Annals of the American Thoracic Society

Responders to the World Trade Center (WTC) site in the aftermath of the 9/11 attacks were exposed to toxic dust, which has been linked to increased risk of respiratory and cardiovascular disease. The respiratory and cardiovascular effects of WTC dust exposure have been studied using pulmonary function tests and the number of cardiovascular events, but computed tomography (CT) scans provide an opportunity to see the early structural changes in the lungs and cardiovascular system before clinical symptoms appear. CT scans are used in the screening and evaluation of respiratory diseases such as lung cancer, interstitial lung disease, and chronic obstructive pulmonary disease, and to visualize coronary arteries and quantify the amount of coronary artery calcifications; in fact, it is possible to detect multiple diseases from a single chest CT scan. While manual evaluation by a radiologist is often the gold standard, automated image analysis tools can quickly and accurately quantify these diseases. We identified non-contrast chest CT scans from members of the World Trade Center General Responders Cohort (WTC GRC) with slice thickness of 2.5 mm or less. We used the open-source Chest Imaging Platform software to compute measures of emphysema and interstitial lung disease and research software from Cornell University to compute measures of pulmonary hypertension and coronary artery calcification. We identified a sex, age (within 5 years), smoking status, one or more CT scans, and follow-up time -matched cohort of participants enrolled in the lung screening program at Mount Sinai. We compared disease measures from the WTC GRC group to the lung screening group to assess whether there was a difference in the extent and progression of disease. There were 4909 chest CT images of members of the WTC GRC that met our image quality criteria. There were 3855 members of the GRC for which we could obtain both chest CT images and clinical data. Of these, there were 2284 members for which we could obtain pulmonary disease measurements on at least one scan, 1246 members for which we could calculate cardiac measurements. The matched controls from the lung screening cohort consisted of 557 participants with 1122 chest CT images that met our image quality criteria and for which we obtained all four disease measures. We compared members of the WTC GRC with matched participants from the lung screening program. One of the key findings is that after a median time of 11-13 years after 9/11, the WTC GRC group exhibited higher burdens of coronary artery calcification, emphysema, and interstitial lung disease compared with a matched control group of lung screening participants. This supports the continued surveillance of WTC responders.

BackgroundThough a normal forced vital capacity (FVC) is typically thought to imply the absence of restriction, recent data suggest that restriction may in fact be common among patients with normal spirometry. However, the clinical significance of restriction with normal spirometry is unknown. Research QuestionWhat clinical characteristics and outcomes are associated with restriction with normal spirometry? Study Design and MethodsWe interpreted pulmonary function tests (PFTs) with both static and dynamic lung volume measurements performed between 2012 and 2025 at four pulmonary diagnostic labs. We used multivariable logistic regression to identify clinical characteristics associated with restriction among patients with normal spirometry and used a Cox proportional hazards model to assess the association of restriction with survival, adjusting for age, sex, forced expiratory volume in 1 second (FEV1) z-score, FVC z-score, and FEV1/FVC z-score. ResultsWe interpreted 83,886 PFTs from 47,597 patients (mean age 58.8 years, 59.8% female, 63.6% White). The prevalence of restriction among patients with normal spirometry was 25.7% Restriction with normal spirometry was more likely in older patients (adjusted odds ratio [aOR] 1.01 per year, 95% CI 1.01-1.01), in non-White patients (aOR 1.33, 95% CI 1.26-1.41), and in patients with a diagnosis (aOR 3.65, 95% CI 3.43-3.88) or radiographic evidence (aOR 3.02, 95% CI 2.79-3.28) of interstitial lung disease (ILD). Restriction with normal spirometry was less likely among female patients (aOR 0.64, 95% CI 0.60-0.67), and patients with a diagnosis (0.74, 95% CI 0.67-0.82) or radiographic evidence (aOR 0.81, 95% CI 0.73-0.89) of chronic obstructive pulmonary disease. Restriction with normal spirometry was associated with increased all-cause mortality (adjusted hazard ratio 1.45, 95% CI 1.34-1.57) as compared to normal spirometry without restriction. InterpretationRestriction with normal spirometry is associated with ILD and with decreased survival. Clinically significant ventilatory impairments are common in patients with normal spirometry.

BackgroundThough European Respiratory Society and American Thoracic Society (ERS/ATS) guidelines for pulmonary function test (PFT) interpretation recommend the use of the forced vital capacity (FVC) lower limit of normal (LLN) to exclude restriction, recent data suggest that the negative predictive value (NPV) of the FVC LLN is lower than has been accepted, particularly among non-Hispanic Black patients. We sought to develop and externally validate a machine learning (ML) model to predict restriction from spirometry and determine whether its use may improve the accuracy and equity of PFT interpretation. MethodsWe included PFTs with both static and dynamic lung volume measurements for patients between 18 and 80 years of age who were tested at pulmonary diagnostic labs within two health systems. We used PFTs from one health system to train logistic regression, random forest, and boosted tree models to predict restriction using demographic, anthropometric, and spirometric data. We used PFTs from the second health system to externally validate these models. The primary measure of model performance was the NPV. Racial equity was assessed by comparing the NPV among non-Hispanic Black and non-Hispanic White patients. FindingsA total of 42 462 PFTs were used for model development and 24 524 for external validation. The prevalence of restriction was 29.8% in the development dataset and 39.6% in the validation dataset. All three ML models outperformed the FVC LLN by a wide margin, both overall and among all demographic subgroups. The overall NPV of the random forest model (88.3%, 95% confidence interval [CI] 87.8% to 88.9%) was significantly greater than that of the FVC LLN (72.7%, 95% CI 72.1% to 73.3%). The NPV of the random forest model was greater than that of the FVC LLN among both non-Hispanic Black (74.6% [95% CI 72.5% to 76.6%] versus 49.5% [95% CI 47.8% to 51.2%]) and non-Hispanic White (90.9% [95% CI 90.3% to 91.5%] versus 79.6% [95% CI 78.9% to 80.3%]) patients. InterpretationML models to exclude restriction from spirometry improve the accuracy and equity of PFT interpretation but do not fully eliminate racial differences.

RationaleShort-term exposure to fine particulates (PM2.5) transiently increases the risk of respiratory exacerbations, but the contribution of chronic, long-term particulate exposure to respiratory exacerbations is poorly defined. ObjectivesTo assess long-term effects of PM2.5 exposure on risk of severe respiratory exacerbations. MethodsA longitudinal cohort of current and former smokers with and without COPD were surveyed every six months for severe exacerbation events. PM2.5 concentrations at participant addresses were estimated using satellite, reanalysis, and ground-based monitoring data sources. Measurements and Main ResultsThe relative risk of severe exacerbation increased by a factor of 1.516 (CI: 1.226, 1.873; p = 0.00012) for every 10 g/m3 increase in long-term PM2.5 exposure across all participants. The effect in the non-COPD participants was greater, with a relative risk of 2.639 (CI: 1.840, 3.756; p<0.0001). Significant effect modifiers with greater effect of PM2.5, included prior exacerbations, female sex, and neighborhood characteristics and as well as smoking status, white race, disease severity, asthma diagnosis, and age at enrollment. Significant positive associations for PM2.5 on exacerbations were identified at levels below the EPA primary annual standard for PM2.5 of 9.0 g/m3. ConclusionsPersistent exposure to fine particulates is a significant risk factor for severe respiratory exacerbations in current and former smokers, and in patients with or at risk of COPD. The effect of fine particulates on the risk of severe exacerbations appears to be greater in those current and former smokers without COPD. The EPA annual PM2.5 standard may be inadequate to prevent ongoing lung injury.

RationaleSupplemental oxygen is often prescribed to patients with interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). The specific costs of oxygen therapy in these diseases have not been fully described in patients living in the United States. ObjectivesEstimate Medicaid/Medicare costs for supplemental oxygen, characterize differences in oxygen equipment utilization, and identify factors impacting the costs of supplemental oxygen therapy in ILD and COPD. MethodsWe reviewed claims data for years 2016-2020 for Pennsylvania residents with ILD or COPD who were dually eligible for Medicaid/Medicare and enrolled in traditional fee-for-service Medicare. A generalized estimated equation (GEE) model was used to identify variables associated with annual oxygen costs. Measurements and Main ResultsA greater proportion of paid claims in ILD were for oxygen services (40.3% vs 22.0%) and for high flow oxygen (4.2% vs 2.2%), though ILD represented the minority of paid oxygen claims (5.2%). Oxygen cost approximately $65/month for both groups. Most oxygen claims ([&ge;]94%) were for stationary concentrators. Liquid devices and stationary gas were the least utilized equipment. Lower costs were associated with living in a competitive bidding area and with markers of advanced age and worse health status. ConclusionsOxygen utilization is greater in ILD but is only a small portion of total oxygen claims compared to COPD. Costs and equipment utilization were similar between groups. Liquid oxygen claims were rare even among subjects requiring high flow. Oxygen therapy is common in these diseases and likely represents a significant contribution to total healthcare costs.

BackgroundEuropean Respiratory Society and American Thoracic Society (ERS/ATS) guidelines for pulmonary function test (PFT) interpretation posit the existence of a "zone of uncertainty." However, as reference equations have been defined only for healthy lung function, the precise borders of the zone of uncertainty remain unspecified. To address this limitation, we sought to define distributions of both healthy and diseased lung function and to use these distributions to map the zone of uncertainty. MethodsWe used a latent class model to define distributions of healthy and diseased FEV1/FVC values. To represent the distribution of healthy FEV1/FVC values, we fit a Box-Cox Cole Green distribution to spirometry from healthy adult participants in the continuous National Health and Nutrition Examination Survey (NHANES). Using the distribution of healthy FEV1/FVC values, we then fit a latent class model to FEV1/FVC data from adult patients who underwent pulmonary function testing at the University of Pennsylvania Health System (UPHS) between 2000 and 2023. The distribution of diseased FEV1/FVC values and the prior probabilities that FEV1/FVC values had been sampled from healthy and diseased populations were selected to maximize the likelihood of the observed UPHS data. We considered the normal, Box-Cox Cole Green, and Box-Cox power exponential distributions for the distribution of diseased FEV1/FVC values and selected the distribution that minimized the Bayesian information criterion. We then mapped the zone of uncertainty by identifying the range of FEV1/FVC values in which the distributions of healthy and diseased lung function overlapped. ResultsPre-bronchodilator spirometry data were collected from 14,075 NHANES participants-- of whom 6,063 were without respiratory symptoms or a history of tobacco use--and 41,437 UPHS patients. Healthy lung function was represented by a Box-Cox Cole Green distribution with a median of 0.81, a coefficient of variation of 0.08, and skewness of 1.70. Diseased lung function was best represented by a Box-Cox power exponential distribution with a median of 0.56, a coefficient of variation of 0.30, skewness of 0.91, and kurtosis of 2.36. In the latent class model, the prior probability that an FEV1/FVC value was healthy was 76.2%, while the prior probability that it was diseased was 23.8%. The overlap of the distributions of healthy and diseased FEV1/FVC values defined a zone of uncertainty in the interval [0.64, 0.95]. The FEV1/FVC values of 33,747 (81.4%) UPHS patients fell within the zone of uncertainty, including 30,288 (99.2%) patients with a normal FEV1/FVC and 3,459 (31.7%) patients with an abnormal FEV1/FVC. ConclusionThis exploratory study presents evidence that in a clinical cohort, most FEV1/FVC values fall within the zone of uncertainty. Further research is needed to develop optimal ways to represent and incorporate this uncertainty into PFT interpretation.

BACKGROUNDVariation in genetic ancestry among admixed racial/ethnic groups may influence the fit of guideline-recommended spirometry reference equations, which rely on self-identified race/ethnicity. RESEARCH QUESTIONWhat is the influence of genetic ancestry on the fit of the guideline-recommended racial/ethnic-based spirometry reference equations in populations of genetically admixed children? STUDY DESIGN AND METHODSCross-sectional fit of guideline-recommended racial/ethnic-based spirometry reference equations was evaluated in control subjects from case-control studies of asthma. Anthropometry, blood samples, and spirometric measurements were obtained in 599 healthy admixed children, aged 8 to 21-years. Genetic ancestry was estimated using genome-wide genotype data. Equation fit was determined as a mean z-score between -0.5 and 0.5 and assessed in self-identified African American (N = 275) and Puerto Rican (N = 324) children using the distribution to determine cut points of genetic ancestry. RESULTSFor African American children, African American-derived equations fit for predicting FEV1 and FVC in those with an African ancestry above the median (81-100%), whereas composite equations for "other/mixed" populations fit for predicting FEV1 and FVC in those with an African ancestry below the median (31-81%). Among Puerto Rican children, White-derived equations fit for predicting FEV1, and the composite equations fit for predicting FVC for those with African ancestry above the median (21-88%). In contrast, in Puerto Rican children with African ancestry below the median (6-21%), only equations derived in Whites provide an adequate fit. INTERPRETATIONGuideline-recommended spirometry reference equations yielded biased estimates of lung function in admixed populations with high variation of African ancestry. Spirometry is due for reference equations that incorporate genetic ancestry, either for more precise application of the current equations or the derivation and utilization of new equations.

RationaleAsbestos is posited to cause otherwise idiopathic pulmonary fibrosis (IPF); establishing this has important diagnostic and therapeutic implications. ObjectivesTo determine the association between occupational asbestos exposure and IPF; to investigate interaction with MUC5B rs35705950 genotype. MethodsMulti-centre, incident case-control study. Cases (n=494) were men diagnosed with IPF at 21 United Kingdom hospitals. Controls (n=466) were age-matched men who attended a hospital clinic in the same period. Asbestos exposure was measured using a validated job exposure matrix and a source-receptor model. The primary outcome was the association between asbestos exposure and IPF, estimated using logistic regression adjusted for age, smoking and centre. Interaction with MUC5B rs3570950 was investigated using a genetic dominant model. Measurements and Main Results327 (66%) cases and 293 (63%) controls ever had a high or medium asbestos exposure risk job; 8% of both cases and controls, had cumulative exposure estimates [&ge;] 25 fibre.ml-1.years. Occupational asbestos exposure was not associated with IPF, adjusted OR 1.1(95%CI 0.8-1.4; p=0.6) and there was no gene-environment interaction (p=0.2). Ever smoking was associated with IPF, OR 1.4 (95%CI 1-1.9; p=0.04). When stratifying for genotype there was significant interaction between smoking and work in an exposed job (p<0.01) for carriers of the minor allele of MUC5B rs3570950. ConclusionsOccupational asbestos exposure alone, or through interaction with MUC5B rs35705950 genotype, was not associated with IPF. However, exposure to asbestos and smoking interact to increase IPF risk in carriers of the minor allele of MUC5B rs3570950. Clinical trial registered with www.clinicaltrials.gov (NCT03211507).

BackgroundLung function assessment is essential for respiratory medicine and health. Recommended international reference values differ by race, which is controversial. We evaluated the effect of adjusting lung function for race on prevalence of lung function impairment, breathlessness and mortality in the US population. MethodsPopulation-based analysis of the National Health and Nutrition Examination Survey (NHANES) 2007-2012. Race was analyzed as black, white, or other. Lung function was assessed as forced expired volume in one second (FEV1) and forced vital capacity (FVC). Predicted normal values were calculated for each person using the Global Lung Initiative (GLI)-2012 equations for 1) white; 2) black; and 3) other/mixed populations. Outcomes were compared for the different reference values in relation to: prevalence of lung function impairment (<lower limit of normal [LLN]), moderate/severe impairment (<50%pred); self-reported exertional breathlessness; and mortality up to 31 December, 2015. FindingsWe studied 14,123 people (50% female); white (n=5,928), black (n=3,130), and other (n=5,065). Compared to those for white, black reference values identified markedly fewer cases of lung function impairment (FEV1) both in black people (9.3% vs. 36.9%) and other non-white races (1.5% vs. 9.5%); and prevalence of moderate/severe impairment was approximately halved. Outcomes among those impaired differed by reference value used: white (best outcomes), other/mixed (intermediate), and black (worst outcomes). Black people with FEV1 [&ge;]LLNblack but <LLNwhite had 48% increased rate of breathlessness and almost doubled mortality, compared to blacks [&ge;]LLNwhite. Lung function [&ge;]LLNwhite identified people with good outcomes, similarly in black and white people. Findings were similar when analyzing FEV1 or FVC. InterpretationRace adjustment of lung function should be abandoned. White reference values are most sensitive and specific to identify impairment, and could be applied across the population for improved assessment and health equity. FundingSwedish Research Council (Dnr: 2019-02081). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE and Embase using search terms including "race", "ethnicity", "pulmonary function", "spirometry", and "prediction equations" from database inception and January 10, 2022, for papers published in English. A total 33 papers related to lung function and race were identified. Race-adjusted lung function reference values were recommended by major guidelines for use internationally. Race-specific references assume a 10-15% lower lung function, such as the forced expired volume in one second (FEV1) and forced vital capacity (FVC), in black people and 4-6% lower in Asian people compared with in whites. Compared to not adjusting for race, race-adjusted lung function values have recently been questioned as they have been found to not improve prediction of outcomes in population-based studies or in people at risk of obstructive pulmonary disease. Concerns have been raised that, contrary to the intent, race-adjusted reference values may contribute to under diagnosis of disease in disadvantage minorities, with the largest differences reported in black (Afro-American) people, and may worsen race-related health inequalities. Data on the impact of race-adjusted lung function values across the ethnically diverse population are limited and data on how to decrease racial bias in lung function assessment are needed. Added value of this studyWe analyzed the impact of using different race-specific (GLI-2012) reference equations for FEV1 and FVC across the US population in the National Health and Nutrition Examination Survey (NHANES) 2007-2012. Outcomes were prevalence of lung function impairment (value < lower limit of normal), breathlessness on exertion, and mortality up to December 31, 2015. Compared to using references for whites, black reference values were less likely to identify lung function impairment across all races but especially in blacks (9.3% vs. 36.9%); and those identified had lower lung function, more breathlessness, and worse prognosis. Black people with lung function normal by black standards but impaired by white standards had increased prevalence of breathlessness and mortality, compared to those normal also by white standards. Thus, race-adjusted reference values labeled black people as normal despite worse outcomes. White normal values identified people with similarly good lung function, and low rates of breathlessness and mortality across races groups. Implications of all the available evidenceThe findings from this study support that race-adjusted reference values markedly under diagnose lung function impairment, and related breathlessness, and mortality in underprivileged groups across the US population. Normal values for whites were most sensitive to identify lung function impairment related to worsening outcomes and people classified as having normal lung function with similar good outcomes irrespective of race group. These findings suggest that lung function should not be adjusted for race. When applied across the population, white reference values were most sensitive to identify smaller or earlier impairment and most specific to identify people with normal lung function with similarly good outcomes across race groups. Given the large impact shown, abandoning the use of race-adjusted lung function values is likely to contribute to improved health equity.

ObjectivesAlthough wood dust remains a leading cause of occupational asthma (OA) in Great Britain, there have been no recent studies in British woodworkers. This cross-sectional study examined asthma risk factors in woodworkers across exposure groups. MethodsParticipants answered a respiratory questionnaire and underwent fractional exhaled nitric oxide (FENO), spirometry, and specific immunoglobulin E measurements. Wood dust exposure was assigned through a specific job-exposure matrix. Multiple regression evaluated asthma risk factors identified a priori including wood dust exposure, atopy, and current asthma symptoms. ResultsA total of 269 woodworkers participated. Median wood dust exposure was 2.00mg/m3 (IQR 1.14 mg/m3). Current asthma symptoms (CAS), work-related respiratory symptoms (WRRS) and eosinophilic airway inflammation (FENO >40ppb) were common, present in 46%, 11% and 19% of the cohort, respectively. Atopic woodworkers were at increased risk of WRRS (OR 2.78, 95% CI 1.11 - 6.92, p<0.05), asthma (OR 3.40, 1.49 - 7.81, p<0.01), and FENO >40ppb (unadjusted OR 2.00, 1.03 - 3.88, p<0.05). No effect was seen for airflow obstruction. Workers with CAS were at increased risk of WRRS and ever asthma (4.29, 2.12 - 8.69, p<0.001) but not FENO >40ppb or airflow obstruction. Increasing exposure did not significantly increase risk of asthma symptoms, asthma, airflow obstruction and inflammation. ConclusionsAsthma symptoms were prevalent among British woodworkers, even at low exposure levels. Atopy significantly increased asthma risk, particularly among symptomatic woodworkers. Further studies to phenotype and endotype populations of workers at risk of, and suffering from, wood dust OA will inform future approaches to screening and diagnosis in these populations. What is already known on this topicWood dust is a leading cause of occupational asthma (OA) in Great Britain. No recent studies have described risk factors for OA in British woodworkers. Evidence identifies atopy, asthma symptoms, and wood species as risk factors for OA, but not consistently so. What this study addsThis cross-sectional study used a detailed job-exposure matrix, questionnaire and clinical data to understand risk factors for asthma in British woodworkers. We found upper airway, asthma symptoms (CAS), work-related symptoms and eosinophilic airway inflammation to be common among British woodworkers, but specific sensitisation to wood dust was low. Among workers with asthma symptoms atopy significantly increased the risk of CAS, asthma, and airway inflammation in woodworkers. Increasing wood dust exposure was not associated with an increased risk of asthma symptoms or asthma. How this study might affect research, practice or policyThis research provides the first epidemiological study on asthma in British woodworkers for decades and highlights specific risk factors for asthma in this group. This data is useful to inform health surveillance programmes and may help inform any future review of exposure limits. This research also helps to understand the phenotype of asthma caused by wood dust which is an area requiring further exploration.

ObjectiveTo evaluate the synergistic effects created by fine particulate matter (PM2.5) and corticosteroid use on hospitalization and mortality in older adults at high-risk for cardiovascular thromboembolic events (CTEs). Design and SettingA retrospective cohort study using a US nationwide administrative healthcare claims database. ParticipantsA 50% random sample of participants with high-risk conditions for CTE from the 2008-2016 Medicare Fee-for-Service population. ExposuresCorticosteroid therapy and seasonal-average PM2.5. Main Outcome MeasuresIncidences of myocardial infarction or acute coronary syndrome, ischemic stroke or transient ischemic attack, heart failure, venous thromboembolism, atrial fibrillation, and all-cause mortality. We assessed additive interactions between PM2.5 and corticosteroids using estimates of the relative excess risk due to interaction (RERI) obtained using marginal structural models for causal inference. ResultsAmong the 1,936,786 individuals in the high CTE risk cohort (mean age 76.8, 40.0% male, 87.4% White), the mean PM2.5 exposure level was 8.3 {+/-} 2.4 g/m3 and 37.7% had at least one prescription for a systemic corticosteroid during follow-up. For all outcomes, we observed increases in risk associated with corticosteroid use and with increasing PM2.5 exposure. PM2.5 demonstrated a non-linear relationship with some outcomes. We also observed evidence of an interaction existing between corticosteroid use and PM2.5 for some CTEs. For an increase in PM2.5 from 8 g/m3 to 12 g/m3 (a policy-relevant change), the RERI of corticosteroid use and PM2.5 was significant for heart failure (15.6%, 95% CI: 4.0%-27.3%). Increasing PM2.5 from 5 g/m3 to 10 g/m3 yielded significant RERIs for incidences of heart failure (32.4; 95% CI: 14.9%-49.9%) and myocardial infarction/acute coronary syndromes (29.8%; 95% CI: 5.5%-54.0%). ConclusionPM2.5 and systemic corticosteroid use were independently associated with increases in CTE hospitalizations. We also found evidence of significant additive interactions between the two exposures for heart failure and myocardial infarction/acute coronary syndromes suggesting synergy between these two exposures. Strengths and Limitations of this StudyO_LIWe conduct analyses using robust causal inference and machine learning techniques and incorporate a large set of individual-level factors that are typically absent in environmental health analyses with large claims data sets. C_LIO_LIWe present statistics that evaluate the synergy between fine particulate matter and corticosteroid therapy on the additive scale, which is more relevant for assessing excess risks and informing policy. C_LIO_LIPatient medical history prior to receiving Medicare benefits is unknowable within a Fee-for-Service claims database, which may lead to exclusion of some high-risk individuals from the cohort. C_LIO_LIWe censor participants after the earlier of the end of first corticosteroid regimen or the first incidence of the outcome of interest, which makes the analyses statistically tractable but sacrifices some information in the data. C_LI

BackgroundInterstitial lung abnormalities (ILA) are radiologic findings of increased lung density or fibrosis in individuals without clinical interstitial lung disease (ILD) and are associated with increased mortality and progression to ILD. Understanding physiologic trajectories of lung function preceding ILA diagnosis may illuminate early mechanisms of lung injury. MethodsWe recruited participants from the Coronary Artery Risk Development in Young Adults (CARDIA) Lung Study, a prospective cohort of adults enrolled at ages 18-30 years and followed longitudinally for 25 years. Percent predicted forced vital capacity (ppFVC) was measured at five study visits over 20 years. Individual ppFVC trajectories were estimated using random coefficient models. Person-specific slopes were incorporated into logistic regression models to examine associations with visually detected ILA on chest CT at exam year 25. Models were adjusted for age, sex, race, body mass index, pack-years of smoking, and study center. ResultsAmong 3,136 participants with complete data, 57 (1.8%) had ILA at mean age 51 years. In univariable and multivariable models, individuals with ILA had greater cumulative decline in ppFVC over the 20 years preceding diagnosis. Each 10% absolute decline in ppFVC was associated with more than twice the odds of ILA (adjusted OR 2.21, 95% confidence interval 1.47-3.31, p = 0.0001). ConclusionsGreater longitudinal decline in FVC from early adulthood was strongly associated with the presence of ILA at midlife. These findings suggest that physiologic impairments precede radiologic evidence of subclinical parenchymal lung abnormalities, underscoring the potential of life course lung function trajectories to identify individuals at risk for developing ILD.

BackgroundWomen are more likely than men to report delays in the diagnosis of chronic obstructive pulmonary disease (COPD), though the etiology of these delays is unknown. We sought to test whether delays in COPD diagnosis persist after the performance of spirometry. MethodsWe used the Optum Labs Data Warehouse to identify patients 18 years of age and older without a prior diagnosis of COPD, with a post-bronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio of less than 0.7 on spirometry. We used a Cox proportional hazards model to compare the time to diagnosis after spirometry in men and women, adjusting for age, race, ethnicity, tobacco use, and post-bronchodilator FEV1/FVC. ResultsThe probability of receiving a COPD diagnosis after the performance of spirometry was lower among women than men (adjusted hazard ratio [aHR] 0.66, 95% confidence interval [CI] 0.50 to 0.88) ConclusionIn this retrospective cohort study of patients with spirometric evidence of obstruction, the time to diagnosis of COPD was greater among women than men. While previous vignette-based studies have found that gender differences in the diagnosis of COPD resolve with the performance of spirometry, we found that gender differences persist after spirometry has been performed. Clinicians were less likely to diagnose COPD in women even when spirometry supported this diagnosis.

ObjectiveMyositis-associated interstitial lung disease (myositis-ILD) consists of two predominant radiologic patterns of lung injury--nonspecific interstitial pneumonia (NSIP) and organizing pneumonia (OP)--that oftentimes coexist. However, it remains unclear whether either is associated with clinical outcomes. We aimed to assess the therapeutic response in patients with NSIP-compared to those with OP-predominant myositis-ILD. MethodsThis retrospective, single-center cohort study recruited participants from the Northwestern University ILD Registry with a circulating myositis-associated antibody, ILD, and at least 6 months of follow-up while on immunomodulatory therapy during a 24-month observation period after diagnosis. Two thoracic radiologists determined the predominant radiologic pattern (NSIP or OP). The primary outcome was the absolute change in forced vital capacity (FVC) at 24 months post-diagnosis. Secondary outcomes included changes in the diffusing capacity of the lung for carbon monoxide (DLCO) and radiologic qualitative and quantitative measures of lung injury. ResultsForty-one participants were included in analyses. 71% had an OP-predominant while 29% had an NSIP-predominant radiologic pattern of lung injury. Both exposure cohorts had improvement in mean absolute FVC (OP cohort = +0.18L [p=0.005], NSIP cohort = +0.24L [p=0.07]) over the 24-month observation period. The OP (p<0.05) but not the NSIP cohort (p=0.20) had an increase in DLCO. The OP cohort demonstrated improvement in the qualitative assessment of follow-up imaging (p<0.05), driven by quantitative improvement in groundglass/consolidative opacities (p=0.006). A subset of participants demonstrated features of NSIP/OP overlap and had greater baseline radiologic severity of lung injury. ConclusionPatients with circulating myositis-associated antibodies and an OP-predominant pattern of lung injury may have a more favorable response to therapy than those with NSIP. Further studies are needed to validate our findings and delineate other features cognate with these associations. Significance and InnovationsO_LIRadiologic phenotyping may predict therapeutic response in myositis-ILD. This study demonstrates that an OP-predominant computed tomography (CT) pattern of lung injury is associated with greater improvement in lung function and radiologic signs of inflammation over 24 months on at least 6 months of immunomodulatory therapy compared with an NSIP-predominant pattern, suggesting that CT pattern may provide clinically meaningful prognostic information. C_LIO_LIFirst study to integrate blinded qualitative radiologic adjudication with quantitative CT scoring in myositis-ILD. By combining dual-radiologist review with Kazerooni quantitative scoring and longitudinal pulmonary function testing, this study offers a rigorous and multidimensional assessment of treatment response. C_LIO_LIExpands risk stratification beyond antibody-based toward imaging-based phenotyping strategies. In a heterogeneous population defined by diverse myositis-associated antibodies, this work introduces radiologic pattern as a practical and accessible framework for anticipating treatment responsiveness. C_LIO_LIProvides hypothesis-generating data for precision management in myositis-ILD. The findings support the concept that imaging-defined subgroups may exhibit differential therapeutic trajectories, laying groundwork for future multicenter studies integrating CT phenotype, antibody profile, and treatment strategy. C_LI

RationaleChildhood cancer survivors (CCS) are at risk for long-term pulmonary complications from treatment-related toxicity. Nitrogen multiple-breath washout (N2MBW) may detect small airway dysfunction earlier than standard pulmonary function tests (PFTs), but its value in CCS remains uncertain. ObjectivesTo determine the prevalence of ventilation inhomogeneity measured by N2MBW in CCS, evaluate whether it detects abnormalities beyond spirometry and diffusion capacity for carbon monoxide (DLCO), and explore associations with treatment exposures. MethodsIn this prospective multicenter study (Bern, Basel, Geneva), we measured lung function in CCS aged 6-21 years who were undergoing routine follow-up. We stratified participants into high-risk (pulmotoxic chemotherapy [busulfan, bleomycin, nitrosoureas], thoracic surgery or radiotherapy, or hematopoietic stem cell transplantation [HSCT]) and standard-risk (other systemic anticancer treatments). PFTs included N2MBW (lung clearance index [LCI], acinar [SACIN] and conductive [SCOND] inhomogeneity), spirometry (forced expiratory volume in 1 second [FEV], forced vital capacity [FVC]), and DLCO. Abnormal values were defined as z-score <-1.645 or >1.645, calculated using the Global Lung Initiative references. We quantified the proportion of participants with isolated elevated LCI and analyzed associations with treatment exposures using multivariable linear regression. ResultsWe included 191 CCS (median 7 years post-diagnosis). Mean LCI was 6.27 (95%CI 6.17-6.37), with 7% abnormal. N2MBW results did not differ between high- and standard-risk groups, but allogeneic HSCT survivors had the highest mean LCI (7.18, 95%CI 5.88-8.37), with 33% abnormal. Survivors had mildly impaired mean FEV1, FVC, and DLCO z-scores (-0.21, -0.34, 0.23), more pronounced in high-risk CCS (-0.67, -0.85, -0.05). Isolated LCI impairment, without abnormalities in spirometry or DLCO, occurred in only 3%. Among treatment exposures, only allogeneic HSCT was associated with higher LCI (1.40, 95%CI 0.57-2.33) and SACIN (1.24, 95%CI 0.20-2.28). ConclusionMost pediatric CCS had normal lung function. N2MBW abnormalities were rare, occurring mainly in allogeneic HSCT survivors. Overall, N2MBW added little beyond standard PFTs, suggesting it may not be needed for routine follow-up at this stage, except after allogeneic HSCT. Larger, longitudinal studies should clarify the onset, progression, and prognostic significance of N2MBW abnormalities and their potential role in risk-adapted follow-up care.

RationalePreserved ratio impaired spirometry (PRISm), defined as an impaired forced expiratory volume in one second (FEV1) with a preserved ratio of FEV1 to forced vital capacity (FVC), is associated with increased risk of airflow obstruction (AFO) and mortality in the general population. However, evidence is limited among the individuals with silicosis, an old occupational disease with an ongoing outbreak in some developed countries. ObjectivesTo investigate the association of PRISm with the risk of mortality and incident AFO in a cohort of workers with silicosis. MethodsA total of 4315 workers aged 18-80 years and diagnosed with silicosis at the Pneumoconiosis Clinic, Tuberculosis and Chest Service during 1981-2019 were enrolled in this study and followed up for a median of 12.3 years till 31 December 2019. Spirometry was included in the diagnostic examination of silicosis and follow-up reassessments. Lung function categories of participants were classified as normal spirometry (FEV1/FVC [&ge;] 0.7, FEV1 [&ge;] 80% predicted), PRISm (FEV1/FVC [&ge;] 0.7, FEV1 < 80% predicted), and AFO (FEV1/FVC < 0.7). The hazard ratio (HR) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusting for age, body mass index, tuberculosis history, smoking, and radiographic characteristics. Measurements and Main ResultsDuring the follow-up period, a total of 2399 (55.6%) subjects died, 1359 of whom died from respiratory-related diseases, and 780 subjects developed AFO. Subjects with PRISm had significantly increased multivariable-adjusted risk of all-cause death (adjusted HR=1.63, 95% CI 1.44-1.85) and respiratory-related mortality (adjusted HR=1.74, 95% CI 1.48-2.05) as compared with the those with normal spirometry. Besides, there was a higher risk of developing AFO in subjects with PRISm than in those with normal spirometry (adjusted HR=1.46, 95% CI 1.22-1.75). No significant interaction was observed between PRISm and smoking status in the risk of all-cause mortality and incident AFO. ConclusionsPRISm is significantly associated with increased all-cause and respiratory-related mortality and a greater risk of progression to AFO among the individuals with silicosis.

IntroductionThe association between air pollution and poor respiratory health outcomes is well established, however less is known about the biological mechanisms, especially in early life. Children are particularly at risk from air pollution, especially during the prenatal period as their organs and systems are still undergoing crucial development. Therefore, our study aims to investigate if maternal exposure to air pollution during pregnancy is associated with oxidative stress (OS) and inflammation in pregnancy or infant lung function at 4 weeks of age, and the extent to which the association is modified by an infants genetic risk of OS. MethodsThe Barwon Infant Study (BIS) is a longitudinal study of Australian children from the region of Geelong, Victoria. A total of 314 infants had available lung function and maternal OS markers. Exposure to annual air pollutants (NO2 and PM2.5) were estimated using validated, satellite-based, land-use regression models. Infant lung function was measured by multiple-breath washout, and the ratio of peak tidal expiratory flow over expiratory time was calculated at 4 weeks of age. An inflammation biomarker, glycoprotein acetyls (GlycA), was measured in maternal (36 weeks) and cord blood, and oxidative stress (OS) biomarkers, 8-hydroxyguanine (8-OHGua) and 8-hydroxy-2-deoxyguanosine (8-OHdG) were measured in maternal urine at 28 weeks. A genetic pathway score for OS (gPFSox) was calculated for each infant participant in the BIS cohort, and high risk defined as score >8. Linear regression was used to explore the association of maternal air pollution exposure with infant lung function, and potential modification by OS genotype was tested through use of interaction terms and other methods. ResultsThere was no evidence of a relationship between maternal exposure to air pollution and infant lung function in the whole population. We did not find an association between air pollution and GlycA or OS during pregnancy. We found evidence of an association between NO2 and lower in functional residual capacity (FRC) for children with a high genetic risk of OS ({beta}=-5.3 mls, 95% CI (-9.3, -1.3), p=0.01). We also found that when NO2 was considered in tertiles, the highest tertile of NO2 was associated with increase in lung clearance index (LCI) ({beta}=0.46 turnovers, (95% CI 0.10, 0.82), p=0.01) in children with a genetic propensity to OS. ConclusionOur study found that high prenatal levels of exposure to ambient NO2 levels is associated with lower FRC and higher LCI in infants with a genetic propensity to oxidative stress. There was no relationship between maternal exposure to air pollution with maternal and cord blood inflammation or OS biomarkers.

RationaleIn contrast to visual assessments, quantitative CT using multiple instance learning (MIL)-usual interstitial pneumonia (UIP) classifier and data-driven textural analysis (DTA) provides objective and reproducible measurements of disease pattern and extent, respectively. However, the understanding of their individual or combined relationships with outcomes in hypersensitivity pneumonitis (HP) remains limited. ObjectivesTo determine whether visual CT patterns of HP or UIP, a MIL-UIP classifier, baseline and changes in DTA over 12 months and DTA at 12 months are associated with progression-free survival (PFS) in HP. MethodsThe primary cohort included 134 participants with HP. Associations between CT variables and subsequent lung function change, and PFS were assessed using linear mixed models and Cox hazards models. Results were validated in a combined dataset from three independent populations (N=216). ResultsVisual patterns of HP or UIP were not associated with PFS. A baseline MIL-UIP classification and DTA were significantly associated with 24-month PFS. However, a MIL-UIP classifier did not significantly predict PFS after adjusting for extent of fibrosis measured by DTA. Over 12 months, a 1-point increase in DTA across and within patients resulted in a significant decline in FVC% and DLCO%. A 12-month change in DTA (HR=1.07, 95%CI 1.01-1.13) and DTA at 12-months (HR=1.03, 95%CI 1.01-1.05) were associated with subsequent 12-month PFS. Similar estimates were observed in the validation cohort. ConclusionsIn HP, the objectively measured extent of lung fibrosis is more prognostic than either a UIP classifier or visual CT patterns of HP or UIP. Baseline DTA, DTA at 12 months, and its change over 12 months are associated with decreased PFS.

Idiopathic pulmonary fibrosis (IPF) is a rare disease that is challenging to diagnose. Patients with IPF often spend years awaiting a diagnosis after the onset of initial respiratory symptoms, and only a small percentage receive antifibrotic treatment. In this study, we examine the associations between social determinants of health (SDoH) and two critical factors: time to IPF diagnosis following the onset of initial respiratory symptoms, and whether the patient receives antifibrotic treatment. To approximate individual SDoH characteristics, we extract demographic-specific averages from zip code-level data using the American Community Survey (via the U.S. Census Bureau API). Two classification models are constructed, including logistic regression and XGBoost classification. The results indicate that for time-to-diagnosis, the top three SDoH factors are education, gender, and insurance coverage. Patients with higher education levels and better insurance are more likely to receive a quicker diagnosis, with males having an advantage over females. For antifibrotic treatment, the top three SDoH factors are insurance, gender, and race. Patients with better insurance coverage are more likely to receive antifibrotic treatment, with males and White patients having an advantage over females and patients of other ethnicities. This research may help address disparities in the diagnosis and treatment of IPF related to socioeconomic status.

Background: Randomized controlled trials have shown that computed tomographic (CT) screening reduces lung cancer mortality. Improved identification of at-risk groups, by leveraging non-smoking risk factors, could help refine screening selection. Aim: To evaluate polygenic risk scores (PRSs) and ambient air pollution (AAP) exposure for risk stratification in the NELSON lung cancer screening cohort. Methods: Two PRSs (PRS-McKay/PRS-Byun) and several AAPs (including nitrogen dioxide, ozone, and particulate matter [PM]) were assessed in the NELSON lung cancer screening trial (N=7,364). PRSs were validated in the Rotterdam Study (N=11,493). Associations with lung cancer, mortality, screening results, and discriminative ability to distinguish lung cancer were evaluated. Results: PRS-McKay and PRS-Byun were associated with lung cancer (odds ratio [OR] per SD [95%CI]: 1.22 [1.08-1.37] and 1.28 [1.13-1.44], respectively) and lung cancer-specific mortality (OR [95%CI]: 1.24 [1.05-1.47], for both), but not with non-lung cancer mortality (OR [95%CI]: 1.01 [0.94-1.10] and 1.03 [0.95-1.12], respectively). Exposure to PM2.5 was associated with lung cancer (OR [95%CI]: 1.11 [1.01-1.22]). PM constituents were associated with adenocarcinoma, particularly PM10 (OR [95%CI]: 1.16 [1.01-1.32]) and ultra-fine particles (OR [95%CI]: 1.16 [1.04-1.30]). PRS and AAP added modestly to the discriminative ability for lung cancer on top of pack-years, age, and sex (area under the curve [95%CI]: 0.659 [0.624-0.695] vs. 0.643 [0.608-0.679]). Conclusions: PRSs and exposure to PM were associated with lung cancer in a high-risk screening population. The primary potential of PRSs may reside in refining lung cancer screening selection toward individuals at higher risk of dying from lung cancer specifically.