Citations

Abstract Rationale Despite its effectiveness at improving outcomes in patients with COPD, pulmonary rehabilitation (PR) attrition rates are high, often exceeding 50%. Fully remote programs, like home-based PR (HBPR), face additional challenges engaging patients in real-world settings. With the growing adoption of wearables, sensor-derived behavioral measures, like sleep patterns, may identify patients most likely to benefit from remote PR. This study evaluated whether incorporating baseline sleep measures from a wrist-worn activity monitor in machine learning (ML) models improved the prediction of 12-week engagement with HBPR in patients with COPD. Methods Among participants (n = 124), the following sleep measures were collected for 1 week before HBPR: sleep duration (min), standard deviation of sleep duration, wake-after-sleep-onset (WASO) (min), standard deviation of WASO, number of awakenings, length of awakenings (min), activity counts, movement index, movement fragmentation index, and sleep fragmentation index. Sleep measures were processed (1) using a previously validated Tudor-Locke algorithm and (2) applying partial least squares-discriminant analysis (PLS-DA) to generate a single latent variable (Composite Sleep Health Score) for inclusion in models. Engagement was defined as completion of one or more recommended activities per week for the full program duration (12 weeks). To determine if the inclusion of objective sleep measures improved the prediction of HBPR engagement, nested model comparisons for parametric (logistic regression and SVM) and non-parametric (decision tree and naïve bayes) ML models were performed. A sensitivity analysis (SA) replaced the Composite Sleep Health Score with sleep regularity (duration and WASO) measures only. Results In models adjusted for age, sex, Charlson Comorbidity Index, current smoker status, modified Medical Research Council (mMRC), and forced expiratory volume in 1 second (FEV1), the inclusion of the Composite Sleep Health Score significantly improved the prediction of 12-week engagement only in SVM models (AUC 0.755; p = 0.007). Specificity (18.2%) and accuracy (68.5%) also improved by 27.3% and 7.3%, respectively. The Composite Sleep Health Score and mMRC scores ranked most frequently as the variables of highest importance. Identical trends were observed in the SA. Conclusion Although preliminary, these findings support additional investigation into the use of wearable-derived sleep measures to improve screening for HBPR eligibility, identifying patients who will clinically benefit from fully remote PR. Building on these primary findings, future researchers should carefully select variables for model inclusion and initiate new hypotheses elucidating the link between objective sleep measures and HBPR outcomes in COPD patients. This abstract is funded by: NIH R56 HL173214, NIH R01 HL140486, and the Robert D. and Patricia E. Kern Center for the Science of Health Delivery

Abstract Most malignant effusions are mononuclear predominant, with only 16-20% being neutrophilic. Neutrophilic predominance should raise suspicion for secondary inflammatory process, particularly empyema. In absence of infection, elevated neutrophils can be a sign of tumor necrosis or tumor lysis. In malignant pleural effusions, markers such as low glucose, low pH, and high LDH may indicate a high tumor burden and are markers of poor outcomes. 64-year-old male with past medical history of metastatic mucinous lung adenocarcinoma status post diagnostic right lower lobe wedge resection and recurrent bilateral malignant pleural effusions, presented to outpatient clinic for therapeutic right-sided thoracentesis. 900 mL of viscus green-brown pleural fluid was removed, and initial fluid studies revealed a neutrophil-predominant exudate with 45,045 total nucleated cells (TNCs) and pH of 7.01. Given concern for infection the patient was admitted, and a right-sided 14 French pigtail pleural catheter was placed. Left-sided thoracentesis was also performed, with pleural fluid studies consistent with a lymphocytic exudate. Vitals on admission were all within normal limits and white blood cell count was 8.9. Chest computed tomography (CT) scan showed extensive bilateral lymphangitic metastases scattered throughout both lungs and bilateral hydropneumothoraces with evidence of a left-sided pleural rind. Infectious workup, including pleural fluid cultures and broad-range bacterial polymerase chain reaction (PCR) were all negative. Cytology of both left and right pleural fluid revealed malignant adenocarcinoma with a substantial amount of necrosis. Patient was discharged home on oral antibiotics with plan to follow up as outpatient for possible tunneled pleural catheter placement. Post-discharge, patient continued to receive intermittent therapeutic thoracenteses. Subsequently readmitted, again with concerns for empyema, bilateral tunneled pleural catheters were placed after infectious workup was again unrevealing. At one month follow up, he reported drainage of 300-500 mL of pleural fluid with alternating daily drainages without complication. Differentiating neutrophilic malignant pleural effusions from empyema is clinically difficult and can lead to delay in definitive pleural treatments. Although it is important to rule out infection, malignancy should remain on one’s differential diagnosis, particularly if the remainder of the patient’s history and presentation are inconsistent with an infectious etiology. This abstract is funded by: None

Abstract A 71-year-old male with a history of progressive pulmonary fibrosis underwent bilateral lung transplantation via clamshell incision seven months prior to presenting with dyspnea and recurrent bilateral pleural effusions. His post-transplant course was complicated by lymphocytic myocarditis, leading to acute hypoxic respiratory failure and heart failure. Outpatient management with torsemide improved fluid status but was discontinued due to worsening renal function, resulting in effusion recurrence. Upon readmission, a right-sided 12 Fr pigtail thoracostomy tube was placed and left thoracentesis was done. Pleural fluid analysis revealed a serosanguineous, lymphocytic, exudative effusion on the right and a neutrophilic, transudative effusion on the left. Both had negative cytology and infectious studies. The left effusion initially seemed to be controlled. Persistent right-sided drainage prompted placement of a right indwelling tunneled pleural catheter (IPC). Pre-procedure imaging showed bilateral effusions, and ultrasound revealed a diminishing right effusion during setup, supporting interpleural communication. To aid IPC placement, one liter of lactated Ringer’s (LR) solution was infused into the right pleural space. Post-procedure imaging showed a large left-sided effusion and a small right effusion (Figure 1.), confirming buffalo chest physiology—fluid migration between pleural cavities due to the clamshell incision. Despite suction drainage and positional maneuvers, the left effusion persisted. Intrapleural administration of lytics via the right IPC failed to evacuate the left effusion. A subsequent left thoracentesis removed one liter of fluid, but recurrence necessitated placement of a left IPC one week later. Three weeks post-placement, the right IPC was removed, and continued drainage from the left IPC prevented recurrence of the right effusion. This case highlights the anatomical alterations following bilateral lung transplantation via clamshell incision, which can lead to atypical pleural fluid dynamics, including interpleural communication and buffalo chest physiology. Awareness of these changes is critical for effective management of pleural effusions in post-transplant patients. This abstract is funded by: None

Abstract Introduction Interstitial lung disease-associated pulmonary hypertension (ILD-PH) is a clinically challenging entity that lies on a pathophysiologic spectrum between pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD). We compared the metabolomes of patients with ILD-PH to those with PAH and ILD to characterize the PAH-ILD axis and determine whether ILD-PH patients can be phenotyped based on their metabolomic similarity to PAH. Methods Using untargeted metabolomics profiles from patients with PAH, ILD, and ILD-PH in the large, U.S.-based, NIH-funded, multi-center PVDOMICS cohort, we trained an anchor-based classifier on PAH and ILD metabolomes using supervised PLS-DA with a 75/25 train/test split. Primary and secondary PH or risk-group classifications in PVDOMICS were based on expert adjudication of clinical data including right heart catheterization hemodynamics, pulmonary function testing, chest imaging, and laboratory results. We then applied the trained model to each ILD-PH patient to assign a PAH similarity score. We classified patients as having a PAH-like or ILD-like metabolomic phenotype using an optimal PAH similarity score cutoff of 0.5 then compared PAH metabolomic similarity to expert-adjudicated primary and secondary WSPH classifications in PVDOMICS. We implemented FELLA, a network-based metabolomics enrichment method, to holistically characterize the biologic underpinnings of PAH, ILD-PH, and ILD metabolomes. Results We analyzed 244 patients with PAH, 54 with ILD, and 47 with ILD-PH. The anchor-based classifier demonstrated high train-test performance with a c-statistic of 0.81 and 78% agreement with expert-adjudicated diagnoses. Among the ILD-PH patients, 23 were classified as PAH-like and 24 as ILD-like (74% agreement with expert adjudication, Cohen’s kappa 0.49, Hedge’s g estimate of 0.86). FELLA enrichment revealed core glycolytic and bioenergetic pathways were enriched in both pure PAH and ILD-PH. Comparison of diffusion Z-scores between groups demonstrated subtle but biologically coherent differences in several reaction-level nodes, including lactate, NADPH oxidoreductase, and phosphofructokinase, which were enriched in ILD-PH. Conclusion Patients with ILD-PH demonstrate clinically relevant metabolomic phenotypes. Examination of the network biology underlying ILD-PH may point to potential therapeutic targets in this vulnerable subgroup with lagging clinical outcomes. This abstract is funded by: Pulmonary Fibrosis Foundation PFF Scholars Program

Abstract Rationale Transthoracic echocardiography (TTE) is a very useful measure of cardiac function in patients with pulmonary hypertension (PH), along with right heart catheterization, which is considered to be the gold standard of measurement. It is non-invasive, quick and a good screening tool to assess the function of a failing right ventricle against elevated pulmonary pressures. Portopulmonary hypertension (POPH) is defined as PH associated with portal hypertension. The Tricuspid Annular Plane Systolic Excursion to Systolic Pulmonary Artery Pressure (TAPSE/SPAP) ratio has been found to be an effective prognosticator in different subtypes of PH. This study focuses on the role of TAPSE/SPAP ratio in prognosis of patients with POPH undergoing liver transplantation. Methods This was a single-center retrospective study of POPH patients undergoing liver transplantation at Mayo Clinic Florida from June 2003 to December 2023. It included patients with POPH with a mean pulmonary pressure >20 mm Hg undergoing liver transplantation. Patients with incomplete TTE data, coexisting renal failure on dialysis and requiring liver retransplant were excluded. This study included 27 patients. The last TTE report before liver transplantation was used for data analysis. The TAPSE/SPAP ratio was investigated as predictor of all-cause mortality following liver transplant using Cox regression and area under ROC curve. (Brackets contain 95% C.I.) Time to death after liver transplantation was considered. Patients were followed till August 1, 2024. (The correlation of this ratio-TAPSE/SPAP with some catheterization measured pulmonary pressures and indices have been included in Table 1.) Results Among 27 patients, 13 were female, 14 male. The most common causes of liver failure in these patients were non alcoholic fatty liver disease (NASH) and alcoholic liver disease. Rarely, some etiologies like sarcoidosis, autoimmune hepatitis, primary sclerosing cholangitis and hepatitis B/C were present. There were 7 deaths among total of 27 patients. The hazard ratio (HR) of TAPSE/SPAP for overall mortality by Cox regression was 0.01 (0.00-0.58), p = 0.03. The area under ROC curve was 0.76 (0.55-0.96), p = 0.01 [Also for TAPSE alone, the area under ROC curve was 0.74 (0.51-0.97), p = 0.05] Conclusion This study infers that TAPSE/SPAP ratio seems to be a good predictor of survival in POPH patients undergoing liver transplant, with a higher ratio associated with decreased all-cause mortality. It suggests that TAPSE alone might also be a good predictor with higher TAPSE associated with decreased mortality. This abstract is funded by: None

Abstract Rationale Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are two distinct pulmonary vascular complications of liver disease. POPH is characterized by pulmonary hypertension and elevated pulmonary vascular resistance while HPS is characterized by intrapulmonary vasodilation and hypoxemia. POPH and HPS reflect opposing pulmonary vascular responses with markedly different therapeutic and transplant implications. Accurate distinction on imaging may aid clinical decision-making and risk stratification. We aimed to quantitatively characterize and compare chest CT imaging features of POPH and HPS compared to controls with isolated portal hypertension (PoH). Methods Three cohorts of HPS, POPH, and PoH were included (n = 5 per cohort). POPH patients with intrapulmonary vasodilation on contrast echocardiography were excluded. Contrast-enhanced chest CTs with slice thickness ≤ 1.5mm obtained closest to the time of diagnosis were selected (mean 2.7 years following diagnosis). CT images were analyzed using a deep learning algorithm developed in-house that segmented and computed volumes of central, interlobar, peripheral, upper peripheral, and lower peripheral pulmonary arteries (PAs); total, upper, and lower pulmonary veins (PVs); and the four cardiac chambers. Resulting volumes were indexed by body-surface area. One-way analysis of variance (ANOVA) was performed with a post-hoc pairwise Mann-Whitney U test for comparison. Results Patients with HPS were 80% male, had a mean age of 48.6±17.4, and mean MELD-Na of 15.4±3.4. The POPH cohort was 20% male, had a mean age of 56.8±11.9, and mean MELD-Na of 13.4±4.0. The PoH cohort was 100% male, had a mean age of 62.8±4.8, and mean MELD-Na of 12.8±8.8. HPS patients had smaller central PA volumes (mean 26.4±1.8 mm2/m2) compared to both PoH (mean 38.6±9.8 mm2/m2, p = 0.03) and POPH patients (44.8±10.8 mm2/m2, p = 0.008). HPS patients, however, had larger lower peripheral PA (mean 30.7±1.9 mm2/m2) and PV (mean 28.3±6.7 mm2/m2) volumes compared to PoH (PAs mean 20.1±4.8 mm2/m2, p = 0.008; PVs mean 18.2±2.8 mm2/m2, p = 0.02) and larger lower peripheral PA volumes compared to POPH patients (PAs mean 22.1±5.1 mm2/m2, p = 0.03). There was no significant difference in volumes between POPH and PoH for all segments. Conclusion Compared to PoH and POPH, HPS is associated with lower central PA volume and higher peripheral PA volume in the lower lungs. Volumes were similar between POPH and PoH; however, this may reflect limited statistical power given the small sample size. Larger studies are needed to further delineate imaging distinctions between POPH, HPS, and PoH. This abstract is funded by: NHLBI

Abstract Rationale Pulmonary hypertension (PH) develops in up to 50% of patients with advanced interstitial lung disease (ILD) and is associated with increased morbidity, mortality, and impaired quality of life. Early recognition is essential, as available therapy for ILD-PH has been shown to improve outcomes. Identifying physiologic markers of PH may facilitate earlier referral for right heart catheterization (RHC) and initiation of targeted treatment. Thus, this study aimed to (1) compare functional parameters between ILD patients with and without RHC-confirmed PH, and (2) assess the applicability of previously proposed ILD-PH screening criteria. Methods We retrospectively analyzed ILD transplant candidates with available pre-transplant pulmonary function tests (FVC%, DLCO%), echocardiographic right-ventricular systolic pressure (RVSP), six-minute walk distance (6MWD) with oxygen requirement, and RHC data. PH was defined according to the 2022 ESC/ERS criteria. Functional parameters were compared between patients with and without PH. Among those without a prior PH diagnosis, screening thresholds derived from previously published tools were applied (RVSP ≥ 35 mmHg, DLCO < 40%, FVC/DLCO > 1.6, 6MWD < 350 m, or oxygen use during 6MWD). Results Of 107 ILD patients evaluated, 90 had complete RHC data (48 ILD-PH, 42 ILD without PH). Group comparisons are summarized in Table 1. Patients with PH had lower DLCO% (median 18.5 [11.5-26.7] vs 26.5 [20.0-34.7], p = 0.08), higher FVC/DLCO ratios (2.68 [2.1-3.4] vs 1.7 [1.4-2.6], p = 0.08), and higher RVSP (55 [39.7-63.2] vs 39.5 [29-48] mmHg, p = 0.002). Oxygen requirement during 6MWD was more frequent in ILD-PH (79.2% vs 61.9%, p = 0.08). Among patients with PH, 38 (79.16%) had no formal diagnosis prior to pre-transplant RHC. Of these cases, all (100%) met ≥3 screening criteria, most commonly DLCO < 40% (n = 38, 100%), FVC/DLCO > 1.6 (n = 37, 97.3%), and 6MWD < 350 m (n = 33, 86.8%). Additionally, 32 patients (84.21%) met ≥4 criteria and 8 (21.05%) met all five criteria. Conclusion In ILD transplant candidates, patients with PH had worse functional profiles when compared to those without PH, and nearly 80% of PH cases were previously undiagnosed. Systematic application of validated PH screening tools in ILD populations may facilitate earlier recognition, potentially improving patient outcomes. This abstract is funded by: None

ABSTRACT Early-life nutrition profoundly influences long-term metabolic health, and breast milk not only provides nutrients but also conveys maternal signals shaping infant metabolic development. While postpartum exercise by lactating women benefits maternal health, its impact on milk-borne signaling remains largely undefined. Small extracellular vesicles (sEVs) in breast milk are key mediators of maternal–infant communication because of their selectively packaged bioactive cargo and resistance to infant digestive enzymes and acids, enabling delivery of their cargo to peripheral tissues. Here, we show that a single session of moderate-intensity postpartum aerobic exercise robustly increases human breast milk sEV concentration, which persists for multiple post-exercise milk collections. Exercise enriches breast milk with sEVs containing regulatory metabolic cargo (proteins, miRNAs, and metabolites), which translates into enhanced mitochondrial capacity in neonatal-stage cells. These findings implicate sEVs as an exercise-responsive signaling compartment in breast milk capable of connecting postpartum maternal physical activity to beneficial infant metabolic programming. Highlights Acute moderate-intensity exercise increases human breast milk sEV concentration The exercise-mediated sEV increase lasts for multiple subsequent milk expressions Exercise coordinates a multi-omic enrichment of sEVs in breast milk Exercised breast milk sEVs enhance mitochondrial respiration in UC-MSCs

Abstract Introduction Pulmonary arterial hypertension (PAH) is a progressive and deadly disease characterized by pulmonary vascular remodeling and eventual right heart failure. A mainstay of treatment for PAH is prostacyclin therapy which can be delivered via continuous subcutaneous (SQ) or intravenous (IV) infusion. Infusion site reactions are a common occurrence with SQ Treprostinil resulting in discontinuation in approximately 10% of patients. Given that switching from SQ to IV prostacyclin therapy contains risks associated with long-term central venous access such as blood stream infections and deep venous thrombosis, the development of better strategies to improve SQ Treprostinil tolerability are needed. Case Report We report two patients with PAH who developed delayed infusion site reactions to SQ Treprostinil. Both patients were female, in their 30s, with severe group 1 PAH (mean pulmonary artery pressures of 44 and 81 mmHg on right heat catheterization at diagnosis), who had been on SQ Treprostinil for approximately 6 years on a dose around 60 ng/kg/min. Within two weeks of starting a new SQ infusion site, each patient developed a raised, hyperemic site reaction in the area of the infusion catheter draining yellow fluid (Figure 1). Skin patch testing was done from an ampule of preservative-free Treprostinil demonstrating a type 1 hypersensitivity reaction. There was no skin reaction to the Tegaderm dressing alone. Dupilumab 300 mg weekly SQ injections were started for these type 1 hypersensitivity reactions with resolution of the site reactions and pain. Because of this, both patients were able to remain on their SQ Treprostinil infusions. Discussion Infusion site reactions to SQ Treprostinil are common and can necessitate discontinuation of the medication. SQ Treprostinil infusion site reactions typically occur within 48 hours of establishing a new SQ infusion site and are thought to be a local vasodilatory reaction to the Treprostinil itself. These reactions can be minimized by analgesic pain medication and by increasing the Treprostinil infusion concentration. Here we describe two infusion site reactions that occurred two weeks after establishing a new site and were consistent with a type 1 hypersensitivity reaction. These reactions were successfully treated with Dupilumab which allowed the patients to remain on SQ Treprostinil. This abstract is funded by: None

Abstract Rationale The pathophysiology and clinical impact of liver injury in pulmonary hypertension (PH) is poorly understood. Liver injury in PH is often attributed to hepatic congestion, but some studies have failed to find strong associations with hemodynamics, suggesting alternative mechanisms. We sought to define the prevalence of liver injury and patterns of liver injury across the spectrum of PH and to determine whether patterns of liver injury were associated with clinical characteristics, hemodynamics and outcomes. Methods We performed an analysis of the PVDOMICS study, a multicenter, prospective, longitudinal cohort study that enrolled incident and prevalent patients with PH and disease comparators. The prevalence of liver injury, defined as aspartate or alanine aminotransferase (AST or ALT) or total bilirubin above the upper limit of normal, and different patterns of liver injury [hepatocellular (elevated AST or ALT with normal bilirubin), cholestatic (elevated bilirubin) and no liver injury] was defined among participants with known or suspected PH. Associations between patterns of liver injury with demographics, hemodynamics, right ventricular function, exercise capacity and quality of life (QoL) were assessed. We used Cox proportional hazards models adjusted for age and sex to assess the association of liver injury patterns with transplant-free survival. Results Liver injury was present in 27.8% (288/1036) of participants (19.0% cholestatic and 8.8% hepatocellular). Patients with liver injury were less likely to be female and have prevalent disease with differences in PH classification (Table 1). Patients with hepatocellular liver injury had a higher body mass index. A cholestatic liver injury pattern was most consistently associated with worse functional class, biventricular filling pressures, pulmonary vascular resistance, right ventricular function, natriuretic peptide elevation, exercise capacity, and REVEAL risk scores. Total bilirubin levels and right atrial pressure as a marker of systemic congestion were weakly correlated (r2=0.02, p < 0.0001). Compared to no liver injury, cholestatic liver injury was associated with an increased risk of death in age and sex adjusted models (HR 1.6, 95% CI 1.3-2.1, p < 0.001) but hepatocellular liver injury was not (p > 0.05). Conclusions Liver injury is common among patients with known or suspected PH. In contrast to a hepatocellular injury pattern, a cholestatic liver injury pattern was most consistently associated with worse hemodynamics, exercise capacity, QoL and survival. However, the weak relationship between right atrial pressure and bilirubin suggests that systemic congestion alone is unlikely to completely explain cholestatic liver injury. Further study is needed to uncouple the pathophysiological basis of cholestasis in PH. This abstract is funded by: NHLBI