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Abstract Rationale Acute cellular rejection (ACR) within first-year post-lung transplantation has important implications for prognosis. Calcineurin inhibitors (CNI), including tacrolimus or cyclosporine, along with cell cycle inhibitors (CCI) and steroids, remain the standard immunosuppression regimen post-transplant. Although tacrolimus is used as the primary CNI, target therapeutic levels vary across recipients due to adverse effects and tolerability, sometimes requiring switching over to Cyclosporine. We hypothesized that ACR within the first year is associated with switching CNI from Tacrolimus to Cyclosporine. Methods We performed a cross-sectional study of 255 adult lung transplant recipients between June 2019 to November 2024 at Mayo Clinic, Florida. Demographics, induction regimens, CNI type and their levels (average low and high levels) were compared between the 2 groups. The institutional maintenance immunosuppression regimen is Tacrolimus, Mycophenolate Mofetil (MMF) and prednisone, but could be switched to Cyclosporine if the previous regimen is not tolerated. The primary outcome was ACR <1 year diagnosed based on biopsy and/or clinical criteria. Comparisons between groups were performed using Chi-Square test for categorical variables and t-test or Wilcoxon Rank sum test for continuous variables. Multivariable regression analysis was performed with ACR <1 year as the outcome to adjust for the confounders. Results Our cohort included 255 lung transplant recipients with median age of 63 years, 61% Male, 84% Caucasians, 88% bilateral lung transplant (Further details elucidated in Table 1). A total of 173 (67%) out of 255 patients had ACR <1 year. The group with ACR < 1 year had higher proportion of Interstitial Lung Disease (ILD) (81% vs 68%, p = 0.044), use of Basiliximab for induction (70% vs 55%, p = 0.018), and cyclosporine instead of tacrolimus (23% vs 11%, p = 0.027). Group with ACR <1 year also had higher Antibody Mediated Rejection (AMR) < 1year (15% vs 6.1%, p = 0.041) and higher CLAD (BOS 0p-3: 43% vs 25.6%, p = 0.033) compared to the group without ACR < 1 year (Table 1.1). Multivariate regression analysis showed ILD (adjusted odds ratio, aOR 2.84, 95% CI 1.31 - 6.27, p = 0.008) and use of cyclosporine (aOR 2.55, 95% CI 1.07 - 6.78, p = 0.034) as independent predictors of ACR < 1 year (Table 2). Conclusions The presence of ACR < 1 year was associated with the use of Cyclosporine over Tacrolimus as a maintenance regimen. Also, ACR < 1year was associated with higher AMR and CLAD. Further prospective studies are needed to study this long-term given its significant prognostic implications. This abstract is funded by: Not Applicable

Abstract Rationale Fungal infections remain a major cause of morbidity and mortality post lung transplant due to unique exposure of the allograft to the external environment and the intensity of immunosuppression. Single-center studies have described variable rates of fungal infections. Contemporary population-level data with temporal trends, pathogen distribution, and associated outcomes are limited. Leveraging a large multicenter real-world dataset, we aimed to characterize incidence, prevalence and clinical outcomes of fungal infections among adult lung-transplant recipients. Methods Data were obtained from the TriNetX Global Collaborative Network (160 HCOs). Adult lung-transplant recipients (≥18 years) were identified between 2005 and 2024, using ICD and CPT procedure codes. Patients with solid organ transplants other than lung, combined-organ transplant or stem-cell transplant and HIV patients were excluded. Patients with pre transplant fungal infections were also excluded. Pre-transplant characteristics included demographics, comorbidities within a year, laboratory values within seven days, and medication within 90 days before transplantation. Post-transplant fungal infections were identified using ICD-10 codes for Aspergillus, Candida, Cryptococcus, Mucorales, Histoplasma, Blastomyces, Coccidioides, and Pneumocystis. TriNetX platform was utilized for statistical analysis. Incidence and prevalence of infections, all-cause mortality and transplant rejection were analyzed. Results A total of 12,857 adult lung-transplant recipients were identified. The mean age at transplantation was 57.6 ± 13.4 years, with a male predominance of (57%) and majority were white (65%). Average BMI was 26.8 ± 5.7 kg/m². The most common pulmonary conditions were COPD (15%), pulmonary fibrosis (17%), pulmonary hypertension (9%), bronchiectasis (3%), and cystic fibrosis (3%). Pre-transplant fungal and viral screening assays were rarely available (<1%). Medication exposure within 90 days prior to transplant demonstrated prednisone prescription (17%) methylprednisolone (7%), tacrolimus (6%), and mycophenolate mofetil (7%). Azathioprine and basiliximab were used in 2% each. Systemic antifungals (voriconazole, posaconazole, or fluconazole) in approximately 1% each.The overall incidence of post-transplant fungal infection was 3 % across full study period, rising to 7% in the modern era (2015-2024). Most frequently identified pathogens were Candida spp. (4.8%) and Aspergillus spp. (2.9%), followed by Pneumocystis Jirovecii (0.5%). Infection rates increased from 22 per 1,000 (2005-2014) to 75 per 1,000 (2015-2024) suggestive of improved diagnostic sensitivity and data capture, and longer post-transplant survival. All-cause mortality 5-year post transplant was 22.1%, and rejection rate was 22.5%. Conclusion Our study highlights a rising burden of fungal infections among lung-transplant recipients with potential implications for early post-transplant surveillance and antifungal prophylaxis strategies. This abstract is funded by: None

Abstract Rationale Fungal infections are common after lung transplantation and may adversely affect graft function and survival, but long-term outcomes remain incompletely defined. Using a large multicenter real-world dataset, we aimed to study the impact of post-transplant fungal infections on clinical outcomes of lung transplant recipients. Methods We conducted a retrospective, cohort study using the TriNetX Global Collaborative Network, which aggregates de-identified electronic health records from >160 healthcare organizations across North America, Europe, and Asia. Adult lung transplant recipients (≥18 years) between 2005 and 2024 were identified using ICD-10 and CPT codes. Patients with post-transplant fungal infection (aspergillosis, candidiasis, mucormycosis, histoplasmosis, coccidioidomycosis, blastomycosis) and matched controls without fungal infection within one year before or any time after transplant were identified. The index date was the date of transplantation. Propensity-score matching was performed on demographics, comorbidities, laboratory values, procedures and immunosuppressive medications. Outcomes included all-cause mortality (primary), allograft rejection, and chronic lung allograft dysfunction (CLAD) at 6 months, 1 year, 3 years, and 5 years. Kaplan-Meier and Cox proportional hazards models were used to estimate risk ratios (RRs), hazard ratios (HRs), and 95% confidence intervals (CIs). Analyses were conducted in TriNetX Analytics (v25.0, Cambridge, MA). Results A total of 3,083 patients with post-transplant fungal infection and 11,625 patients without infection were identified. Mean age was 58 ± 13 years, and 56% were male. The most common pulmonary comorbidities were chronic obstructive pulmonary disease, unspecified pulmonary fibrosis, idiopathic pulmonary fibrosis and bronchiectasis. Immunosuppression exposure was similar across groups. After propensity score matching across 56 clinical variables, both groups (1,790 per group) were well balanced. Mortality was higher in the fungal infection cohort at all follow-up points: 13.% vs 9% at 6 months (RR 1.45, 95% CI 1.2-1.75, p = 0.001), 17.8% vs 13% at 1 year (RR 1.36, p = 0.0001), 27.7% vs 21% at 3 years (RR 1.28, p < 0.0001), and 33 % vs 25% at 5 years (RR 1.32, p < 0.0001). Allograft rejection remained consistently higher (46-61% vs 22-34%), while CLAD occurred two- to three-fold more frequently (1.8-5.7% vs 0.7-2%). Conclusion Post-transplant fungal infection is independently associated with significantly increased mortality, acute rejection, and CLAD following lung transplantation. These findings underscore the need for early fungal surveillance, optimized antifungal prophylaxis, and individualized immunosuppression strategies to improve long-term patient outcomes. This abstract is funded by: None

Abstract Rationale Pulmonary hypertension (PH) is a major determinant of peri- and post-transplant outcomes in liver-transplant recipients. While baseline mean pulmonary artery pressure (mPAP) is routinely assessed, the prognostic value of dynamic hemodynamic improvement during the transplant hospitalization remains poorly defined. This study evaluated whether changes in mPAP (ΔmPAP) independently predict one-year mortality after liver transplantation. Methods This retrospective study utilized data obtained from the Medical Information Mart for Intensive Care (MIMIC-IV) database to identify patients who underwent allogenic liver transplant (ICD-10-PCS code 0FY00Z0) between 2008 and 2019. Patients were excluded if they did not have invasive pulmonary hemodynamics data available through the database. The primary outcome of interest was one year mortality. Among 278 patients who underwent allogenic liver transplant in the given timeframe, 195 liver-transplant were included in the final analysis. Pulmonary pressures were extracted longitudinally and summarized as the first (baseline) and last mPAP values; ΔmPAP was defined as (first − last). The primary outcome was one-year all-cause mortality. Logistic regression models evaluated associations between ΔmPAP (continuous), baseline mPAP, age, and Charlson Comorbidity Index (CCI). Results The cohort included 195 patients (mean age 56 ± 9 years), of whom 62% were male. The mean baseline mPAP was 27 ± 8 mm Hg, and the average ΔmPAP was −8 ± 6 mm Hg. Compared with survivors, non-survivors had higher baseline mean mPAP (29 ± 9 mm Hg vs. 26 ± 7 mm Hg, p = 0.02) and smaller ΔmPAP improvement (−6 ± 5 mm Hg vs. −9 ± 6 mm Hg, p = 0.01). Age and CCI were similar between groups (p > 0.1 for both). On univariate analysis, both higher baseline mPAP (OR 1.09 per mm Hg, p = 0.011) and greater ΔmPAP reduction (OR 0.92 per mm Hg, p = 0.013) predicted one-year mortality. In the multivariable model including ΔmPAP, baseline mPAP, age, and CCI, we noted that ΔmPAP remained the only independent predictor (OR 0.90 per mm Hg, 95 % CI 0.83-0.97, p = 0.009) for 1 year mortality. Increase in baseline mPAP, age and CCI demonstrated non-significant trend towards 1-year mortality risk. Conclusions Greater reduction in mean pulmonary artery pressure during hospitalization independently predicted improved one-year survival after liver transplantation. These findings highlight hemodynamic reversibility being as a key determinant of post-transplant outcomes. Further large scale prospective studies are warranted to evaluate the prognostic utility of hemodynamic parameters in liver transplant patients. This abstract is funded by: None

Abstract Background Lung transplantation remains the accepted treatment modality of choice for life-threatening advanced lung disease due to established benefits of improving survival and functional status of the patients. However, the annual mortality of lung waitlist candidates remains high, reflecting ongoing donor-recipient mismatches and prolonged wait times. Modalities such as extracorporeal membrane oxygenation (ECMO) have been effectively used as a “bridge to transplant” (BTT) in high-risk patients on waitlist. Objective To evaluate trends in ECMO utilization, waitlist dynamics, and outcomes among lung transplant candidates between 2018 and 2024, with emphasis on the use of ECMO as a bridge to transplantation. Methods We conducted a retrospective chart review of all ECMO runs performed between 2018 to 2024 at the Mayo Clinic Florida Hospital. Among these, patients who underwent evaluation for lung transplantation were identified, and their waitlisting patterns, transplant outcomes, and peri-transplant ECMO status were described. Results Between 2018 and 2024, a total of 348 ECMO runs were recorded among 293 patients. Annual ECMO runs increased steadily from 17 in 2018 to 83 in 2024 (2019: 33, 2020: 30, 2021: 61, 2022: 56, 2023: 68, 2024: 83). Out of these patients, 142 underwent evaluation for lung transplantation and 133 (93.67%) were placed on the waitlist. Among waitlisted patients, 105 (78.9%) were listed before ECMO initiation, 23 (17.3%) during ECMO, and 5 (3.8%) after decannulation. Waitlist outcomes included 116 (87.2%) transplanted, 16 (12.0%) deaths before transplant, and 1 (0.8%) clinical improvement precluding transplant. Among 116 transplanted patients, 36 patients (31.03%) received ECMO as a bridge to lung transplantation. The annual patients bridged with ECMO demonstrated a progressive rise: 1 (2019), 3 (2020), 9 (2021), 6 (2022), 9 (2023), and 8 (2024). Among these 36 patients, 29 (80.56%) remained on ECMO support in the immediate post-transplant period. At the latest follow-up, mortality among BTT recipients was 9 (25%). Conclusion ECMO utilization has expanded substantially over the past several years reflecting its expanding role in supporting critically ill patients. There has been increased utilization of ECMO as a bridge to lung transplantation in order to support high risk candidates awaiting donor organs. The post-transplant mortality among BTT recipients was 25%, which highlights the importance of peri-transplant management to optimize long-term outcomes in this high-risk cohort. This abstract is funded by: None

Abstract Introduction Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of surfactant-derived lipoproteinaceous material within the alveoli, resulting in impaired gas exchange. While most cases are autoimmune, caused by anti-GM-CSF antibodies, secondary PAP results from macrophage dysfunction due to malignancy, infection, or inhalational toxins. E-cigarette or vaping product use-associated lung injury (EVALI) is an emerging clinical entity, but its potential to trigger secondary PAP remains poorly defined. We report a unique, treatment resistant case of vaping-induced secondary PAP, expanding the clinical spectrum of EVALI. Description A 28-year-old male with a 9-year history of daily nicotine vaping and frequent cannabis wax inhalation presented with progressive exertional dyspnea, hypoxemia, and digital clubbing. Chest CT showed diffuse ground-glass opacities and interlobular septal thickening, characteristic of the classic “crazy paving” pattern. BAL revealed PAS-positive lipoproteinaceous material, and lung biopsy confirmed intra-alveolar surfactant accumulation and foamy macrophages, consistent with PAP. Negative anti-GM-CSF antibodies excluded autoimmune PAP. Despite vaping cessation and aggressive management, including 5 months of systemic corticosteroids, a 7-day trial of inhaled GM-CSF (sargramostim), and empiric antibiotics, his condition progressed to respiratory failure requiring high-flow oxygen (FiO2 70%). Whole-lung lavage was deferred due to refractory hypoxemia. Ultimately, he underwent bilateral lung transplantation, highlighting the profound severity and irreversible nature of the disease. Discussion This case underscores an urgent public health concern as vaping use surges among young adults. Chronic inhalation of nicotine and cannabis aerosols may result in irreversible alveolar macrophage dysfunction, culminating in secondary PAP. The patient’s lack of response to standard therapies and progression to end-stage respiratory failure emphasizes the seriousness of vaping-related lung injury. Clinicians should maintain a high index of suspicion for PAP in young patients with unexplained respiratory symptoms and a history of vaping. Public health efforts must prioritize regulation and education to reduce vaping-related lung disease. This abstract is funded by: None

Abstract Rationale Secondhand exposure to electronic nicotine products is driven by exhaled emissions. Eliminating heat and combustion may reduce exhaled toxic carbonyls. Methods In a 4-day within-subject crossover, six adults each used four devices after 24-hour abstinence: an NHNC nebulization device (Bluesky), a coil-heated ENDS (RELX), a heated-tobacco device (IQOS), and a heated aerosol device (Marlboro). For each condition, paired pre-use exhaled blank and post-use exhaled samples were collected; 50 L of exhaled breath was captured post-use. Nicotine and 12 carbonyls were quantified (DNPH/activated-carbon with HPLC). Primary endpoint: within-subject change (Δ, post-pre) in total carbonyls (μg/50 L). Secondary: Δ acetaldehyde and Δ acrolein. Results The exhaled carbonyls(within-subject change, post-pre) in total differed markedly across devices: Bluesky (non-heated, non-combustion; NHNC) 0.85 ± 6.99, RELX 4.41 ± 2.58, IQOS 62.38 ± 21.77, Marlboro 80.73 ± 20.24 (p = 0.0015). Bluesky had significantly lower total exhaled carbonyls than IQOS (p = 0.0077) and Marlboro (p = 0.0021, μg/50 L; mean±SD), with a nonsignificant trend versus RELX (p = 0.945). For acetaldehyde, Bluesky was lower than all three (Bluesky 0.20 ± 0.16 vs. RELX 1.93 ± 0.86, p = 0.016; vs IQOS 43.08 ± 16.70, p = 0.0044; vs Marlboro 65.40 ± 13.69, p = 0.00025, μg/50 L). For acrolein, average exhaled volume was 0.54 ± 6.94 (Bluesky), 1.35 ± 2.05 (RELX), 7.94 ± 6.07 (IQOS), and −1.86 ± 5.09 (Marlboro); pairwise differences vs Bluesky were not significant after correction (p ≥ 0.37, μg/50 L). Conclusions In a controlled, within-subject comparison using exhaled breath as a proxy for secondhand aerosol, the NHNC nebulization device (Bluesky) produced near-zero average increment in total exhaled carbonyls, whereas heated devices—particularly heated-tobacco—showed order-of-magnitude higher increases. These descriptive data support the hypothesis that removing heat and combustion from nicotine aerosolization can materially reduce exhaled carbonyl burden relevant to secondhand exposure. Larger, randomized studies with standardized capture and enhanced nicotine quantification are warranted. This abstract is funded by: Pneuma Respiratory.Inc

Abstract Background Sleep disorders are increasingly recognized as important risk factors for cardiovascular disease (CVD), yet their contribution to cardiovascular mortality remains insufficiently examined at the population level. This study aimed to evaluate long-term trends in CVD mortality where sleep disorders were identified as contributing causes of death. Methods We analyzed U.S. national mortality data from 1999 to 2020 among individuals aged 15 to 84 years. Cases were selected where CVD (ICD-10: I11.0, I11.9, I20-I25, I48, I49.0, I49.9, I50.0, I50.1, I50.9) was the underlying cause and sleep disorders (ICD-10: G47.0-G47.3) were listed as contributing causes. Joinpoint regression was employed to assess temporal changes in age-adjusted mortality rates (AARs), with standard errors provided in the input data and model selection performed using Weighted BIC. APCs were estimated using the Empirical Quantile Method with 5001 resamples. Results A total of 118,440 deaths were included across 22 annual time points. Joinpoint regression identified two significant inflection points (2005 and 2018). From 1999 to 2005, AARs increased sharply (APC = 14.47%; 95% CI: 11.56-19.54; p = 0.0016), followed by a slower rise from 2005 to 2018 (APC = 6.62%; 95% CI: 4.23-10.83; p < 0.000001), and a renewed acceleration from 2018 to 2020 (APC = 11.54%; 95% CI: 7.01-14.12; p < 0.000001). Males had more than twice the AAR compared to females (3.00 vs. 1.31 per 100,000). Black individuals had the highest burden by race (AAR = 2.55), and geographic variation ranged widely from 0.70 in New York to 3.38 in Wyoming. Conclusions Over two decades, cardiovascular mortality with contributory sleep disorders has risen significantly, with widening demographic and geographic disparities. These findings reinforce that sleep disorders are not merely comorbidities but pivotal, modifiable drivers of cardiovascular morbidity and mortality. Untreated sleep conditions such as insomnia, obstructive sleep apnea, and circadian disruptions exacerbate autonomic dysfunction, inflammation, hypertension, and metabolic dysregulation. Addressing sleep health must become a core component of cardiovascular risk reduction strategies, both in clinical practice and public health policy. Failure to integrate sleep disorder screening, diagnosis, and management into CVD care pathways risks perpetuating a preventable and growing burden of disease. This abstract is funded by: None

Abstract Rationale Low-sodium oxybate (LXB; Xywav®) is FDA approved for treatment of cataplexy and excessive daytime sleepiness (EDS) in people ≥7 years of age with narcolepsy, and for idiopathic hypersomnia in adults. LXB Prescribing Information includes a Warning and Precaution for respiratory depression and sleep-disordered breathing; therefore, data on safety of LXB in people with obstructive sleep apnea (OSA; a common comorbidity among people with narcolepsy or idiopathic hypersomnia) are needed. This post hoc analysis of DUET (Develop hypersomnia Understanding by Evaluating low-sodium oxybate Treatment; NCT05875974), a prospective, open-label phase 4 study, evaluated respiratory parameters in participants taking LXB with or without comorbid OSA, in 3 cohorts: narcolepsy or idiopathic hypersomnia (LXB ≤9 g/night), or narcolepsy (LXB >9 g/night). Methods Participants underwent the following study periods: screening, 8-day baseline (BL; off-LXB for narcolepsy and idiopathic hypersomnia cohorts; on-LXB 9 g/night for >9 g cohort), 2-8-week dose titration, 2-week stable-dose, 8-day end-of-treatment (EOT; on optimized total nightly dosage; ≤12 g for the >9 g cohort), and 2-week safety follow-up. Participants with BL apnea-hypopnea index (AHI) >10 (treated/untreated OSA) were excluded from the study. Overnight polysomnography assessments conducted at BL and EOT included respiratory parameters: AHI, central apnea index (CAI), and percentage of total sleep time spent with oxygen saturation (SpO2) <90% (T90). Treatment-emergent adverse events (TEAEs) were assessed by OSA group. Least squares mean changes were adjusted for BL values. Results Fifty-five participants enrolled in the narcolepsy cohort, 9% (5/55) had comorbid OSA; 22% (10/46) and 31% (15/48) had comorbid OSA in the idiopathic hypersomnia and narcolepsy >9 g cohorts, respectively (3, 9, and 12 were on OSA treatment throughout the study). Most participants (narcolepsy, idiopathic hypersomnia, narcolepsy >9 g) were female (72.7%, 80.4%, 62.5%) and White (80.0%, 84.8%, 77.1%). No worsening of sleep-disordered breathing was observed during LXB treatment, as evidenced by respiratory parameters AHI, CAI, and T90 assessed at BL and EOT in either participants with or without OSA (Table 1). Percentages of participants with/without OSA reporting ≥1 TEAE were 60.0%/62.0% (narcolepsy), 80.0%/72.2% (idiopathic hypersomnia), and 66.7%/78.8% (narcolepsy >9 g). Most TEAEs were mild or moderate; 1 serious TEAE each occurred in the idiopathic hypersomnia cohort (with OSA) and the narcolepsy >9 g cohort (without OSA). Conclusions No worsening respiratory signals were observed with LXB treatment in participants with or without comorbid (mild or treated) OSA in the narcolepsy, idiopathic hypersomnia, or narcolepsy taking >9 g LXB dosage cohorts. This abstract is funded by: Jazz Pharmaceuticals

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.