Raúl San José Estépar

In this multi-institutional, multiphantom study, photon-counting detector CT provided more accurate and reproducible lung densitometry while maintaining comparability with energy-integrating detector CT protocols.

Extract There are shared antecedent risk factors [1, 2] and pathobiological mechanisms [3] between pulmonary fibrosis and cardiovascular disease, suggesting these two distinct disease entities may be linked though common biological pathways. Studies consistently demonstrate a higher prevalence of cardiovascular disease among individuals with interstitial lung disease (ILD) [4]; however, these studies largely capture cardiovascular status at a single point, after pulmonary fibrosis has developed. This cross-sectional approach limits insight into whether cardiovascular health (CVH) truly represents an upstream risk factor for the development and progression of ILD.

Pulmonary hypertension, defined by elevated pressure in the pulmonary circulation, is morbid and diagnosing is challenging as no early-stage blood markers are currently available. Here we show that large-scale proteomic profiling across several independent observational cohorts identifies 22 proteins associated with echocardiography-derived pulmonary artery systolic pressure, several of which are independently associated with invasive measures of pulmonary vascular disease, structural remodeling of the pulmonary vasculature, and subsequent risk of pulmonary hypertension. Genetic analyses support a potential causal role for NOTCH3 and identify a common splice-regulating genetic variant that may modify susceptibility to pulmonary vascular stressors. Protein-based clustering further reveals two distinct biological subtypes associated with increased risk of pulmonary hypertension. Together, these findings identify candidate biomarkers of pulmonary hypertension, implicate pulmonary vascular remodeling in early-stage disease with a potential causal role for NOTCH3, and discover and validate two distinct endotypes of pulmonary hypertension risk in the community.

Background: World Trade Center (WTC) rescue and recovery workers have developed several occupational exposure-related lower airway diseases and are on longitudinal health surveillance. The role of chest computed tomography (CT) in occupational health surveillance remains to be established. Aims: We used semiquantitative visual chest CT measurements to investigate the association between pre-WTC or WTC occupational exposure indicators and interstitial lung abnormalities and disease (ILAD) in WTC workers and volunteers. Methods: Participants were former WTC workers and volunteers who underwent periodic spirometry and chest CT examinations. We estimated the odds of ILAD, as assessed by the International Classification of High-resolution Computed Tomography for Occupational and Environmental Respiratory Diseases (ICOERD), in relation to pre-WTC and WTC occupational exposure indicators. Results: Of 918 participants, 175 (19%) had evidence of ILAD on post-WTC CT examinations, and were more likely older, non-Latino White, and to smoke cigarettes. None of the pre-WTC and WTC occupational exposure indicators were associated with post-WTC findings of ILAD. In post hoc subgroup analyses, the odds of ILAD among Latinos were 39% lower (ORadj 0.61, 95% CI 0.28–0.78), and the odds of having an intermediate-accelerated longitudinal FEV1 decline for the Polish subgroup were 71% higher (ORadj 1.71, 95% CI 0.94–3.14) compared to others. Conclusions: Pre-WTC and WTC occupational exposure indicators were unassociated with presence of ILAD. Post hoc analyses revealed strong subgroup negative and positive associations among Latino or Polish subgroups and ILAD and intermediate-accelerated FEV1 decline, respectively, suggesting the need for further investigation into exposure differences among those subgroups.

Objective: Rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP), and novel autoantibodies including anti-malondialdehyde-acetaldehyde (MAA), anti-carbamylated protein (CarP), and anti-peptidylarginine deiminase (PAD) have been associated with clinical RA-associated interstitial lung disease (RA-ILD), but comprehensive autoantibody profiling across clinical and subclinical RA-ILD is lacking. Methods: We retrospectively identified patients with clinically-indicated chest computed tomography (CT) imaging (discovery dataset) and prospectively enrolled RA patients across 5 US sites for research chest CT screening (validation dataset). Clinical ILD (≥10% extent, symptomatic and diagnosed) and subclinical ILD (≥5% extent, undiagnosed with/without symptoms) were adjudicated by thoracic radiologists and analyzed by deep-learning quantitative computed tomography (QCT). Thirty-one biomarkers were measured and log-standardized. We used multivariable logistic regression with 10% false discovery rate (FDR) in the discovery dataset and considered replication if p<0.05 in the validation dataset. Results: We analyzed 1,005 participants: the discovery dataset comprised 149 clinical RA-ILD, 378 RA-noILD, 50 IPF, and 99 healthy controls; the validation dataset comprised 38 subclinical RA-ILD and 291 RA without subclinical ILD. Five autoantibodies replicated across both datasets for RA-ILD risk had higher QCT interstitial abnormalities: RF IgA, RF IgM, CCP3 IgA, CarP IgG, and PAD3 IgG. A composite panel of these autoantibodies had negative predictive values for RA-ILD of 0.81 (discovery) and 0.94 (validation). Conclusion: RF IgA/IgM, CCP3 IgA, CarP IgG, and PAD3 IgG were associated with clinical and subclinical RA-ILD. These biomarkers implicate carbamylation and citrullination in RA-ILD pathogenesis and may be clinically useful for risk stratification.

Background: The transition from lung injury to chronic lung disease is poorly defined. We previously described a quantitative measure of visually normal lung with high attenuation (CT lung injury) associated with greater risk of progression to divergent radiologic phenotypes, including interstitial lung abnormalities and emphysema. The underlying biology of this finding remains unclear.Methods: Plasma proteomics were measured in COPDGene (phase 2) using the SomaScan platform and burden of CT lung injury was quantified. Associations between proteins and CT lung injury were evaluated using multivariable linear regression. Findings were replicated in CARDIA (year 25). In CARDIA, associations between proteins measured at year 15 and CT lung injury at year 25 were also evaluated. Proteins associated with CT lung injury in COPDGene and CARDIA years 15 and 25 were then evaluated for associations with future quantitative interstitial abnormalities (QIAs) and emphysema at year 35. Findings: Among 3,188 COPDGene participants, 252 proteins were associated with CT lung injury (FDR p<0.05). Of those, 18 had overlapping significance in CARDIA at years 15 and 25, and tissue level expression was highest in lung tissue. Ten proteins were associated with future development of QIA and 3 proteins were associated with future emphysema.Interpretations: We identified 18 proteomic biomarkers of CT lung injury, consistent across two independent cohorts of diverse age and tobacco exposure. Different proteins were associated with future development of QIAs or emphysema, raising mechanistic questions regarding biologic divergence in pathways between early lung injury and chronic lung diseases.

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: Aging is associated with increases in pulmonary pressure related to concomitant age-associated left ventricular remodeling, diastolic dysfunction, and declines in pulmonary function. Little is known regarding morphological changes in the pulmonary arterial vasculature underlying these associations. Our aim was to determine the associations between pulmonary vascular arterial remodeling, reflected in distal pruning and proximal dilation, and cardiac structure and function, pulmonary pressure, and functional outcomes. METHODS: Among 2275 participants in the community-based Atherosclerosis Risk in Communities study (ARIC) who underwent echocardiography and noncontrast cardiac computed tomography at study visit 7 (2018–2019), we quantified the fraction of total pulmonary vascular area comprised of arterial vessels with cross-sectional area 10 mm ² (aBVg10/aTBV) using a validated image processing approach. We assessed the associations of aBV5/aTBV and aBVg10/aTBV with echocardiographic measures of cardiac structure and function and pulmonary artery systolic pressure using multivariable linear regression models adjusted for demographics and cardiovascular risk factors. We also evaluated associations of pulmonary vascular arterial remodeling metrics with circulating NT-proBNP (N-terminal pro–B-type natriuretic peptide), self-reported dyspnea, and incident heart failure. RESULTS: Mean age was 80±4 years, 61% were women, 22% reported Black race, and mean left ventricular ejection fraction was 64±7%. Mean aBV5/aTBV was 0.30±0.08, and aBVg10/aTBV was 0.45±0.09. Lower aBV5/aTBV, reflecting greater distal pruning, and higher aBVg10/aTBV, reflecting greater proximal dilation, were both associated with greater left ventricular remodeling, worse diastolic function, and worse systolic function. Lower aBV5/aTBV and higher aBVg10/aTBV demonstrated nonlinear associations with greater pulmonary artery systolic pressure. Both lower aBV5/aTBV and higher aBVg10/aTBV were associated with higher circulating NT-proBNP and greater odds of moderate to severe dyspnea. Higher aBVg10/aTBV, in particular, was associated with greater risk of incident heart failure over a 4-year follow-up with a hazard ratio of 1.25 (95% CI, 1.03–1.51) per one SD in aBVg10/TBV. CONCLUSIONS: Among older adults, pulmonary vascular arterial remodeling is associated with greater left ventricular remodeling, worse diastolic and systolic dysfunction, greater pulmonary artery systolic pressure, greater odds of significant dyspnea, and greater risk of heart failure development. Our findings clarify the morphologic changes in the pulmonary vasculature that link cardiac dysfunction to higher pulmonary pressure in late life and may appear before symptomatology.

Background: Bronchiectasis is increasingly recognized on chest CT among tobacco-exposed individuals, yet its longitudinal changes and prognostic significance are poorly understood. We tested whether progression of CT-based bronchial dilation over time is associated with higher mortality among tobacco-exposed individuals. Methods: We conducted a longitudinal analysis of the prospective COPDGene Study. Participants were aged 45-80 years and had a smoking history of at least 10 pack-years. They were enrolled at 21 centers across the United States between November 2007 and April 2011 and were followed up through July 2023 The percentage of airways with an airway-to-artery diameter ratio (AAR)>1 was quantified on CT using a validated artificial intelligence–based tool. A higher percentage of AAR>1 indicates a greater extent of bronchial dilation. Progression of bronchial dilation was defined as an increase in percentage of AAR>1 from baseline to 5-yr follow-up CT scan. Multivariable proportional hazard models were used to assess the association between bronchial dilation and all-cause mortality. Findings: Among 4,282 participants with baseline and 5-yr imaging data, 3,508 (81.9%) demonstrated CT-based bronchial dilation progression. During a median follow-up of 10.7 years (IQR 5.4-13.0), 836 (19.5%) deaths occurred. Mortality rates were higher in participants with progression than in those without (20.8% vs 13.7%). Bronchial dilation progression was associated with increased all-cause mortality after adjustment (adjusted hazard ratio 1.48, 95% CI 1.18-1.87). Interpretation: In tobacco-exposed individuals, progression of CT-based bronchial dilation was prevalent and was associated with increased all-cause mortality.