Citations

Abstract Introduction: Eosinophilic Granulomatosis with Polyangiitis (EGPA) is an ANCA-associated vasculitis (AAV) that causes eosinophil-rich granulomatous vasculitis affecting small vessels. While pulmonary manifestations of EGPA are diverse, development of pulmonary fibrosis is rare. We present two cases of EGPA with pulmonary fibrosis.Case 1: A 31-year-old female with refractory asthma, chronic rhinosinusitis, recurrent ear infections, presented with productive cough, dyspnea, wheeze with relief from antibiotics and steroids. Labs noted peripheral eosinophilia, elevated IgE, P-ANCA positivity with equivocally positive PR3 antibody. CT chest revealed bilateral lower lobe predominate honeycombing, traction bronchiectasis, subpleural reticulations indeterminate for UIP. Pulmonary function tests (PFTs) noted complex restriction with mildly reduced diffusion capacity of carbon monoxide (DLCO). Exhaled nitric oxide (ENO) was elevated at 132 parts per billion (ppb) (normal <39 bbp). Bronchoalveolar lavage (BAL) demonstrated eosinophilia. CT of the sinuses, infectious workup, anti-cyclic citrullinated peptide antibody (CCP), and genetic testing for hypereosinophilia were negative. Treatment with prednisone and Mepolizumab months led to significant improvement of respiratory symptoms.Case 2: A 69-year-old man with refractory allergic rhinitis and chronic sinusitis, gastroesophageal reflux (GERD) presented with eight years of chronic productive cough, dyspnea on exertion, weight loss, dysphagia. Labs noted peripheral eosinophilia, elevated IgE, isolated P-ANCA positivity. CT chest noted peripheral predominant reticulations, traction bronchiectasis, and ground-glass opacities indeterminate for UIP. PFTs noted severe restrictive pattern with reduced DLCO. ENO was elevated at 54 ppb (normal <30 ppb). CT of sinuses noted bilateral mucosal thickening and polyps. BAL and biopsies were unable to be performed prior to prednisone initiation given severity of symptoms and hypoxemia. Prednisone led to dramatic symptom improvement. Mepolizumab initially added but discontinued due to side effects and he denied Mycophenolate due to concern for side effects.Discussion: While pulmonary fibrosis in patients with P-ANCA and MPO positive microscopic polyangiitis (MPA) has been well described, it is rare in EGPA. In cases of ILD associated with EGPA, usual interstitial pneumonia (UIP) is the most common imaging finding, with nonspecific interstitial pneumonia (NSIP) and unclassified interstitial lung disease (ILD) also reported. Fibrosis develops either secondary to eosinophilic release of profibrotic and inflammatory cytokines and deficiency of anti-inflammatory neutrophil extracellular traps (NET), as described with idiopathic eosinophilic pneumonia, or due to overlap with MPA. Similar to MPA, fibrosis in our cases preceded development of systemic vasculitis, although many cases of AAV with pulmonary fibrosis report concomitant systemic vasculitis. Despite adequate initial treatment, fibrosis may progress, requiring antifibrotics.

Abstract Introduction: Idiopathic CD4 lymphocytopenia is a disorder with CD4 counts below 200 cells/mm3 or less than 20% of total lymphocytes without an acquired or genetic cause. Case Summary: A 41-year-old female with history of Celiac disease complicated by hyposplenism developed fevers, weight loss, sicca symptoms, widespread erythematous rash, sinusitis, multifocal pneumonia refractory to antibiotics and pulmonary embolism. Workup demonstrated isolated weakly positive PR3 antibody of 1.2 (reference range < 1.0), CD4 count of 78 with negative ANA, ENA, HIV, CMV, EBV, HTLV, fungal, mycobacterial testing and mildly low IgM. PET-CT noted FDG avidity in the paranasal sinuses, lung opacities and salivary glands. Sinus biopsy showed chronic inflammation and fibrosis. Sputum cultures were positive for MSSA and Pseudomonas. Lung biopsy noted fibrinous organizing pneumonia. Skin biopsy demonstrated pauci-inflammatory vacuolar interface dermatitis with discontinuous weak granular deposition of C3 on basement membrane. A small-intestinal biopsy noted villous blunting and polymorphous T cell infiltration of the lamina propria. Bone marrow biopsy redemonstrated polytypic T cells with inverted CD4:CD8 ratio, but neither harbored an abnormal T cell population. Treatment for presumptive GPA was undertaken with corticosteroids, Rituximab, and Avacopan with transient improvement. CRP was elevated at 65.1 mg/dL (reference range < 5.0mg/dL). However, CD4 count had increased to 260 (reference range 365-1437) with 20% CD4 cells, low B cells, normal CD8 and NK cells, and IgG4 levels elevated at 180 mg/dL (reference range 2.4-121.0). LDH was elevated at 455 U/L (reference range 122-222) but flow cytometry, SPEP, and FLC ratio were unremarkable. Rhinoscopy demonstrated purulence, nasal septal perforation, and crusting of the larynx and subglottis. Salivary gland biopsy noted chronic sialadenitis without malignancy. Repeat CD4 count was 93. Given recurrent, refractory pulmonary infections, IVIG was considered, but prior to administration the patient developed worsening hypoxemia and pressor requirements and was transitioned to comfort cares. Discussion: It is crucial to rule out conditions causing lymphopenia, such as severe sarcoidosis, Sjogren's, IgG4-related disease, cutaneous T cell lymphoma, and splenectomy. While common complications include opportunistic infections, invasive cancers and autoimmunity, their absence may be explained by normal CD3 and CD8 counts. Despite complications, mortality is generally not increased, although baseline CD4 counts of less than 150 cells/mm3 may predict death. Decreases in CD4 counts in the setting of rising immunoglobulin levels may represent antibody production against lymphocytes. While evidence on the use of IVIG is limited, it may be beneficial when hypogammaglobulinemia or life-threatening infections are present.

Abstract RATIONALE: Absolute Blood Eosinophil Counts (BEC) in bronchiectasis patients offer insights into inflammatory patterns and potential treatments. In non-cystic fibrosis bronchiectasis (NCFB), BEC≥300 cells/μL characterizes Eosinophilic Bronchiectasis (EB), a type-2 inflammation endotype estimated in 20% of patients. Guidance on BEC assessment strategy (i.e., number, frequency and timing of BEC≥300 defining this endotype) is unclear. We hypothesize that EB incidence varies by BEC≥300 assessment strategy. We also investigate eosinophilic inflammation in CF for comparison. Objectives: Assess BEC≥300 incidence in NCFB and CF cohorts. METHODS: From January 2023 to October 2024, BEC were measured in 9,953 stable bronchiectasis patients across Mayo Clinic, including 9,806 with NCFB (J47.9; 66,780 CBCs) and 147 with CF (E84.0; 1,405 CBCs). Incidence of BEC≥300 was evaluated in relation to CBC frequency and timing (i.e., BEC≥300 on first, second, last, any, any two, first two simultaneously) and the number of CBCs per patient. RESULTS: In the NCFB cohort, median age was 74 years (IQR:66-82), with 59.5% female. Median CBCs/patient was 3 (IQR:1-7). Incidence of BEC≥300 on the first CBC was 19.8%. Among patients with ≥2 CBCs (n=7,075), incidence was 20.1% on the first, 19.8% on the second, and 20.0% on the last. This incidence rose to 36.3% when considering any CBC/patient. BEC≥300 on at least two CBCs was 29.3%, decreasing to 11.8% when considering consecutive BEC≥300 on both first and second CBCs. The incidence of BEC≥300 increased linearly with the number of CBCs obtained: 24.6% for those with 1-3 CBCs, up to 64.6% for >12 CBCs. In the CF cohort, median age was 36 years (IQR:27-52), with 55.1% female. Median CBCs/patient was 4 (IQR:2-8). BEC≥300 was present in 22.9% of first CBCs, rising to 36.3% when considering any CBC and 29.3% when present on at least two CBCs. Similar to the NCFB cohort, incidence increased with the number of CBCs: 26.5% for 1-3, up to 77.3% for >12. CONCLUSIONS: The incidence of BEC≥300 in our NCFB cohort remained steady at 20% at any specific measurement point, consistent with prospective literature. However, nearly half of those with BEC≥300 on the first or second CBC did not meet this threshold on both. Incidence significantly increased when any CBC was considered, and more CBCs were available. Similar observations were made in the CF cohort. Clearer BEC assessment strategies are needed to define clinically significant eosinophilic inflammation in bronchiectasis, to better identify patients who may most benefit from type 2 inflammation-targeted treatments.

Abstract Introduction: Non-Cystic Fibrosis Bronchiectasis (NCFB) is an obstructive pulmonary disease associated with structural lung disease, altered mucociliary clearance, hyper mucus secretion, recurrent infection, and airway inflammation that results in significant morbidity and mortality. Aspergillus sp (Asp) is a common fungi isolated in respiratory specimens of those with lung disease and is associated with both infectious and allergic pulmonary diseases such as Asthma and Cystic Fibrosis. Despite individuals with NCFB having similar phenotypes as these conditions, the impact of Asp on this population is poorly understood. Methods: We performed a cross-sectional retrospective analysis from the US Bronchiectasis and NTM Research Registry (BRR). NCFB patients without a history of lung transplant who had at least one respiratory Asp culture were included. We compared patients with no history of Asp grown from respiratory culture to those with at least one positive respiratory culture for Asp during the available period. Patient demographics, bacterial culture history, lung function, comorbidities, modified Bronchiectasis Severity Index (mBSI), and sputum parameters were analyzed descriptively. Comparisons between groups were conducted using Kruskal-Wallis, independent sample t-tests, and chi-square tests for continuous and categorical variables as appropriate. Results: 3985 people with NCFB met inclusion criteria. 3359 (84.3%) individuals were Asp culture negative compared to 626 (15.7%) individuals with Asp. There were notable differences in race, showing higher proportions of non-Hispanic white (90.4 vs 82.2%) in this population. While the frequency of Chronic Obstructive Pulmonary Disease and Primary Ciliary Dyskinesia were similar, there were more individuals with Asthma (31.3 vs 24.7%, p<0.001) and Allergic Bronchopulmonary Aspergillosis (ABPA) (6.4 vs 2.4%, p<0.001) in the Asp positive group (Figure 1A). The Asp positive group had higher blood eosinophils (150.0 vs 124.0 cells/uL, p=0.026, Figure 1B), had nominally lower lung function (73.5 vs 75.3% ppFEV1, p=0.089), and were more likely to have at least one or more positive bacterial cultures (62.9 vs 51.9%, p<0.001, Figure 1C). There was no significant difference in sex, age, exacerbations, Pseudomonas aeruginosa or NTM positive cultures, sputum volume, or mBSI. Conclusion: Individuals with NCFB and history of one or more positive Asp cultures were more likely to be non-Hispanic white, have a diagnosis of Asthma and/or ABPA, higher blood eosinophils, and more positive airway bacterial cultures. Further work is needed to better understand how Asp contributes to bronchiectasis progression. More expansive analysis and multivariant modeling is underway to better understand the impact of Asp in people with NCFB.

Abstract Introduction: The airway inflammation of asthma is characterized by immune phenotypes, often classified as Type 2 inflammation high or low. Social determinants of health (SDoH) can influence asthma risk and severity, but whether or not SDoH influence immune phenotypes is unclear. The social deprivation index (SDI) is a composite measure of seven neighborhood level characteristics: poverty level, less than 12 years of education, single parent household, living in rented housing unit, living in overcrowded housing unit, households without a car, and non-employed adults under 65 years of age. The scale of SDI ranges from 1 to 100, correlating with increasing deprivation. We hypothesized that social deprivation influences immune phenotype of asthma, and that deprivation effects vary by sex and race. Methods: Using the American Community Survey summary file spanning 2015 to 2019, we linked SDI to participant zip codes for 680 Black and White participants in the Severe Asthma Research Program (SARP), a NHLBI-multicenter network phenotyping asthma across the US from 2001-2024 (table 1). We compared SDI among the cohort by sex, race and asthma severity, and correlated SDI to superoxide dismutase (SOD) and T2-high biomarkers, such as eosinophils, IgE and Fraction of Exhaled Nitric Oxide (FENO). Results: SDI is similar across healthy and asthmatic participants (SDI: median [interquartile range]: healthy: 40 [56]; asthmatics: 51 [53], P = 0.53). When evaluated by race, SDI is significantly higher in Black asthmatics, independent of sex (SDI: Black male: 76 [4], White male: 35 [45]; P<0.0001; Black females: 77 [35], White females: 40 [45]; P<0.00010). Within SARP asthmatics, SDI shows a positive association with the T2 inflammatory markers, log IgE (R=0.13 [90%CI: 0.1, 0.2)] and log FENO (R=0.15 [90%CI: 0.1, 0.2]), while it correlates negatively with log of absolute neutrophil count (R= -0.12 [90%CI: -0.19,-0.1]). The antioxidant enzyme SOD increases with SDI (R=0.11, [90% CI: 0.04, 0.17]). Notably, within Black asthmatic males only, SDI is associated with Type 2 biomarkers, showing a positive correlation with log FENO (R=0.24 [90%CI: 0.1,0.4]) and negative correlation with log IgE levels (R= -0.25, [90% CI: -0.4, -0.1]). No association was found between SDI and eosinophils or with SOD in Black males. Conclusions: Neighborhood level social deprivation is associated with a unique asthma phenotype in Black males. Black males living at high social deprivation have a lower IgE and higher FENO, with no change in SOD activity.

Abstract Background:Chronic obstructive pulmonary disease (COPD) is a major global health burden, with genome-wide association studies explaining only a fraction of its heritability. Recent advancements, including large-scale, multi-ancestry whole-genome sequencing and a focus on severe, early-onset cases, offer promising avenues to identify additional COPD-related variants. Furthermore, recent studies show that adjusting for polygenic risk scores (PRS) enhances statistical power to detect rare variants, advancing efforts to understand COPD's genetic basis. Methods:We performed a whole genome sequencing association study of severe, early-onset COPD (FEV1 < 50%, age ≤ 55), FEV1 and FEV1/FVC in eight population-based studies (ARIC, CARDIA, CFS, CHS, FHS, HCHS/SOL, JHS, MESA) and seven COPD-enriched studies (COPDGene, ECLIPSE, Boston Early-Onset COPD Study, LTRC, TCGS (Poland), ICGN, SPIROMICS). We performed single-variant analyses using regenie software, applying a genome-wide significance threshold of P < 5.0 x 10-8. For rare variant set (MAF <1%) analysis, we annotated variants with loss of function or deleterious missense using WGS Annotator and prediction tools LOFTEE, SIFT, and PolyPhen2, then analyzed these variants with SKATO-ACAT method in regenie, adjusting for covariates including sex, sequencing center, and principal components of ancestry. We additionally evaluated adjusting the analyses for PRSs for lung function traits. Results: We analyzed 53,028 participants including 34,751 European, 12,508 African, 1,088 Latino American, and 674 East Asian ancestry. Across cohorts, we analyzed 5,063 severe (FEV1 < 50%) COPD cases, among whom 1,103 were early-onset (age ≤ 55). Excluding variants within 1 Mbp of known variants, single-variant analysis identified 68 novel associations (MAC ≥ 30), with 8 common associations (MAF ≥ 1%) in 6 genomic regions. Our most significant novel association for severe early-onset COPD was rs74297390 (intergenic to POM121L12, MAF = 9.6%, Beta = 0.41, P = 3.5 x 10-8). For FEV1 and FEV1/FVC ratio, variants near DKK2 and AKR1E2 were significantly associated and were replicated in an independent dataset (Shrine et al., 2019). DKK2 is an antagonist in the Wnt pathway. In a preliminary variant set analysis, CHRM3-AS1 was associated with severe early-onset COPD, GPAT with FEV1, and COL8A1I and HMCN1 with FEV1/FVC. With PRS adjustment, ST6GALNAC5 was associated with FEV1/FVC. Conclusions: In a whole genome sequencing study of lung function and severe early-onset COPD, we identified new loci for COPD-related phenotypes, including two novel loci that replicated in an independent dataset. Ongoing work involves variant set-based analyses with additional covariate adjustments, as well as PRS adjustments for binary traits.

Abstract RATIONALE: The alveolar epithelium consists of two cell types (AT2 and AT1) derived from a common Distal Progenitor (DP). Understanding how the epithelium of alveoli functions and becomes differentiated is essential for treatment of lung diseases. One possible regulator of cell fate is cell membrane tension (CMT), a biophysical property measured by the energy required to deform the membrane and known to be an important regulator of cell movement and endocytic processes. AT1 fate selection is largely driven and reinforced by YAP (Yes-associated protein), a mechano-sensitive transcription factor gated from entering the nucleus by the size of nuclear pores, which increases upon stretch. Here, we investigated whether and how CMT regulates the transduction of stretch-dependent YAP signaling and the remodeling into AT1 cells. METHODS: DPs were isolated from E15.5 mice and cultured on Matrigel for use in differentiation experiments. Immunostaining for AT1 and AT2 markers, Phalloidin, DAPI and YAP were used to assess YAP localization and architectural changes. We generated transgenic mice containing a pan-epithelial Cre (TgNkx2.1-Cre), a Cre-dependent driver of ltta (TigreAi140), and a TetOff regulated construct expressing YAP1 (Rosa26teto-Yap1), resulting in constitutive Yap1 expression in Cre-expressing DPs. CMT is measured both with optical trap technology and with the use of FlipTR dye, which uses Fluorescence Lifetime Imaging Microscopy (FLIM) to determine CMT. RESULTS: To demonstrate the role of CMT in timing AT1 fate, we found that CMT lowers in DPs concomitantly with differentiation, and that flattening cells (likely AT1s) have even lower CMT than round cells (likely AT2s). Using organotypic culture, we found that raising CMT with MBCD, PEG, or Matrigel embedding largely stops differentiation of DPs. Surprisingly, even when YAP is overdriven in mice in E15.5 distal progenitors, early precocious AT1 differentiation is not observed, suggesting YAP signaling is not alone sufficient to drive AT1 fate selection in DPs with higher CMT. We reproduced this finding when culturing DPs under high CMT conditions-promoting high YAP/TAZ levels via LATS inhibition was also not sufficient to select for AT1 fate. Finally, we found that high CMT disrupts nuclear YAP localization, nuclear-actin attachment, and cytoskeletal remodeling that is typically when DPs remodel towards AT1 fate. We propose that high baseline CMT in DPs prevents cellular remodeling, specifically that it suppresses the formation of actin-nuclear associations that imbue the nucleus with stretch sensitivity, thereby preventing an increased sensitivity to stretch and thus higher YAP signaling.

Abstract Introduction: Tuberculosis (TB), a substantial cause of morbidity and mortality among human immunodeficiency virus (HIV) infected individuals, accounted for 161,000 deaths among HIV-co-infected patients in 2023. Tuberculosis preventive therapy can play a detrimental role in reducing the global burden. However, prolonged treatment duration compromises adherence and ultimately efficacy. This systematic review and meta-analysis aimed to assess the treatment adherence and effectiveness of rifapentine-isoniazid prevention therapy relative to the standard isoniazid therapy. Methods: This study was conducted following the PRISMA guidelines. A comprehensive literature search was conducted over PubMed/Medline, Google Scholar, Cochrane Library, and ClinicalTrials.gov from inception till 28 October 2024. Recruited articles were screened against the predefined inclusion criteria, and relevant data was extracted into a spreadsheet. Comprehensive Meta-Analysis (CMA) was used for data synthesis. Results: This meta-analysis included four studies containing data from 8,068 patients, with 5640 randomized to the rifapentine-isoniazid group while 2428 received isoniazid. Tuberculosis incidence varied from 0.21 to 2.0 and 0.63 to 1.9 per 100 person-years in the rifapentine-isoniazid arm and isoniazid alone group respectively. However, the pooled analysis showed a non-significant difference between the two groups (OR: 1.12; CI: 0.65 to 1.93; p=0.69) as shown in Figure 1. Similarly, no significant difference was noted across deaths in each group (OR: 0.76; CI: 0.43 to 1.34; p=0.35). While the two preventive therapies were non-inferior in terms of effectiveness, a significant improvement in treatment completion was observed with the rifapentine-isoniazid group (OR: 5.14; CI: 2.96 to 8.96; p<0.0001). Conclusion: The short-term rifapentine-isoniazid preventive therapy was non-inferior to the standard isoniazid therapy, however, a marked improvement in treatment completion was noted with the former.

Abstract Rationale: Although guidelines recommend the use of provocative testing to diagnose pulmonary venous hypertension (PVH) that is unapparent at normal resting right heart catheterization (RHC), the incremental value of provocative testing is unknown. We aim to evaluate the incremental diagnostic capability of inhaled nitric oxide (iNO), fluid challenge (FC) or invasive cardiopulmonary exercise testing (iCPET) to unmask PVH using previously defined hemodynamic cutoffs. Methods: We included subjects from the NHLBI-funded Pulmonary Vascular Disease Phenomics (PVDOMICS) study. Our analysis included patients with World Symposium on Pulmonary Hypertension (WSPH) Group 2 disease (G2PH) and G2PH comparators (WSPH Group 2 phenotype without a diagnosis of PH) as determined by the PI or adjudication panel. We then applied a protocol-driven provocative approach based on the feasibility of modalities available in most catheterization labs. Using a pulmonary capillary wedge pressure (PCWP) cutoff of >15, frequencies were identified for subjects based on resting PCWP and with iNO. Frequencies were also identified for: those who received FC with a PCWP cutoff of ≥18 or those who received iCPET with PCWP cutoff of >20 (upright) or >25 (supine). Results: There were 419 subjects identified with WSPH Group 2 disease (Figure). Roughly half were found to have a PCWP >15 during resting RHC (N = 207). Of the remaining subjects with a resting PCWP ≤15 (N = 150), 42 subjects were found to have a PCWP >15 with iNO administration (40.0%). Of the remaining 63 subjects with PCWP ≤15 following iNO administration, nearly half (N = 26, 48.0%) demonstrated a PCWP ≥18 following FC while 8 subjects (14.8%) demonstrated an elevated PCWP following iCPET. Conclusions: There is a high proportion of G2PH patients (∼35%) who appear hemodynamically similar to precapillary PH at rest. Inhaled nitric oxide vasodilatory challenge unmasks G2PH in many patients. In situations where iNO does not disclose the G2PH phenotype, provocation with FC or iCPET can be useful as a supplementary provocative maneuver. Future directions will focus on agnostically assessing the utility of provocation based on grouping subjects by resting hemodynamics as well as assessing the use of provocation in other forms of PH.

Abstract Rationale: Prior studies report association between pulmonary artery (PA) dilation on computed tomography (CT) imaging and pulmonary hypertension (PH). These studies predate expansion of PH hemodynamic diagnostic criteria and do not report patient mortality. As such, little is known about the presence of vascular changes in mild PH or their association with survival. We sought to investigate these relationships in individuals without significant parenchymal lung disease. Methods: We obtained CT images for subjects with group 1 or 2 PH, disease comparators, and healthy controls enrolled in the Pulmonary Vascular Disease Phenomics (PVDOMICS) study. We used Osirix imaging software to measure the main, left, and right PA (MPA, LPA, and RPA) and MPA:aorta (PA:Ao) ratio by diameter and cross-sectional area at locations consistent with prior studies. We evaluated associations with mortality and mean PA pressure (mPAP) using multivariable Cox and linear regression models adjusting for age, sex, and BMI. Descriptive statistics are presented as mean ± SD. Results: We identified 558 subjects (59 controls, 138 comparators, and 361 PH [267 group 1, 94 group 2]). 79 subjects had mPAP < 21 mmHg, 39 had mPAP 21-24 mmHg, and 371 had mPAP ≥ 25 mmHg. Increased MPA, LPA, and RPA diameter and area, PA:Aodia, and PA:Aoarea were associated with decreased survival (all p < 0.001) after multivariable adjustment. First versus third quantiles of all measurements were associated with mortality, with adjusted hazard ratio of 2.99 [95% CI 1.77, 5.05] for MPA diameter (2.84 vs 3.82 cm), 3.74 [2.07, 6.74] for MPA area (7.26 vs 12.74 cm2) and 5.24 [2.58, 10.66] for LPA area (4.55 vs 7.03 cm2). All measures significantly increased alongside PH severity from mPAP < 20 to 21-24 to ≥ 25 mmHg (see figure 1 for MPA diameter). All measures positively correlated with mPAP, including MPA diameter (ρspearman = 0.55) and PA:Aodia (ρ = 0.56). After multivariable adjustment, Q1 to Q3 increments in MPA diameter and PA:Aodia were associated with mPAP increase of 12.5 [10.7, 14.4] and 13.9 [11.9, 15.8] mmHg, respectively. BMI showed no correlation with PA size (ρ = 0.076 for MPA area, -0.051 for PA:Aodia). Conclusions: PA size increases alongside PH severity using updated hemodynamic criteria and is associated with incremental increases in PA pressure and mortality. LPA dilation demonstrates particularly strong association with mortality. PA size does not correlate with BMI. These novel findings enhance our understanding of vascular changes across the PH disease spectrum.