ABSTRACT Background The systemic immune responses associated with persistent respiratory symptoms (PRS) after exposure to airborne environmental pollutants remain poorly understood. Objective To identify immune disturbances associated with PRS, defined as persistent wheeze, cough, or breathlessness, we examined systemic immune responses and airway function in a cross-sectional cohort with detailed histories of airborne pollutant exposure. Methods Never-smoking post-deployment Veterans with PRS (n=16) or without PRS (n=24) underwent chest computed tomography, pulmonary function testing, and oscillometry to assess structural and functional airway abnormalities. Peripheral blood mononuclear cells (PBMCs) were stimulated with anti-CD3/CD28 antibodies, lipopolysaccharide, or β-glucan, and cytokine production was measured. Correlation analyses evaluated associations between cytokine responses and physiological measures of airway function. Results Oscillometry, but not conventional pulmonary function testing or chest computed tomography, detected small-airway abnormalities in participants with PRS, including significantly greater frequency dependence of resistance and higher resonant frequency. Baseline PBMC cytokine concentrations were similar between groups. After stimulation, however, PBMCs from participants with PRS showed increased IL-17A production consistent with a type 17 (T17) response; innate stimulation also increased the type 2 (T2) cytokines IL-33 and IL-4. T2/T17 cytokine responses correlated positively with oscillometric measures of small-airway dysfunction. Conclusion Individuals with PRS exhibited a stimulus-dependent systemic T2/T17 immune signature that was associated with early small-airway dysfunction. Clinical Implication Stimulus-dependent systemic immune profiling, combined with oscillometry, may help identify early respiratory abnormalities in pollutant-exposed individuals whose conventional pulmonary tests remain normal. KEY MESSAGES Oscillometry detected early small-airway dysfunction in pollutant-exposed individuals with persistent respiratory symptoms, whereas conventional pulmonary function tests and chest CT did not distinguish the groups. Immune stimulation revealed a mixed T2/T17 systemic signature in participants with persistent respiratory symptoms, including increased IL-17A and stimulus-dependent increases in IL-4 and IL-33. T2/T17 cytokine responses correlated with oscillometric abnormalities, linking systemic immune dysregulation to small-airway dysfunction and suggesting a potential approach for identifying early pollutant-associated respiratory disease. CAPSULE SUMMARY A stimulus-dependent systemic T2/T17 immune signature correlated with oscillometric evidence of small-airway dysfunction, identifying a potential early respiratory phenotype in pollutant-exposed individuals with persistent respiratory symptoms.

BACKGROUND:We investigated associations of self-reported and job exposure matrix (JEM) assigned civilian occupational exposure to vapors, gas, dust, or fumes (VGDF) with respiratory symptoms among previously deployed US Veterans. METHODS:An interviewer-administered questionnaire ascertained self-reported civilian occupational VGDF exposure. A JEM categorized occupational VGDF based on longest-held civilian occupation and industry of employment. Models tested associations of self-reported and JEM-assigned VGDF with dyspnea, chronic bronchitis (CB), or wheeze, adjusting for smoking and other covariates. RESULTS:Among 1868 participants (mean age 37.8 ± 13.1 years); 1654 (89%) males; the median occupational duration was 6 years. The prevalence of JEM-assigned VGDF exposure or self-reported civilian occupational VGDF exposure was 31% for both, with modest agreement between them (kappa 0.48). Any JEM VGDF exposure was statistically significantly associated with increased odds of CB (odds ratio [OR]) 1.75; 95% Confidence Interval [CI] 1.05-2.20). Self-reported VGDF exposure was less strongly associated with increased CB odds (OR 1.18; 95% CI 0.85-1.86). JEM alone demonstrated a statistically significant association with CB (OR 1.77; 95% CI 1.31-2.68); combined JEM and self-reported VGDF demonstrated a similar but not statistically significant association with CB (OR 1.68; 95% CI 0.90-2.35). Self-reported VGDF alone was not positively associated with CB, dyspnea, or wheeze. CONCLUSIONS:Civilian occupational VGDF exposures (assessed by self-report and JEM) were common. Exposure to VGDF was most consistently associated with increased odds of CB, underscoring the need to consider civilian occupational factors when assessing Veterans' health.

RATIONALE:Occupational exposures to dust and fumes are associated with increased respiratory symptoms and worse lung function, however, their effect on future clinical outcomes has been incompletely explored. OBJECTIVES:To examine the associations between self-reported occupational exposure to dust and fumes on future respiratory exacerbations, cardiovascular events, and other clinical outcomes in smokers. METHODS:Current and former smokers, aged 45-80, enrolled in COPDGene were assigned to four mutually-exclusive occupational exposure groups (No Exposure, Dust-Only, Fumes-Only, Dust-and-Fumes Exposure) based on questionnaire responses at baseline. Clinical outcomes were assessed prospectively for up to 15 years. Respiratory exacerbations (REs) were defined as worsening respiratory symptoms requiring treatment with steroids and/or antibiotics; binary outcomes included atherosclerotic cardiovascular disease (ASCVD), cancer, pneumonia, and blood clots. Multivariable-adjusted models estimated the association between occupational exposure category and each clinical outcome. MEASUREMENTS AND MAIN RESULTS:Among 8,991 participants (mean ± SD age 60.1 ± 9.0 years, 51.7% male, 49.3% current smokers), the prevalence of dust-only, fumes-only, and dust-and-fumes exposure was 12.0%, 12.4%, and 34.4%, respectively. Self-reported occupational exposure to both dust-and-fumes was associated with increased risk of future REs (adjusted rate ratio, aRR [95% CI] 1.38 [1.26-1.52]) relative to those reporting no exposures. Exposure to both dust-and-fumes was also associated with an increased risk (adjusted odds ratio, aOR, [95%CI]) for future ASCVD (1.35 [1.17-1.56]) and pneumonia (1.39 [1.19-1.63]), but was not associated with future cancer or blood clots. CONCLUSION:Self-reported occupational exposure to dust-and-fumes is associated with increased future risk for multiple clinically-relevant outcomes among tobacco-exposed individuals. CLINICALTRIALS.GOV:NCT00608764 (COPDGene).

Understanding the potential health implications of living near nuclear power plants is important given the renewed interest in nuclear energy as a low-carbon power source. Here we show that U.S. counties located closer to operational nuclear power plants have higher cancer mortality rates than those farther away. Using nationwide mortality data from 2000-2018, we assess long-term spatial patterns of cancer mortality in relation to proximity to nuclear facilities while accounting for socioeconomic, demographic, behavioral, environmental, and healthcare factors. Cancer mortality is higher across multiple age groups in both males and females, with the strongest associations among older adults, males aged 65-74 and females aged 55-64. While our findings cannot establish causality, they highlight the need for further research into potential exposure pathways, latency effects, and cancer-specific risks, emphasizing the importance of addressing these potentially substantial but overlooked risks to public health.

OBJECTIVE:To assess care-seeking patterns and incident diabetes risk following SARS-CoV-2 infection in a prospective longitudinal cohort. RESEARCH DESIGN AND METHODS:We used data from the Veterans Health Administration (VHA)-based, prospective longitudinal study Epidemiology, Immunology, and Clinical Characteristics of COVID-19 (EPIC3) and electronic health records from participants with and without a history of SARS-CoV-2 infection who were free from diabetes at baseline and enrolled between June 2020 and September 2022 (n = 1,212); participants were followed prospectively for a median of approximately 4 years. We fit Cox proportional hazard models to examine associations of prior SARS-CoV-2 infection with incident diabetes. Models were adjusted for age, sex, race, smoking status, BMI, education, and comorbidities, as well as number of laboratory test days in the year prior. RESULTS:Men comprised 79.4% of the cohort. Median age was 50.1 (SARS-CoV-2-positive) and 57.2 (SARS-CoV-2-negative) years. After accounting for time-varying SARS-CoV-2 infection status, compared to participants with a negative test, participants with a positive test had fewer days/year with clinic visits (18.2 vs. 25.4, p < 0.001), laboratory tests of any kind (3.1 vs. 4.3, p < 0.001), and glucose tests (1.8 vs. 2.8, p < 0.001) post-enrollment; however, the number of days/year on which they had HbA1c tests was not significantly different (0.7 vs. 0.7, p = 0.094); diabetes incidence was 16.1 and 21.2 per 1,000 person-years in SARS-CoV-2 positive and negative groups, respectively. SARS-CoV-2 was not associated with adjusted diabetes-free survival overall, in inpatients or in outpatients (adjusted HRs: 0.82 [95% CI, 0.51-1.35], 1.03 [0.27-3.96], and 0.79 [0.44-1.39], respectively). CONCLUSION:Although SARS-CoV-2-positive participants used healthcare less often than those without, HbA1c testing rates were similar. We did not replicate prior reports of higher diabetes risk after SARS-CoV-2, although small sample size may have reduced power to detect modest associations. NCT: NCT05764083.

Radon is a natural radioactive gas well-known for its carcinogenic effects. The association between radon and lung cancer is well-documented, with radon exposure the leading cause of lung cancer in non-smokers and the second leading cause of lung cancer in smokers in adults. However, relatively little is known about the association between radon and non-cancer respiratory disease. This review examines the role of radon's non-cancer pulmonary health effects in children, as there have been several recent studies highlighting a potentially under-recognized threat to lung health. Recent epidemiologic data in adults suggest radon and particle radioactivity attributable to radon decay products are associated with reduced pulmonary function and non-cancer related COPD morbidity and mortality, while in pediatrics, modeled radon has been reported to be associated with asthma morbidity. Recent findings of radon's non-cancer respiratory effects further highlight the role of avoidance of this environmental exposure and radon mitigation1 as an implementable strategy to improve lung health. Further research is needed to expand our understanding of radon's potential role in non-cancer respiratory health and how to optimize radon mitigation strategies to improve non-cancer pulmonary health morbidity and outcomes. The purpose of this state-of-the-art review is to provide an overview of the current state of knowledge of radon's non-cancer respiratory health effects, highlighting our current understanding of radon's known health outcomes, synthesize how health outcome findings of this topic have changed over time to give rise to our current understanding of radon's pulmonary health effects in children, and suggest future directions for research.

Land-based military deployers to Afghanistan and/or Southwest Asia (SWA) encountered exposure to high concentrations of respirable particulate matter (PM) from multiple sources, including desert dust, burn pit smoke, and military occupations. Adverse lung health effects following deployment have been noted, including upper and lower respiratory tract symptoms, asthma, and small airway and other abnormalities on lung biopsy. The American Thoracic Society (ATS) convened a workshop in 2018 to review studies assessing postdeployment respiratory health, describe emerging research, and highlight knowledge gaps. Progress on understanding postdeployment health prompted a second ATS workshop to update current knowledge by (1) reviewing new studies linking exposure assessments to symptoms and/or clinical disease; (2) describing the spectrum of lung pathology reported in previously deployed personnel; (3) evaluating current knowledge of long-term health outcomes after deployment; (4) reviewing data from recent experimental models of deployment-related respiratory diseases (DRRDs); and (5) providing recommendations for future research priorities. Workshop participants agreed that there is substantial evidence linking deployment-related exposures to respiratory symptoms, pulmonary diagnoses, and lung pathology. Knowledge gaps include understanding: (1) the extent and mechanisms through which specific exposures result in impaired pulmonary function, small airways disease, and potentially future chronic pulmonary diseases; (2) the contribution of exposure-related foreign material in the lung to clinical and pathologic findings; and (3) the relationship of pathologic findings to respiratory health, especially those involving small airways.

RATIONALE:Greater ambient air temperatures may have implications for respiratory health. While prior research has primarily examined the associations of air temperature with lung health in the general population, individuals with chronic obstructive pulmonary disease (COPD) may be particularly susceptible. This study aims to assess the associations between air temperature and pulmonary function, as well as biomarkers of inflammation and oxidative stress, in this potentially susceptible population. METHODS:We conducted a study of 166 participants with COPD (either a former or no history of smoking) from eastern Massachusetts, United States, who completed up to 4 visits over 12 months at the VA Boston Healthcare System between 2012 and 2017, yielding 620 observations. Daily mean temperature exposures, at a spatial resolution of 4 × 4 km, were assigned to geocoded home addresses. We used generalized additive mixed models to investigate associations of short-term temperature exposures at 0- to 1-day, 2- to 6-day, 0- to 6-day, and 0- to 13-day moving averages with repeated lung function measurements, blood biomarkers of systemic inflammation (high-sensitivity C-reactive protein [hsCRP], interleukin 6, soluble vascular cell adhesion molecule 1), and urinary biomarkers of oxidative stress (8-hydroxy-2'-deoxyguanosine, malondialdehyde), adjusting for confounders (eg, air conditioner usage and season). We performed mediation analyses to determine if temperature-lung function relationships were mediated by inflammatory or oxidative stress pathways. RESULTS:The population was 97.0% male, mean (SD) age = 72.8 (8.4) years, mean (SD) percent predicted forced expiratory volume in 1 second (FEV1%) = 66.2 (21.8), and mean (SD) temperature = 10.2 °C (10.4 °C). Higher temperature exposures at all moving averages were associated with lower FEV1. For example, per 5 °C increase in temperature at lags of 0 to 1 and 0 to 13 days, FEV1 decreased by (mL, 95% CI) 12.06 (-23.14 to -0.98) and 16.24 (-29.23 to -3.25), respectively. Similarly, higher temperature exposures were associated with lower forced expiratory volume in 1 second/forced vital capacity. There were positive associations between higher temperature across all moving averages and higher hsCRP. For instance, a 5 °C increase in temperature at lags of 0 to 1 days and 0 to 13 days was associated with percent increases in hsCRP of 6.37 (95% CI, 1.05-11.97) and 9.40 (95% CI, 3.02-16.16), respectively. hsCRP did not mediate the temperature-lung function relationship. Associations were similar, adjusting for indoor and outdoor air pollution. No associations were observed with forced vital capacity or other inflammatory or oxidative stress biomarkers. CONCLUSION:Short-term exposures to higher air temperatures were associated with lower lung function and higher hsCRP concentrations among individuals with COPD, suggesting that rising air temperature may be an important determinant of health in this susceptible group.

RATIONALE: Isolated diffusing abnormalities have been noted in Veterans deployed to Southwest Asia and Afghanistan who have environmental exposures which may reflect early structural pulmonary parenchymal and airway abnormalities that can be detected by CT imaging. METHODS: Veterans with land-based deployments, independent of medical treatment, were invited to participate in VA Cooperative Study #595, “Service and Health Among Deployed Veterans.” A subset of participants at 4 VA Medical Centers (Boston, Houston, Minneapolis, and Seattle) completed an additional assessment (a mean 14.7 years post-deployment) that included an inspiratory and expiratory high-resolution CT scan and measurement of diffusing capacity for carbon monoxide (DLCO). Scans were analyzed for %-emphysema (<-950 Hounsfield units (HU), inspiratory scan); %-gas-trapping (<-856 HU, expiratory scan); %-functional small airways disease (fSAD) defined as regions with gas trapping, but not due to emphysema; and Pi10, the square root of the airway wall area of a hypothetical 10-mm diameter airway, extrapolated by measuring distal to lobar airways. Multivariable linear regression models were used to assess associations between CT measures and diffusing capacity after adjustment for body mass index and study site. RESULTS: There were 117 participants (N=17, 14.5% women) with a mean (SD) age =47.0 (10.5) years and mean BMI=31.1 (6.3) who were deployed for a mean 13.0 (7.2) months, and included 15 (12.8%) former smokers with <10 pack-years (median 1.0)). Mean DLCO was 29.1 (6.5) mL/min/mmHg, DLCO % predicted 99.3% (14.4), with 6 (5.1%) participants with a DLCO below the lower limit of normal. Overall, the percentage of emphysema, gas trapping, and fSAD were below established pathological reference values: %-emphysema: median (25%ile-75%ile) =2.3 (0.8-4.4), 95%ile 9.3; %-gas trapping=3.0 (1.1 – 9.4), 95%ile 26.0; %-fSAD 2.5 (1.1-6.7) 95%ile, 22.9; Pi10=2.8 (2.7-2.9) mm. CT parameters were not associated with DLCO % predicted (Table). Sensitivity analyses that included models adjusting for smokers, pack-years and history of COVID infection were performed, and there was no association between CT measures and DLCO was seen. CONCLUSION: Among previously deployed Veterans who were randomly selected independent of symptoms or medical treatment the DLCO % predicted was generally preserved. There were no associations between the early CT changes of emphysema, gas trapping or airway thickness with diffusion capacity. This suggests that diffusing capacity may not be an early marker of mild lung abnormalities in deployed veterans.

Dyspnea, a debilitating symptom of COPD, worsens health-related quality of life (HRQL), reduces daily physical activity, increases health care utilization, and is more closely associated with survival than airflow limitation. Thus, having treatments that reduce dyspnea in COPD is important. Pulmonary hypertension (PH) is a common complication of COPD that is associated with severe dyspnea, more frequent COPD exacerbations, and increased mortality. Multiple causes of PH, including a reduction in bioavailable vasodilator nitric oxide (NO), are associated with COPD (COPD-PH). Phosphodiesterase type-5 inhibitor (PDE5i) therapy restores NO signaling and improves hemodynamics and dyspnea in patients with Group 1 Pulmonary Arterial Hypertension, but has not been proven effective in COPD-PH. In a prior study (ClinicalTrials. gov identifier: NCT01862536), we investigated effects of 12 months of oral PDE5i therapy with tadalafil on 6-min walk distance (6MWD) in a multi-center, randomized, placebo-controlled trial funded by the Department of Veterans Affairs. While tadalafil did not change 6MWD at 12 months, the treatment group experienced clinically meaningful improvements in patient-reported dyspnea and HRQL at 6 months. Because of the importance of mitigating dyspnea in COPD-PH, we developed a new study protocol examining the effect of PDE-5i therapy in COPD-PH, with a reduction in dyspnea the primary outcome. In the current study (NCT05937854), we will conduct a prospective, randomized, double-blind, multi-center clinical trial to evaluate the effects of 6 months of maximally tolerated therapy with tadalafil (target dose 40 mg/day) versus placebo on dyspnea, as measured by University of California San Diego Shortness of Breath Questionnaire.

U.S. military personnel deployed to Afghanistan and Iraq were stationed on bases impacted by airborne hazards including emissions from combustion sources. Due to limited environmental monitoring during military operations, exposure levels remain poorly characterized. We used satellite observations to identify the locations and persistence of combustion sources on and near military bases in Afghanistan and Iraq from 2002 to 2012, the peak period of open-air combustion. Daily fire detections from the Moderate Resolution Imaging Spectroradiometer (MODIS) were clustered using density-based methods to identify persistent burning within 5 km of bases. Validation was conducted using military imagery and Google Earth. A sensitivity analysis compared MODIS fire detections to those from the newer Visible Infrared Imaging Spectroradiometer (VIIRS) at a civilian burn pit in Djibouti. MODIS detected 285,810 fires in Iraq and 3702 in Afghanistan. Clustering identified 398 bases in Iraq and 122 in Afghanistan with burning nearby. In Iraq, persistent clusters were linked to oil and gas flares, while smaller clusters on bases in both countries were consistent with burn pits. MODIS and VIIRS both detected the Djibouti burn pit, but VIIRS recorded three times more fire detections, highlighting its sensitivity in detecting biomass and waste burning.

Given the importance of internal dosimetry from inhaled or ingested radioactive particles attributable to nuclear fuels and fission, in this study we analyzed samples collected from indoor home dusts and surface soils in areas surrounding and up to 13 km from the Pilgrim Nuclear Power Plant (PNPP) in Plymouth, Massachusetts (USA). Indoor dust (n=15) from homes (n=10) and outdoor soil samples (n=31, yielding a total of n=46 original samples) were analyzed by γ-spectrometry, and α- and β-rate counting. Sixteen aliquots (16) from the 46 samples were analyzed by α-spectrometry for varying combinations of isotopic uranium, and isotopic thorium, and by Scanning Electron Microscopy with Energy Dispersive X-ray analysis. Detection of uranium and thorium confirmed that radioactive particles were of power plant origin. The presence of fission-related radionuclides was also confirmed by α- and γ-spectrometry. The highest activities of cesium-137 and lead-210 were observed in public areas outside of radiation protection zones near the PNPP, but evidence of fission related radionuclides was found up to 12.1 km. Testing of soil and dust collected <1 km from the plant detected up to 20 times the background activity for cesium-137 and lead-210. Elevated thorium-234, and trace activities of cobalt-60 and uranium-235 were detected in surface soils sampled <1 km from the plant using γ-spectrometry, including uranium (>0.5%) and thorium (>5.0%) in microparticles. These isotopes were undetected or at background at beyond these distances. This study suggests that radioisotopes released from nuclear power plants may be found in the soils and indoor dusts of surrounding homes.

RATIONALE: It is vital to have female representation in clinical and observational studies. However, certain clinical studies impose risks unique to female participants, particularly those involving radiation exposure with imaging studies, such as CT scans. Many IRB templates include a rigorous list of exclusions for biologic females prior to radiation exposure. These exclusion criteria often place unnecessary limitations on enrolling female participants. METHODS: We recruited Veterans with and without respiratory symptoms who participated in the Department of Veterans Affairs (VA) Cooperative Study #595, “Service and Health Among Deployed Veterans” for additional testing that included a Chest CT. We utilized informed consent template language to create inclusion and exclusion criteria for the study to mitigate potential risk associated with radiation exposure. Eligible female Veterans of childbearing potential were required to utilize birth control, have a negative pregnancy test, and maintain the use of birth control for the duration of the study. Childbearing potential was defined as individuals who are pre-menopausal and have not undergone a hysterectomy or surgical sterilization. We identified barriers to study inclusion and calculated participant eligibility after implementing a protocol modification that reduced these barriers.RESULTS: The original requirement for birth control use excluded female Veterans from participating in the study.We identified multiple instances where birth control was not used and did not place the participant at increased risk of pregnancy. These included: i) in same-sex relationships, ii) tubal ligation, iii) male partner unable to father children (vasectomy, congenital abnormalities, etc.) and iv) infertility, including those with prior therapies/procedures that preclude pregnancy. Of the 40 women screened between July 2022 and September 2024, 10 were ineligible based on lack of contraceptive use and childbearing potential. Eliminating the barrier of contraceptive use, enabled eight out of the ten participants who would have been excluded otherwise to be eligible for the study based on childbearing potential. This increased the overall eligibility for female Veterans from 75% (30/40) to 95% (38/40) (P=.008, McNemar exact test). CONCLUSIONS: Changing the protocol to address issues of contraceptive use increased the overall eligibility of female participants. Despite increased effort to include women in clinical research trials, unanticipated barriers still exist. This has implications in pulmonary studies where exposure to radiation, certain procedures, and/or drug administration can limit inclusion. Exclusion criteria that could impact participation for women should be reviewed and tailored to fit individual protocol needs to create more inclusive studies.

RATIONALE: The lung clearance index (LCI) is a sensitive, noninvasive marker to estimate small airway disease. The performance of LCI, relative to spirometry and forced oscillometry technique (FOT)-based measures, and relationship to respiratory symptoms, among Veterans deployed to Southwest Asia and Afghanistan exposed to high levels of particulate matter has not been well-studied. METHODS: Veterans with previous land-based deployments who enrolled in the Department of Veterans Affairs (VA) Cooperative Study #595, “Service and Health Among Deployed Veterans (SHADE)” at 4 sites (Boston, Houston, Minneapolis, Seattle) were invited to return (a mean=3.9 years later, mean=14 years post deployment) to complete a standardized respiratory questionnaire, spirometry, oscillometry (FOT), and nitrogen multiple breath washout (MBW). Self-reported respiratory symptoms (dyspnea, chronic cough, or wheeze) were categorized as never, persistent, remitted between initial and follow-up visits, or new onset after the initial visit. The LCI is derived from the MBW (cumulative expired volume/ functional residual capacity, FRC) and values were averaged from 2 or 3 available acceptable FRC trials. Linear regression models examined associations between LCI and symptoms and pulmonary function measures. RESULTS: Among 117 participants (15.4% women) recruited, mean age=47.0 (10.5); BMI=30.9 (6.3), 14.5% former cigarette smokers (median pack-years 1.0), we found persistent symptoms in 17.1%, 18.0% remitted, and 11.1% were new onset. Mean (SD) %-predicted FVC =106.1 (12.6), FEV1=101.9 (14.1), FEV1/FVC=95.9 (6.9). The mean (SD) LCI = 9.2 (1.4); range 6.7 to 14.1. Adjusting for age, sex, height, BMI and site, the adjusted mean LCI for different categories of respiratory symptoms were: never symptoms 9.2 (95% CI 8.7, 9.7); persistent 9.4 (8.7, 10.0); remission 9.3 (8.6, 9.9); and new onset 10.3 (9.5, 11.1) [p-value 0.0502 comparing new onset vs. never, all other comparisons NS]. FVC and FEV1 were inversely associated (p<0.01) with LCI (Table 1). Increasing X5 (decreasing lung stiffness) was associated with decreased LCI, and increased elastance (Fres) with increased LCI. Changes in LCI per interquartile range of FOT or spirometry measure were small (∼0.6 units or less). There were no associations with measures of airflow obstruction (R5, R19, R5-R19, FEV1/FVC), CONCLUSION: Among previously deployed Veterans with largely normal FVC and FEV1, new-onset respiratory symptoms were weakly associated with LCI. The LCI was inversely associated with FVC, FEV1 and positively associated with abnormalities of reactance, suggestive of functional changes located within the lung periphery. These findings suggest that small increases in LCI may reflect mild or early lung disease among deployed veterans.

Introduction / Rationale Interstitial lung abnormalities (ILAs) are highly prevalent and are associated with increased mortality and progression to clinically-evident interstitial lung disease (ILD). Due to shared risk factors (i.e., older age, smoking), individuals enrolled in lung cancer screening (LCS) may be at increased risk for ILAs, however methods to systematically identify these abnormalities through visually-based radiologist reporting or quantitative imaging analysis (QIA) methods have been incompletely explored. Methods Data from Veterans referred to and enrolled in the VA Boston LCS program (4/2019-4/2024) were systematically extracted from the electronic health record (EHR) and included demographics, smoking history, respiratory symptoms (yes/no), and any history of chronic respiratory disease (CRD; yes/no) based on keyword search of the patient's “Active Problems”. Data from clinical pulmonary function tests (PFTs) was also systematically extracted. Among LCS enrollees who completed a low-dose chest computed tomography (LDCT), radiologist-reported ILA (yes/no) was assessed using systematic search for selected keywords within the clinical report. QIA was performed on a subset of LDCTs using the Chest Imaging Platform extension for 3D-Slicer. Three QIA-based definitions for ILA were defined as follows: (a) total volume of high-attenuation areas (HAAs)≥5%, (b) lower lung field HAAs≥5%, and (c) cranial-caudal difference in HAAs≥2%. Differences in the prevalence of clinically-diagnosed CRD, respiratory symptoms, and mean total lung capacity (TLC) by PFTs and QIA by radiologist-reported and QIA-assessed ILA status were assessed using Chi-squared tests or Student's t-tests; a p-value <0.05 was considered significant. Results Among 4,849 unique referrals, 3,445 patients enrolled in LCS and 2,767 had LDCTs completed (mean±SD age 65.8±7.1, 94% male, 60% current smokers, 47.8±21.3 pack-years) and were retained for analysis. 924 patients (33%) had a clinical diagnosis of CRD and 851 patients (31%) reported respiratory symptoms; 1,324 patients (48%) had clinical PFTs performed of which lung volume testing (TLC data) was available in 858 (31%). Overall prevalence of radiologist-reported ILA was 5% (Table 1); among the subset with QIA performed (n=982), the prevalence of ILA varied between 8%-32%. There were no significant differences in clinical CRD diagnosis or respiratory symptoms by the presence/absence of radiologist-reported or QIA-assessed ILA, however, significant differences in TLC by both PFT and QIA methods were observed. Conclusion Both radiologist-reported and QIA-assessed ILA are associated with detectable differences in TLC which may antedate symptoms and clinical diagnoses. Future studies including longitudinal assessments for associations with clinical outcomes are warranted.

RATIONALE: The spring and fall seasons in Eastern Mediterranean are characterized by moderate temperatures, low precipitation and atmospheric instability that increase potential exposure to aeroallergens through frequent desert dust storms and high pollen counts. Although aeroallergen exposure may worsen asthma in atopic children, the association of atopy with respiratory health in a region characterized by overlapping seasonal dust and pollen periods, such as Cyprus and Crete, Greece, has not been examined. METHODS: We conducted a secondary analysis of respiratory health data collected during a randomized clinical trial in primary school children with asthma in Cyprus and Crete, which included the use of air purifiers and recommendations to limit outdoor activities (NCT03503812). The study took place in spring 2019 and 2021 in Cyprus and spring 2019 and fall 2021 in Crete. Children were assessed 3 to 4 times over 4 months, including allergen sensitization evaluated at the end of the follow-up using skin prick tests with a panel of 14 aeroallergens common in Cyprus and Crete. Mixed effect models were used to assess associations between atopy and respiratory health measures, adjusting for study arm, country, year, weeks on study, age, and gender. RESULTS: The analytical sample included 133 children (79 atopic and 54 non-atopic; mean (SD) age=9.5 (1.6) years; 64% boys). Over the study period, atopic children exhibited 113.2% (95% CI=66.7%, 172.5%) higher fractional exhaled nitric oxide (FeNO) levels and were more likely to use asthma medication in the preceding month (OR=2.30, 95% CI=1.06, 4.98), compared to non-atopic children with asthma. There was no significant difference in childhood Asthma Control Test (c-ACT) scores (median=23 to 25 at each study visit) or healthcare visits. Among atopic participants, there was a significant weekly decline in %-predicted FEV1 (-0.28, 95% CI=-0.43, -0.13) and FEV1/FVC% (-0.15, 95% CI=-0.24, -0.07). Sensitivity analyses that only included children assessed during spring (pollen season) yielded similar findings. The most common sensitizing antigens among atopic children were seasonal, including Olive (55.4%) and tree mix (45.2%). Children with only seasonal sensitization had the highest odds ratio (OR=4.62, 95% CI=1.53, 13.97) for asthma medication use during the study compared to non-atopic children. CONCLUSIONS: Lower pulmonary function, increased medication use and higher FeNO among atopic children with asthma suggest that atopic children may be prone to worse asthma morbidity compared to non-atopic children during the overlapping seasonal dust and pollen periods in Cyprus and Crete, despite no meaningful change in monthly c-ACT score.

BACKGROUND: Incidental findings (IFs) are common on low dose CT obtained during lung cancer screening (LCS). The identification and management of clinically significant IFs is a challenging aspect of LCS programs and there is no standardized method of reporting IFs to primary care providers or patients. We explored the prevalence of incidental findings and radiologist use of the “S” modifier to identify clinically significant findings compared to what the LCS team identified as a clinically significant finding. We also presented a standardized reporting approach that provides suggested actions for providers and patients. METHODS: We conducted a review of a sample of low-dose CT scans of the chest reported between August 17, 2023 and April 29, 2024 completed at VA Boston Healthcare System, omitting scans with findings concerning for lung cancer. We assessed the reporting of incidental findings by the radiologist, compared this to identification of clinically significant incidental findings by the lung cancer screening team, and evaluated factors associated with number and occurrence of incidental findings (via complete case regression). RESULTS: Among 495 patients (Mean Age: 69.0 (6.6), 94.4% Male, 53.2% Current Smoker), 444 scans were retained for analysis. Scans had a median of seven incidental findings. The most common incidental finding was multiple pulmonary nodules (77.9%). There were 165 low-dose CT with findings the lung cancer screening team considered clinically important, however, radiologists only assigned the “S” modifier to 35 scans. CONCLUSIONS: All scans reviewed had incidental findings and nearly 40% had a finding that was clinically significant to the lung cancer screening team. There was inconsistent reporting between the radiologists and lung cancer screening team on clinical significance. Radiologists identified fewer clinically important findings than the lung cancer screening team and applied the “S” modifier inconsistently. There is no standardized method for reporting clinically significant low-dose CT results to primary care providers or patients. Our approach provides a structured approach, acknowledges multiple clinical opinions, and provides a framework for communication.

Importance:Deployment to Afghanistan and Southwest Asia has been associated with adverse respiratory health outcomes. However, the impact of inhalational exposures (eg, vapor, dust, gas, fumes), which are known correlates of reduced lung function and future chronic lung disease, during military service time outside this deployment period has not been assessed. Objective:To assess military inhalational exposures during nonwartime routine activities and their associations with chronic respiratory symptoms. Design, Setting, and Participants:This cross-sectional study used data from the US Department of Veterans Affairs Service and Health Among Deployed Veterans study. US veterans who served between October 7, 2001, and February 28, 2017; deployed to Afghanistan or Southwest Asia; and living near 6 Veterans Affairs sites were randomly selected from Defense Manpower Data Center records. Participants completed interviewer-administered multi-item questionnaires about 29 exposures related to active duty military service time when not deployed. Onsite visits occurred between April 27, 2018, and March 13, 2020, and analyses were performed between April 1, 2023, and February 10, 2025. Exposure:Inhalation exposures during active duty military service time. Main Outcomes and Measures:The main outcomes were chronic respiratory symptoms of dyspnea, wheeze in the previous 12 months, and chronic bronchitis. Using factor analysis, the 29 exposures were reduced to 20 items and categorized into 5 factors. Responses were scored ordinally (0, 1, 2) according to exposure prevalence and duration. Generalized linear modeling was used to explore associations between exposures and chronic respiratory symptoms. Results:The sample included 1712 veterans (median [IQR] age, 37 [33-45] years; 1522 male [88.9%]) who had military service other than during their deployment to Afghanistan or Southwest Asia. The median (IQR) total active duty military service duration was 77 (57-128) months, with 82.8% of their service time spent outside the theater of conflict. The prevalence of dyspnea, chronic bronchitis, and wheeze was 7.0% (117 participants), 7.1% (121 participants), and 15.2% (260 participants), respectively. The most commonly reported exposure categories were combustion and ground dust (1014 participants [59.2%]), aircraft maintenance (812 participants [47.4%]), and heavy equipment maintenance (783 participants [45.7%]). Adjusted multivariable analyses identified significant associations between heavy equipment maintenance exposures and dyspnea (odds ratio [OR], 1.33; 95% CI, 1.06-1.68) and wheeze (OR, 1.29; 95% CI, 1.10-1.52). Aircraft maintenance exposures were significantly associated with wheeze (OR, 1.22; 95% CI, 1.01-1.47). No statistically significant associations were found between these exposures and chronic bronchitis. Conclusions and Relevance:This cross-sectional study shows significant associations between heavy equipment maintenance and aircraft maintenance inhalation exposures outside of deployment with chronic respiratory symptoms among US veterans. These findings suggest that certain military inhalational exposures may contribute to the development of chronic lung disease and that policy interventions to reduce such exposures may protect the long-term respiratory health of military personnel.

RATIONALE: Returning Veterans deployed to Southeast Asia were exposed to high levels of airborne particulate matter below 2.5 µm (PM2.5) from burn-pit smoke and other deployment-related pollutions. Excessive PM2.5 exposure could lead to immune dysfunction, increasing susceptibility to asthma, infections, and chronic lung diseases. PM2.5 exposure associated with immune and pulmonary dysfunction in returning Veterans has not been fully elucidated. METHODS: Veterans participating in the Department of Veterans Affairs Cooperative Study (CSP #595) were randomly invited to participate in the Lung Effects of Deployment Exposure (LEDE) at four sites (Houston, Boston, Minneapolis, and Seattle). Forty-three non-smokers with and without chronic respiratory symptoms assigned to minimal or high PM2.5 exposure groups completed a standardized respiratory questionnaire and underwent a full lung function test and peripheral blood mononuclear cell (PBMC) collection. We designed a proof-of-principle study to assess immune cell responses to general stimulants ex-vivo. PBMCs (1x 106 in triplicates) were stimulated with vehicle (cell culture media), lipopolysaccharide (LPS), or T lymphocyte coactivators (anti-CD3 and -CD28 antibodies) for 24 hours to measure cytokine production. We collected supernatant and measured levels of innate and T helper (Th)1, Th2, and Th17 cytokines using LegendPlex. RESULTS: The minimally exposed participants had median FEV1=4.1L, FVC=5.0L, FEV1/FVC=0.80, TLC=6.7L, and DLCO=29 mmol/min. In those with high PM2.5 exposure, the median FEV1=3.9L, FVC=4.6L, FEV1/FVC=0.84, TLC=6.0L, and DLCO=28 mmol/min. Within the minimal PM2.5 exposure cohort, asymptomatic versus symptomatic Veterans, respectively, were median FEV1=4.4L and 2.9, FVC=5.1L and 4.9, FEV1/FVC=0.81 and 0.76, TLC=6.6 and 7.1L, and DLCO=29 and 24 mmol/min. Within the high PM2.5 exposure cohort, asymptomatic versus symptomatic Veterans, respectively, displayed median FEV1=4.3 and 3.7, FVC=5 and 4.5, FEV1/FVC=0.84 and 0.84, TLC=6.7 and 5.8, and DLCO=30 and 26. Our proof of principle ex vivo study showed LPS stimulation specifically increased proinflammatory cytokines IL-6 and TNF, while ⍺-CD3+⍺-CD28 activation increased Th2 (IL-5, IL-9, IL-22) and Th1-associated (IFN-γ, TNF) cytokines. CONCLUSION: Veterans with high PM2.5 exposure exhibited a trend for decreased FEV1, FVC, TLC, and DLCO than those minimally exposed, suggesting that high PM2.5 exposure could contribute to impaired lung function. Within the high exposure group, symptomatic Veterans displayed decreased FEV1, FVC, TLC, and DLCO, although not statistically significant except DLCO. Our ex vivo PBMC stimulation model discriminated skewed innate and adaptive cytokine signatures, enabling us to distinguish unique cytokine responses associated with increased exposure to PM2.5, decreased pulmonary function, and symptoms in returning Veterans.