial dysregulation (downregulated ciliated and club cell function) was primarily restricted to current smokers. Conclusions In adult ever-smokers, lower ALR is associated with transcriptomic evidence of heightened neutrophil- and macrophage-driven airway inflammation and reduced ciliated and club cell expression, associations that were most evident among current smokers. Whether these cross-sectional patterns, which suggest impaired mucociliary defense and a diminished capacity to clear inhaled particulates, are the result of pre-existing reduced ALR, its cause, or both, will require further investigation. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C, 75N92024D00012), grants from the NIH/NHLBI (U01HL137880, U24HL141762, R01HL182622, R01HL144718, and R01HL093081), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; Theravance Biopharma; Verona; and Mylan/Viatris.

Abstract Rationale Eosinophilic airway inflammation in COPD is associated with more frequent exacerbations,lower lung function,and corticosteroid responsiveness.DNA methylation captures information about genetic factors and environmental exposures, but is under-studied in eosinophilic COPD.We hypothesized that sputum cell methylation patterns reflect genomic regulation of inflammatory endotypes in COPD by DNA sequence variation. Methods We analyzed DNA previously extracted from induced sputum cells for a prior study(PMID38261629) for which sufficient quantity DNA remained for methylation arrays.For this analysis,we focused on n = 132 SPIROMICS participants with ≥20 pack-years smoking history.Samples were stratified into tertiles based on sputum eosinophil proportions,previously determined from sputum cell differential analysis by the centralized sputum analysis core for SPIROMICS(Univ of North Carolina).We assessed proportion of DNA methylation (β values) spanning 936,866 CpG sites using the Illumina Infinium Methylation EPICv2.0 BeadChip Array,which we transformed into M values(meffil R package). To identify differentially methylated regions (DMRs)(FDR<0.05 in minimum of 2 CpG sites per gene region),we contrasted CpG β values between the high-eosinophil and low-eosinophil tertiles(N = 44 each),using the DMRcate package.We tested for enrichment of genes overlapping with significant DMRs using Enrichr (GWAS Catalog 2025 gene set library).To identify genetic variants associated with DNA methylation levels,we performed Methylation Quantitative Trait Loci (meQTL) analysis using TensorQTL.For each CpG site,we tested associations with SNPs within a ± 500 kb window (cis-meQTL).The linear regression model included age,sex,BMI,smoking status,smoking pack-years,study site,inhaled corticosteroid use, the first two genetic principal components, cell-type proportions (macrophages/monocytes, neutrophils, squamous epithelial cells, lymphocytes), and eosinophil tertile . Significant meQTLs were identified at an FDR<0.05 using Benjamini-Hochberg correction. Results A total of 532 eosinophil-associated DMRs (FDR < 0.05) were identified between the high- and low-eosinophil groups,encompassing 446 unique genes.The top enriched pathways related to counts of eosinophils (adjusted p = 0. 00002464), lymphocytes (adjusted p = 0.0001860), and the sum of eosinophils-plus-basophils (adjusted p = 0.0001860).We identified 18,432 significant SNP-CpG/meQTL pairs (FDR < 0.05),suggesting extensive genetic influence on airway DNA methylation patterns.Among the n = 521 eosinophil-associated CpGs that overlapped with meQTLs,rs55687040 (TENT2,a gene involved in mRNA and miRNA processing) is a GWAS locus for FEV1/FVC ratio (PMID: 26634245), suggesting possible genetic control of airway eosinophilic methylation signatures. Conclusions Our findings disclose distinct DNA methylation signatures associated with sputum eosinophil proportion in COPD.A subset of these CpGs are regulated by genetic variants,suggesting an integrated genetic-epigenetic mechanism underlying airway eosinophilic inflammation with the potential to influence COPD risk and severity. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C), grants from the NIH/NHLBI (U01 HL137880, U24 HL141762, R01 HL182622, and R01 HL144718), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; and Theravance Biopharma and Mylan/Viatris.

Abstract Rationale Thymic stromal lymphopoietin (TSLP) is an epithelial alarmin chiefly implicated in T2 airway inflammation, though it may also participate in broader (non-T2) inflammatory processes. The utility of airway epithelial gene expression of TSLP and its specific receptor subunit, cytokine receptor-like factor 2 (CRLF2), as biomarkers of downstream inflammation and clinical outcomes remains unclear. Methods We analyzed RNA sequencing data from bronchial airway brushing obtained in phase 1 of the SPIROMICS bronchoscopy sub-study (N = 161: 23 never-smokers, 67 ever-smokers with COPD, 71 ever-smokers without COPD). We related airway TSLP and CRLF2 expression to clinical, hematologic/sputum measures, and gene-expression signatures of T2/eosinophilic and neutrophilic inflammation, including to our published T2 signature and to eosinophil and neutrophil signatures derived from single-cell atlas data. Associations used Spearman correlations and linear models adjusted for age, sex, race/ethnicity, COPD status, smoking status, and pack-years. Results CRLF2 expression correlated with gene-expression evidence of both T2/eosinophilic and neutrophilic inflammation: T2 signature (ρ = 0.26, p < 0.001), eosinophil signature (ρ = 0.44, p < 0.001), and neutrophil signature (ρ = 0.39, p < 0.001). CRLF2 was positively associated with log sputum neutrophil count (ρ = 0.24, p = 0.024) and blood neutrophil count (ρ = 0.036, p < 0.001), but not with sputum or blood eosinophil counts. Higher CRLF2 related to worse baseline lung function, particularly among current smokers, (lower post-bronchodilator FEV1: ρ = −0.21, p = 0.008), as well as greater 5-year FEV1 decline across current and former smokers (ρ = −0.22, p = 0.007). Significant findings persisted after covariate adjustment. In contrast, TSLP expression, although strongly correlated with expression of the epithelial alarmin IL33 (ρ = 0.53, p < 0.001), was negatively correlated with CRLF2 (ρ = −0.24, p = 0.002) and with eosinophil and neutrophil gene-expression signatures (ρ = −0.26 and −0.33, both p < 0.001). TSLP expression showed no association with sputum or blood cell counts. Conclusions In bronchial epithelium from SPIROMICS, gene expression of CRLF2, but not of TSLP, tracked with downstream alarmin-relevant inflammatory programs, consistent with a regulatory role in TSLP signaling through TSLPR, as well as with clinically meaningful outcomes. CRLF2 expression was associated with evidence of both T2/eosinophilic and neutrophilic inflammation, and with lower baseline FEV1 and accelerated FEV1 decline, suggesting engagement of a broader, clinically relevant inflammatory milieu. By contrast, epithelial TSLP transcript levels mirrored IL33 gene expression but were not associated with cellular or transcriptomic inflammation. These findings position CRLF2, rather than TSLP expression itself, as a potential airway biomarker of TSLP-axis activity and disease impact with potential implications for patient stratification as well as strategic approaches for TSLP-pathway-targeted therapies. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C, 75N92024D00012), grants from the NIH/NHLBI (U01HL137880, U24HL141762, R01HL182622, R01HL144718, and R01HL093081), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; Theravance Biopharma; Verona; and Mylan/Viatris.

Abstract Rationale Deficiency of alpha-1 antitrypsin (AAT), the protein encoded by SERPINA1, remains the strongest genetic risk factor for COPD. Individuals heterozygote for the type Z variant, termed the PI*MZ genotype (estimated global prevalence n = 35,000,000), experience varying respiratory morbidity beyond expected from tobacco smoking alone. AAT is a pleiotropic protein which inhibits not only neutrophil elastase but also neutrophil chemotaxis mediated by leukotriene B4 (LTB4) [by antagonizing the LTB4 receptor (LTB4R)] and interleukin-8 (IL-8). Although LTB-4 and IL-8 gene variants and protein levels have independently been implicated in COPD, their potential role in PI*MZ is unknown. Methods COPDGene and SPIROMICS are observational tobacco-smoke and COPD-enriched cohort studies. Participants were phenotyped by spirometry and CT imaging, with whole genome sequencing data available via TOPMed. We analyzed participants with PI*MM (COPDGene n = 9,732; SPIROMICS n = 2,105) and PI*MZ (COPDGene n = 300; SPIROMICS n = 83). LTB-4 (ALOX5AP, LTA4H, LTB4R) and IL-8 (CXCL8, CXCR1, CXCR2) associated gene variants (exonic and intronic) with a minor allele frequency of ≥ 0.05 were extracted. We assessed statistical interactions between MZ status and chest CT outcomes or FEV1% predicted using the SPAGxECCT package with adjustment for relatedness (genetic related matrix) and ancestry (top ten PCs). Baseline protein LTB4R (SPIROMICS only) and IL-8 (both cohorts) protein levels were measured via SomaScan, and statistical interactions between MZ status and AAT concentration were explored. Models were adjusted for age, sex, BMI, smoking status, and pack-years. Given the candidate gene discovery approach, significance was defined as nominal p-value<0.05 Results We identified the following number of variants in genes of the LTB-4 or IL-8 pathways: 87 shared between cohorts; 133 unique to COPDGene; 1 unique to SPIROMICS. LTB-4-related polymorphisms were associated (p < 0.05) with any radiographic outcomes in 22 variants (COPDGene) vs. 23 variants (SPIROMICS), with a single overlap (rs17074984 in ALOX5AP). Two LTB-4-pathway variants were associated with FEV1% predicted in SPIROMICS (both in ALOX5AP), but none in COPDGene. AAT plasma concentrations displayed a statistically significant interaction with FEV1% predicted (p = 0.046) and PRMemphysema (p = 0.013) for LTBR4, but not for IL-8. There was not an interaction by MM/MZ status and protein levels. Conclusions Predominantly LTB-4, and not IL-8, pathway-related genetic variants and protein levels may contribute to disease heterogeneity among PI*MZ individuals. The association of circulating LTB4R protein with reduced lung function, particularly among those with low AAT levels, further suggest interactions between AAT and the leukotriene pathway in PI*MZ individuals. Thus, PI*MZ individuals may uniquely derive benefit from leukotriene-targeting pharmacotherapy. This abstract is funded by: NIH NHLBI K23HL173570

Abstract Background Muscle loss in COPD results from both disuse atrophy and systemic inflammation. We sought to identify inflammatory biomarkers associated with loss of pectoralis muscle area in COPD using serial CT scans and peripheral blood proteomics. Design We analyzed five-year longitudinal data from COPDGene, an ongoing observational cohort of current and former tobacco smokers with or without airflow obstruction. We quantified pectoralis major muscle (PMM) area on chest CT scans using a 3D convolutional neural network (CNN) trained on CT volumes and annotations provided by the TotalSegmentator project. We compared participants with CT PMM data and plasma proteins by SOMAScan (1K platform) from Phase 2 and 3 (paired n = 1,191). The correlation coefficient (r) between longitudinal changes in protein and in PMM area was plotted against the false discovery rate (FDR)-adjusted p-values. Proteins significantly associated with muscle loss (blue) or gain (red) were visualized using volcano plots. We then analyzed a subset (paired n = 500) of individuals with BMI>25 in Phase 2 whose BMI declined in Phase 3. Proteomic models were adjusted for age and clinical center. Pathway analysis utilized G:Profiler. Results Of the participants with paired proteomic and PMM data, mean PMM area was 21.7 ± 17.3 cm² at Phase 2 and 21.3 ± 17.9 cm² at Phase 3, with an annual change in PMM area of -0.31 + 0.99 cm². Multiple proteins were associated with muscle loss from Phase 2 to 3 (including leptin, FABP, and growth hormone receptor) and muscle gain (including F172A, GMEB2, and RNF41) (Fig 1a). Significant pathways were related to cancer, growth factor receptor dysregulation, and PI3K/AKT signaling. When restricting to those with BMI>25 who experienced BMI decline at Phase 3, muscle loss was associated with increased leptin and PACAP, versus association of gain with increased GDF118, EF1β, and FJF6 (Fig 1b). In the entire group, leptin declined between Phase 2 to Phase 3 in n = 571 participants and increased or was unchanged in n = 620. Compared with leptin decline, unchanged or increased leptin was associated with significantly greater interval PMM loss (−2.25 ± 9.75 cm² vs + 0.98 ± 9.43 cm²; p < 0.001) (Fig 1c). Conclusion Loss of PMM over five years was associated with several plasma proteins, including FABP and growth hormone receptor. The top biomarker, leptin, is a pleiotropic adipokine that regulates energy balance and inflammation. Integrating imaging and proteomics may identify future therapeutic targets to mitigate skeletal muscle loss in COPD. This abstract is funded by: This work was supported by NHLBI grants U01 HL089897 and U01 HL089856 and by NIH contract 75N92023D00011

Introduction Despite the identification of multiple susceptibility loci by genome-wide association studies (GWAS), considerable chronic obstructive pulmonary disease (COPD) heritability remains unexplained. Aim To identify interaction networks of airway epithelial cell DNA methylation in COPD and further explore potential correlations with airway bacterial composition, as potentially collective regulators of biological pathways influencing COPD severity. Methods Using DNA isolated from bronchial airway brushings of 67 ever-smokers (>20 pack-years) from the SubPopulations and InteRmediate Outcomes Measures in COPD Study (SPIROMICS), we assessed proportion of DNA methylation (β) by epigenome-wide association study (EWAS) and examined associations of differentially methylated CpG probes (DMPs) with risk for moderate-to-severe COPD (N=34) versus absent or mild COPD (N=33). We tested co-methylation modules generated by Weighted Correlation Network Analyses (WGCNA) for associations with moderate-to-severe COPD and with bacterial genus-level relative abundances (16S rRNA sequencing). Results EWAS-identified nominally significant DMPs enriched for lung function GWAS loci. Eigengenes in six WGCNA modules were associated with moderate-to-severe COPD (false discovery rate <0.05). Four of those modules were enriched for forced expiratory volume in 1 s/forced vital capacity GWAS loci, and five overlapped with DMPs from EWAS. Overlapping CpG loci in three COPD-associated modules were adjacent to mucin genes; one had 10 genes highly ranked by connectivity with MUC5B, including important pathway genes: B3GNT6 , DGKI and ITGA8 . CpGs in an independent COPD-associated module showed the most correlations with Rothia , with directionality suggestive of negative associations with moderate-severe COPD. Conclusions Bronchial epithelial DNA methylation modules enriched for lung function GWAS loci associate with COPD severity in SPIROMICS. Potential module relationships to bronchial bacterial composition require further validation.

Abstract Rationale Inflammation is central to chronic obstructive pulmonary disease (COPD) pathogenesis but incompletely represented in COPD prognostic models. The neutrophil-to-lymphocyte ratio (NLR) is a readily available inflammatory biomarker. Objectives To explore the associations of NLR with smoking status, clinical features of COPD, and future adverse outcomes. Methods We analyzed NLR calculated from the complete blood count of participants who currently or formerly smoked (n = 2,624) and tobacco-naive control subjects (n = 187) in the SPIROMICS multicenter observational cohort study. We assessed the stability of NLR at 6 weeks and 1 year, the association with select blood biomarkers, and the impact of smoking on NLR and cell counts. We stratified participants by NLR quartiles to compare cross-sectional clinical features at enrollment, prospectively observed exacerbations at 1 year, and mortality during longitudinal follow up. Results Higher NLR quartiles were broadly associated with more severe clinical features of COPD. NLR values were repeatable at 6 weeks (intraclass correlation coefficient, 0.74) and 1 year (intraclass correlation coefficient, 0.62). The impact of smoking on NLR varied with the severity of airflow limitation, mediated by an interaction between smoking, forced expiratory volume in 1 second percent predicted, and neutrophil counts but not lymphocyte counts. The highest NLR quartile (&gt;3.11) was associated with an increased risk of exacerbation over 1 year (adjusted odds ratio, 1.51; 95% confidence interval, 1.18, 1.92) and increased risk of mortality (adjusted hazard ratio, 1.41; 95% confidence interval, 1.20, 1.66) compared with quartiles 1–3. Conclusions Elevated NLR in stable COPD is a widely available biomarker associated with increased risk for exacerbation and death. The impact of cigarette smoking on NLR varies with disease severity.

Rationale Immunoglobulin A (IgA) deficiency, a rare, highly heritable trait, is associated with frequent pulmonary infections, emphysema, airway changes and low lung function; however, it is unclear if reduced IgA levels may affect lung structure and function. Methods Serum IgA, IgA1 and galactose-deficient IgA1 (Gd-IgA1) levels were measured in the population-based Multi-Ethnic Study on Atherosclerosis (MESA). The MESA Lung Study measured percent emphysema on cardiac CT and airway dimensions on chest CT, and performed spirometry. Regression models were evaluated after adjustment for demographic and CT factors. Mendelian randomisation (MR) analyses were conducted using genetic variants from the Trans-Omics for Precision Medicine (TOPMed) programme. A replication analysis was performed in the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS). Measurements and main results Among 5497 participants, lower log-normalised serum IgA levels were associated with greater percent emphysema (β=−0.084; 95% CI −0.14 to –0.026; p=0.005), which was confirmed on MR (β=−0.79; 95% CI −1.4 to –0.18; p=0.011). Greater log-normalised serum Gd-IgA1 levels were associated with airway wall thickness (β=0.0079; 95% CI 0.0017 to 0.014; p=0.012; n=2580) and decline in the forced expiratory volume in one second (FEV1) (β=−0.012; 95% CI −0.021 to –0.0036; p=0.0055; n=2778) and FEV1/forced vital capacity (FVC) ratio (β=−0.0028; 95% CI −0.0048 to –0.00084; p=0.0054; n=2778). Conclusion Lower serum IgA levels were associated with greater percent emphysema. Additionally, higher Gd-IgA1 levels were associated with airway wall thickness and lung function decline. These findings support a protective role of IgA in emphysema pathogenesis and possible deleterious role of Gd-IgA1 in airway diseases.

Abstract Rationale Reliable data about the natural history of lung function decline in alpha-1 antitrypsin (AAT)-deficient Pi*MZ heterozygotes is largely missing. Objectives We hypothesized that, in adults with a tobacco smoking history, lung function deteriorates faster in Pi*MZ compared with the Pi*MM genotype. Methods We identified 1,856 Pi*MM and 79 Pi*MZ participants with ⩾20 pack-years tobacco smoking history from the SPIROMICS (Subpopulations and Intermediate Outcomes Measures in COPD Study) cohort by DNA sequencing and followed them over a median of 4.8 years, comparing radiographic and clinical characteristics between the two groups over time using regression models. Results Adjusted for age, sex, race, smoking pack-year history, and smoking status, Pi*MZ participants had a lower baseline percent predicted forced expiratory volume in 1 second (FEV1) (65.4% vs. 75.1%; difference 95% confidence interval [CI], −15.4% to −3.9%), more radiographic emphysema (&lt;−950 Hounsfield units%, 12.9% vs. 7.8%; difference 95% CI, 2.8% to 7.5%), and nonsignificantly lower lung density. In the longitudinal analysis, the FEV1 annual rate of decline was similar in both groups over the course of the study (−34.5 ml/yr vs. −34.6 ml/yr for Pi*MZ and Pi*MM; difference 95% CI, −16.9 to 17.1 ml/yr). There were no significant differences between Pi*MZ and Pi*MM individuals in the annualized change in lung density, emphysema, patient-reported outcomes, exacerbations, or survival. The proportion with faster FEV1 decline (annual loss ⩾40 ml) was similar in Pi*MZ and Pi*MM groups. In both groups, faster FEV1 decline was associated with more air trapping and small airway disease at baseline. In Pi*MZ only, faster decline was associated with higher blood eosinophil counts (310 vs. 220 cells/μl; difference 95% CI, 30 to 140 cells/μl). In the subgroup analysis limited to a small number of currently smoking participants, no significant differences in longitudinal outcomes were found. Conclusions Despite a lower FEV1 and more emphysema at enrollment, the longitudinal analysis did not demonstrate significantly greater lung function decline or lung density loss in Pi*MZ compared with Pi*MM participants with tobacco smoking history. Limited sample size and duration of longitudinal follow-up constrain generalizability of our findings, thus prohibiting the conclusion that longitudinal trajectories did not differ between these groups. However, our results may suggest that earlier life events could be responsible for more extensive lung disease at enrollment in Pi*MZ compared with Pi*MM tobacco-exposed individuals.

Abstract Rationale Among tobacco-exposed persons with preserved spirometry (TEPSs), we previously demonstrated that different lung volume indices—specifically, elevated total lung capacity (TLC) versus elevated ratio of functional residual capacity to TLC (FRC/TLC)—identify different lung disease characteristics in the COPDGene cohort. Objective We sought to determine differential disease characteristics and trajectories associated with lung volume indices among TEPSs in the SPIROMICS cohort. Methods We categorized TEPSs (n = 814) by tertiles (low, intermediate, and high) of TLC or residual volume–to-TLC ratio (RV/TLC) derived from baseline computed tomography images and then examined clinical and spirometric disease trajectories in mutually exclusive categories of participants with high TLC without high RV/TLC ([TLC]high) versus high RV/TLC without high TLC ([RV/TLC]high). We examined differences in computed tomography–measured emphysema (Hounsfield units [HU] ⩽−950; parametric response mapping [PRM] of emphysema), air trapping (HU⩽−856; PRM of functional small airway disease; a disease probability measure for non-emphysematous gas trapping), airway geometry (the mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), respiratory symptoms (on the modified Medical Research Council Dyspnea Scale; COPD Assessment Test [CAT]; St. George’s Respiratory Questionnaire [SGRQ]; and Short Form-12 [SF12]), and outcomes (annualized exacerbation rate) between the two categories at baseline and over follow-up time up to 8.5 years, using regression modeling adjusted for age, sex, height, weight, and smoking status (current vs. former smoker) and burden (pack-years). Results In TEPSs, the pattern of spirometric disease progression differed between participants with [TLC]high and those with [RV/TLC]high: There was increased forced vital capacity with stable forced expiratory volume in 1 second in participants with [TLC]high, versus unchanged forced vital capacity but nominally decreased forced expiratory volume in 1 second in those with [RV/TLC]high. Compared with participants with [TLC]high, TEPSs with [RV/TLC]high had less emphysema (by HU ⩽−950) but more airway disease (by HU ⩽−856; PRM of functional small airway disease; disease probability measure for gas trapping, and mean square root of wall area of a hypothetical airway with 10 mm internal perimeter), more respiratory symptoms (on the modified Medical Research Council Dyspnea Scale, CAT, SGRQ, and SF12), and more severe exacerbations at baseline. Over an average follow-up of 4.1 ± 2.4 years (range = 0.5–8.5 yr), TEPSs with [RV/TLC]high also had a higher likelihood of developing more severe spirometric disease (preserved ratio impaired spirometry or Global Initiative for Chronic Obstructive Lung Disease Classification 2) and worsening of their respiratory symptoms (on the CAT and SGRQ). Although the incidence rates of respiratory exacerbations, hospitalizations, and mortality were not significantly different between the two categories over the follow-up period, TEPSs with [RV/TLC]high were more likely to have been prescribed a respiratory inhaler at their last follow-up visit. Conclusions In these TEPSs from the SPIROMICS cohort, lung volume stratification by TLC versus RV/TLC identifies two pre-COPD phenotypes with distinct respiratory symptoms, radiographic features, and clinical trajectories. The characteristics of these pre-COPD phenotypes match those previously described in the COPDGene cohort using TLC versus FRC/TLC stratification.