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Abstract Rationale Lung-protective ventilation protocols use predicted body weight (PBW) to set tidal volumes. However, biases exist in these formulas, with overestimation of lung capacity in older, shorter, female, and non-White patients—groups that experience higher mortality rates during invasive mechanical ventilation (IMV). This study investigated associations between pre-admission forced vital capacity (FVC), driving pressure, and patient outcomes. Methods This multicenter retrospective study included adults (18-95 years old) with pre-admission spirometry who required IMV between 01/01/2016 and 05/31/2025 across the Mayo Clinic, spanning 11 ICUs within 5 hospitals in 4 states. Patients were stratified by FVC/PBW ratio quartiles. The primary outcome was 28-day mortality. Trends were assessed using linear or logistic regression, with FVC/PBW as a continuous variable. Mediation analysis examined pathways between FVC/PBW and mortality, with driving pressure (cm H2O, standardized) as the mediator, and adjusted for covariates including age, sex, SOFA score, and BMI. Absolute risk differences and number needed to harm (NNH) were estimated for key thresholds (e.g. FVC/PBW ≥45 mL/kg, PFTs within 2 years). Results Among 4,839 patients (38.7% female, mean (±SD) age 64.5±13.5 years), FVC/PBW ratio demonstrated substantial individual variation, with a mean of 48.3 ± 13.4 mL/kg. There was systematic variation by demographics (Figure): females had significantly lower ratios than males (45.4 versus 50.2 mL/kg, P < 0.001), and ratios were lower with older age from 52.5 mL/kg in patients <65 to 43.2 mL/kg in those ≥85 years (P < 0.001 for trend). Patients in the lowest FVC/PBW quartile had higher 28-day mortality compared to the highest quartile (26.0% versus 17.0%, P < 0.001) and higher driving pressures (14.0 versus 10.0 cm H2O, P < 0.001; Figure). In mediation analysis (n = 4,147), driving pressure mediated the relationship between FVC and mortality. Each 1-SD increase in FVC/PBW was associated with 0.364-SD lower driving pressure (P < 0.001) and 2.4% lower mortality. The adjusted indirect effect through driving pressure was significant (ACME -0.024, 95% CI: -0.029 to -0.019), accounting for the mortality effect. Sensitivity analyses across binary thresholds, age quartiles, outlier exclusion, and obstructive pathology confirmed robust mediation. Patients with FVC/PBW <45 mL/kg (N = 1,644; 39.6%) had 28-day mortality of 17.8% versus 13.5% for ≥45 mL/kg (risk difference 4.3%, 95% CI 1.8-6.8%; NNH: 23 patients). Conclusions Pre-admission lung function was strongly associated with mortality in adults receiving IMV through driving pressure-mediated pathways. Driving pressure is a modifiable target, especially in patients with smaller lung capacities at highest risk for ventilator-induced lung injury. Further prospective investigation is needed to confirm these findings. This abstract is funded by: National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health (NIH) Grant Number K23HL151671

Abstract Rationale Community-acquired pneumonia (CAP) remains a leading cause of morbidity and mortality worldwide; current guidelines recommend either the use of β-lactam therapy with a macrolide (azithromycin; AZM) or monotherapy with a fluoroquinolone for treatment. Limited evidence exists on their comparative effectiveness. To address this gap, we examined the differences in outcomes among CAP patients treated with β-lactam therapy plus AZM or fluoroquinolone monotherapymethods: We emulated a randomized clinical trial that hypothetically assigned patients to β-lactam therapy plus AZM or fluoroquinolone. Eligible patients were all adults hospitalized for nonsevere community-acquired pneumonia (CAP) based on ATS/IDSA criteria; at Mayo Clinic hospitals (3 academic and 16 community) between May 2018 and September 2022 and received one of the two treatments within 12 hours of admission. Ensemble machine learning with augmented inverse probability weighting (AIPW) was used to evaluate “intention to treat” effects on hospital-free days (HFDs), 180-day mortality, use of advanced respiratory support, in-hospital mortality, and the composite of advanced respiratory support and/or in-hospital mortality. We used the E-value and post-discharge systolic blood pressure (SBP) (negative outcome) to evaluate effects of potential unmeasured confounding and alternative “doubly robust” inverse probably weighting with regression adjustment (IPWRA) to evaluate robustness of the findings. Results 2,451 patients (2,142 β-lactam therapy plus AZM and 309 fluoroquinolone) were eligible and included in the analyses: 53.9% were female, 86.8% were White, and mean age was 58.4 years (SD: 17.02). Compared with β-lactam therapy plus AZM, the fluoroquinolone group experienced significantly higher HFD (1.50 days; 95% CI: 1.08, 1.91), lower use of advanced respiratory support (RR: 0.32; 95% CI: 0.09, 0.54), lower in-hospital mortality (RR: 0.14; 95% CI: 0.00, 0.40), and composite of advanced respiratory support and/or in-hospital mortality (RR: 0.29; 95% CI: 0.08, 0.49). Moderate to large e-values (ranging from 3.50 to 4.74) and use of negative outcomes (post-discharge SBP) suggested that unmeasured confounding is unlikely to change the findings. Sensitivity analysis using IPWRA showed very similar results. Conclusion Among hospitalized patients with non-severe CAP, treatment with fluoroquinolone monotherapy was associated with more hospital-free days, lower in-hospital mortality, and reduced need for advanced respiratory support compared with AZM and β-lactam combination. The findings highlight the role of fluoroquinolone as a beneficial alternative CAP patients. However, further studies are needed to explore the underlying mechanisms driving these differences and assess whether specific patient subgroups may benefit most from quinolone-based therapy. This abstract is funded by: none

Abstract Rationale In fungal endemic regions, differentiating benign from malignant pulmonary nodules on CT scans remains a major diagnostic challenge. Coccidioides nodules frequently resemble malignant lesions on CT and PET imaging, presenting significant challenges for differentiation, even among radiologists. Consequently, the benign biopsy and resection rate, especially in the Southwestern US, remains high. We previously developed [DOI:10.1371/journal.pone.0196910] and externally validated [DOI:10.1183/13993003.02485-2020] the Benign versus aggRessive nODule Evaluation using Radiomic Stratification (BRODERS) machine learning (ML) classifier to non-invasively distinguish between benign and malignant pulmonary nodules with an AUC of 0.87. However, its performance in certain benign nodules with malignant surface and texture characteristics like in coccidioidomycosis had a suboptimal AUC of 0.65. In this study, we redesigned our radiomics model by including numerous clinical features. Methods In this retrospective study, 113 pulmonary nodules (66 Coccidioides and 47 adenocarcinoma spectrum) detected on CTs with ground truth pathology diagnosis were identified by screening for key terms like “nodule”, “cocci”, and “adenocarcinoma” from both CT and pathology reports using a large language model trained on clinical textual data (Illuminate®). Clinical features such as demographics, smoking history, and laboratory studies were extracted by trained clinicians from the electronic medical record. All nodules were segmented and radiomic features extracted using a semi-automated seed growing algorithm previously described [DOI: 10.1097/JTO.0b013e3182843721]. The database was randomly split into an 80%-20% development and hold-out set prior to ML modeling. Feature selection for variables was conducted utilizing Elastic Net Regression, which provides a balanced approach between Lasso and Ridge regression. A logistic regression model was developed using the selected features and ground truth information of the training cohort. The true performance of the model was tested on the hold-out set. Results 160 radiomics and 22 clinical features were extracted. Elastic Net regression identified 44 features that contributed the most. Some of these clinical features include presence of satellite lesions, smoking history, and presence of positive IgG coccidiomycosis serology. The AUC of the ROC curve for the hold-out test set was 0.86. Conclusions The clinical features of significance that emerged during multimodal modeling are explainable. Designing explainable ML models is important, especially in the Southwestern US where Coccidioides nodules can appear to be malignant to both human experts and ML models. Although coccidioidomycosis serologies alone lack sensitivity and specificity to diagnose Coccidioides nodules, integrating them with a multimodal ML model can improve differentiation between benign Coccidioides and malignant adenocarcinoma nodules. This abstract is funded by: None

Abstract Alveolar macrophages (AMs) are critical for host defense and immunity against Pneumocystis. Through surface-associated receptors, AMs recognize, phagocytose, and kill Pneumocystis organisms, producing cytokines that promote pathogen clearance but also contribute to lung inflammation and injury. The EphA2 receptor, a member of the receptor tyrosine kinase (RTK) family, contains an extracellular region that binds activating ligands (Ephrins) and, more recently, has been shown to bind fungal β-glucans, leading to activation of its intracellular tyrosine kinase domain. The EphA2 signaling pathway has important roles in cancer, angiogenesis, and inflammatory diseases such as atherosclerosis. EphA2 is highly expressed in epithelial and endothelial cells, and emerging evidence indicates that it serves as a critical regulator of host defense against bacterial, viral, and fungal pathogens. In oropharyngeal candidiasis, EphA2 was identified as a receptor for fungal β-glucans in oral epithelial cells, mediating proinflammatory signaling through signal transducer and activator of transcription 3 (STAT3) and mitogen-activated protein kinase (MAPK) pathways. Our laboratory recently demonstrated that EphA2 on lung epithelial cells binds Pneumocystis organisms, and that β-glucans from these organisms activate downstream signaling leading to IL-6 release. However, the role of EphA2 signaling in AM immune responses during Pneumocystis pneumonia (PCP) remains unknown. To address this, we examined EphA2-deficient (EphA2−/−) AMs stimulated with Pneumocystis β-glucans. Compared to wild-type AMs, EphA2−/− AMs exhibited significantly decreased production of proinflammatory cytokines, including IL-6 and TNF-α. In CD4-depleted mouse models of PCP, EphA2−/− lungs displayed markedly reduced levels of inflammatory cytokines and increased organism burdens, indicating impaired immune activation but preserved fungal persistence. Importantly, in CD4-depleted mice undergoing standard trimethoprim-sulfamethoxazole (TMP/SMX) therapy, concurrent administration of the EphA2 small-molecule inhibitor ALW-II-41-27 significantly reduced lung TNF-α responses without evidence of toxicity. These findings demonstrate that EphA2 receptor signaling plays a critical role in regulating macrophage-mediated inflammatory responses to Pneumocystis. While EphA2 deficiency dampens pulmonary inflammation, it also compromises fungal clearance, highlighting a delicate balance between host defense and immunopathology. Our data suggest that targeted modulation of EphA2 signaling during anti-Pneumocystis therapy may provide a novel adjunctive approach to reduce detrimental lung inflammation associated with PCP, potentially improving outcomes in affected patients. This abstract is funded by: NIH R01 HL-62150

Abstract Rationale Pneumocystis pneumonia (PJP) remains a major opportunistic infection in immunocompromised hosts, with limited therapeutic options. Previous studies identified a conserved cysteine residue (C353) in Pneumocystisphosphoglucomutase (PGM), analogous to that found in other pathogenic fungi but absent in mammalian PGMs, suggesting an exploitable antifungal target. We aimed to define the functional significance and therapeutic potential of targeting Pneumocystis PGM. Methods Full-length P. jirovecii and P. murina PGM cDNAs were cloned into S. cerevisiae pgm2Δ yeast (deficient in PGM activity) using the pYES2.1 TOPO vector for heterologous expression. Recombinant yeast lysates were tested for PGM activity in the presence of the thiol-reactive inhibitor ISFP10 (0-200 μM). Parallel assays were performed using recombinant human PGM lacking C353. Yeast growth inhibition in these strains in the presence of ISFP10 was also measured over 72 hours. For in vitro and ex vivo assays, P. murina organisms were treated with ISFP10, and viability was quantified via qPCR of the mitochondrial 16S ribosomal copy number. Precision-cut lung slice (PCLS) ex vivo cultures from a murine PCP model and in vivo CD4-depleted mice were used to assess ISFP10 efficacy and toxicity. Results Both P. jirovecii and P. murina PGMs showed potent, dose-dependent inhibition of enzymatic activity by ISFP10 up to 12.5 μM, with no inhibition of human PGM at concentrations up to 200 μM. Yeast complementation assays confirmed that ISFP10 significantly reduced the growth of pgm2Δ yeast expressing Pneumocystis spp. PGM. In vitro incubation of P. murina with ISFP10 resulted in significant reductions in organismal 16S mitochondrial copy number, comparable to pentamidine. In ex vivo PCLS models, ISFP10 decreased P. murina burden without affecting uninfected tissue viability. In vivo, ISFP10 administration for seven days significantly reduced fungal burden in CD4-depleted mice with an acceptable safety profile. Conclusions These findings demonstrate that Pneumocystis PGM activity depends on a conserved cysteine residue that is selectively targetable by ISFP10. Pharmacologic inhibition of PGM impairs P. murina viability in vitro, ex vivo, and in vivo with minimal host toxicity. Collectively, these data establish PGM as a promising, fungus-specific antifungal target and support the further development of small-molecule inhibitors targeting Pneumocystis PGM. This abstract is funded by: NIH R01 HL-62150, R21 AI-181542

Abstract Introduction Pneumocystis jirovecii pneumonia (PJP) is a significant opportunistic infection in immunocompromised patients. While cancer patients experience significant immunosuppression that increases their susceptibility to PJP, outcomes of this infection stratified by specific tumor types remain poorly characterized. Methods This retrospective study identified adults with PJP and either solid or hematologic malignancies using the National Inpatient Sample (2016-2022). Exclusion criteria included age <18 years, COVID-19 positivity, concurrent solid and hematologic malignancies, HIV positivity, or missing data. Baseline characteristics were compared between the two cancer groups. Multivariable regression analyses, adjusting for potential confounders, were conducted to estimate adjusted odds ratios for adverse events, treatments, and mortality. All analyses accounted for the complex survey design of the dataset. Results We found 11565 admissions involving PCP matching our selection, with 55.6%(6430) liquid and 44.4%(5135) solid cancers. Both groups contained an elderly population (mean age in solid: 64.25 years, vs. mean age in liquid: 63.36 years, p = 0.139), and mostly males( 51.32% of solid and 66.33% of liquid cancers, p < 0.01). The adjusted Deyo Charlson Comorbidity Index Scores were also comparable(1.65 in solid vs. 1.55 in liquid cancers, p = 0.195). Majority of patients in both groups (73.97% of solid and 72.55% of liquid) were Whites(p = 0.155), insured via Medicare(52.98% of solid and 54.60% of liquid,p=0.580), and hospitalized at urban teaching centers(85.69% of solid and 87.17% of liquid, p = 0.341). Among patients with solid tumors, 32.03% were respiratory/thoracic cancers, 11.88% were breast cancers, 11.10% were gastrointestinal cancers. Among patients with hematologic malignancies, the most common diagnoses were lymphoma (48.4%) followed by leukemia (37.2%). Patients with hematologic malignancies recorded reduced rates of acute respiratory failure, mechanical ventilation requirements, and intubation. In contrast, no significant differences were observed between groups for cardiovascular complications including cardiac arrest and septic shock. Acute kidney injury odds were similarly comparable between the two cohorts(Table 1). Our analysis demonstrated significantly lower mortality in hematologic malignancy patients compared to solid tumor patients, but with longer lengths of stay (15.4 days vs 13.2 days) and higher hospital charges ($234,616 vs $188,792). Conclusions Our findings demonstrate that solid malignancies may pose a bigger threat to PJP outcomes as compared to hematological cancers, warranting further investigation to set up appropriate preventive strategies and treatment protocols. This abstract is funded by: None

Abstract Respiratory viral infections such as influenza and SARS-CoV-2 can lead to the development of chronic lung disease and impaired pulmonary function long after the recovery from acute illness. However, the mechanisms underlying these post-acute sequelae remain poorly understood. Using human lung samples from patients with post-acute sequelae of COVID-19 with pulmonary fibrosis (PASC-PF) and an aged mouse model of chronic lung disease following acute viral infection, we found that CD4+ T cells were enriched near the dysplastic Krt8Hi epithelial regions of the lung. Similarly, in aged mice, CD4+ T cells localized to Krt8Hi areas, and their spatial distribution correlated positively with the extent of epithelial dysplasia. Further analysis of bronchoalveolar lavage (BAL) fluid from COVID-19 convalescent individuals revealed a distinct population of FoxP3−PD-1HiCD4+ T cells highly expressing ICOS, CD69, and CD103 - markers characteristic of both T follicular helper (TFH) and tissue-resident memory (TRM) cells, which we have defined as tissue-resident helper (TRH) cells previously. Notably, the frequency of these TRH-like cells correlated positively with the extent of reticulate or consolidated regions on chest CT scans, indicative of lung fibrosis. Furthermore, the frequency of these cells was negatively associated with lung functional parameters including forced vital capacity (FVC). These findings suggest that PD-1HiCD4+ TRH-like cells expand in PASC and may contribute to chronic lung sequelae. Given that Bcl6 is required for TRH differentiation, we employed an aged, CD4-specific, inducible Bcl6-deficient (Bcl6iΔCD4) mouse model to evaluate the functional contribution of these cells to post viral lung fibrosis. Bcl6 deficiency led to a marked reduction in total and antigen-specific PD-1HiCD4+ TRH cells, as confirmed by flow cytometry and immunofluorescence. Strikingly, Bcl6 iΔCD4 mice displayed significantly decreased inflammatory and fibrotic lesions in the lung compared to wild-type controls. Moreover, Bcl6 iΔCD4 mice exhibited enhanced lung regeneration, evidenced by increased AT1 and AT2 epithelial cells and improved pulmonary function. Together, these findings identify Bcl6-dependent CD4+ TRH responses as key drivers of post-viral chronic lung sequelae. This study reveals a novel immunopathogenic mechanism linking persistent tissue helper memory T-cell responses to impaired lung repair and fibrosis, providing new insight into the development of post-viral lung disease and potential therapeutic targets for conditions such as respiratory long COVID. This abstract is funded by: American Lung Association, NIH

Abstract When evaluating malignant anterior mediastinal masses, thymic carcinoma and lymphoma represent the most common etiologies. We present a case of a patient with an incidentally found anterior mediastinal mass, initially suspected to be thymic carcinoma, who was ultimately diagnosed with primary mediastinal classical Hodgkin lymphoma. A 55-year-old woman with no contributory past medical history presented to her primary care provider with several weeks of cough which was unresponsive to antibiotics and corticosteroids. A chest x-ray demonstrated a large mediastinal mass and subsequent CT chest further revealed an anterior mediastinal mass measuring 15 x 6 x 13 cm. A PET-CT showed intense FDG uptake in the mediastinal mass (SUVmax 14.5) and FDG-avid right pleural lesions suggestive of metastases (SUVmax 4.5). She was referred to outpatient pulmonary clinic. Given imaging findings, thymic carcinoma was initially favored. Following multidisciplinary discussion with Thoracic Surgery, neoadjuvant chemotherapy was recommended prior to any consideration of surgical resection given the size and involvement of mediastinal structures. Thus, CT-guided biopsy was pursued to confirm the diagnosis, but unexpectedly revealed classical Hodgkin lymphoma of the nodular sclerosis subtype. She was diagnosed with stage IVA disease and urgently initiated chemotherapy with nivolumab, doxorubicin, vinblastine, and dacarbazine (N-AVD). A repeat PET-CT two months after initiation of treatment demonstrated marked metabolic and anatomic response, with the mediastinal mass reduced to 8.9 x 5.4 cm with an SUVmax of 2.1. Similarly, the FDG-avid pleural metastases had a decrease in SUVmax to 1.0. The patient was continued on the same treatment regimen. Although thymic carcinoma was initially suspected, a biopsy was obtained because surgical resection was not planned as the initial step in management. Typically, thymic malignancies are not biopsied prior to surgery due to the risk of tumor seeding and the preference for definitive resection, with some exceptions. In this case, the decision to biopsy resulted in the unexpected diagnosis of primary mediastinal classical Hodgkin lymphoma, a particularly rare entity among anterior mediastinal masses. This case underscores the importance of individualized diagnostic strategies and the role of tissue confirmation when clinical or therapeutic circumstances deviate from standard practices. This abstract is funded by: None

Abstract Rationale Rural populations in the US experience a higher lung cancer burden compared to urban residents, potentially due to differences in risk factors and access to preventative care and early detection. We sought to characterize tobacco use, smoking cessation, and lung cancer screening patterns by rurality to identify modifiable gaps in the lung cancer care continuum. Methods We analyzed data from current and former smoking adults in the Southern Community Cohort Study, a large prospective cohort recruited from community health centers across 12 southeastern states. Participants aged 65-80 years with at least 9 months of Medicare Part A/B and less than 3 months of Part C coverage between 2014 and 2020 were included. Data were linked with the National Death Index and Medicare claims for outcome ascertainment. Rurality was defined using Rural-Urban Commuting Area (RUCA) codes. We compared demographic characteristics, smoking patterns, use of smoking cessation interventions, and receipt of low-dose computed tomography (LDCT) screening between rural and urban participants over time. Results Among 10,114 adults included (56% urban; 46% rural), 54% were female, 55% identified as Black/African American, about a third reported less than a high school education, and 45% lived in areas in the highest quartile of deprivation. Urban residents were of similar age (66 vs 67 years), and more likely to currently smoke (42% vs 35%), but had fewer baseline smoking pack-years (27 vs 30 pack-years) than rural residents. Approximately 2% died of lung cancer during follow-up. Using the USPSTF 2013 lung cancer screening criteria, 27% of urban and 26% of rural residents were eligible. This increased unevenly to 38% urban and 35% rural under the USPSTF 2021 criteria. LDCT uptake was low, increasing from 0% in 2014 to 6% in 2020 among screening-eligible participants. Use of cessation interventions was similarly low. Among current smoking participants, 7% received smoking cessation counseling, and 3% had a varenicline prescription. These patterns remained relatively stable over time, with no significant rural-urban differences in LDCT and cessation intervention use. Conclusion Despite modest differences in smoking prevalence and screening eligibility, we found comparable lung cancer mortality and similarly low utilization of LDCT and cessation interventions among rural and urban residents. Our findings suggest that, among people in lower socioeconomic groups, shared socioeconomic constraints may extend beyond the rural-urban divide. Further research is needed to understand how social determinants of health may be addressed to improve lung cancer outcomes across the screening continuum. This abstract is funded by: NIH

Abstract Introduction Solid tumors modify local angiogenesis and co-opt surrounding vasculature to maintain energy supply required for ongoing growth. This process is often complicated by metastasis and hemorrhage. Pulmonary tumors can rarely create intrapulmonary shunt physiology and hypoxemia in this manner; this has been described most often in bronchoalveolar carcinoma. We present a case of malignant intrapulmonary shunt occurring with spindle cell sarcoma, which resolved with arterial embolization. Case Presentation A 72-year-old male with a history of stage IV spindle cell sarcoma with abdominal, vertebral, and pulmonary metastases presented to an outpatient appointment with three weeks of fatigue and decreased exercise tolerance. He had no history of parenchymal lung disease nor any home oxygen requirement. In clinic, he was found to require 6L per minute of supplemental oxygen to maintain saturation of 88%. He was directly admitted to the oncology service. Initial laboratory evaluation was unremarkable. CT imaging demonstrated normal lung parenchyma, no pulmonary embolism, and an 11cm vascular tumor involving proximal branches of the local pulmonary artery (Figure). Transthoracic echocardiography (TTE) with agitated saline revealed a large intrapulmonary shunt. As the patient had limited response to oxygen therapy, this intra-tumoral shunt was deemed the most likely cause of his hypoxemia. Surgical resection was considered but was deemed to confer limited clinical benefit in the setting of multiple metastases. Embolization of the local pulmonary artery was therefore pursued with Interventional Radiology. The patient tolerated the procedure well with complete resolution of hypoxemia post-procedure. His energy and mobility improved, and he was discharged home. Three months later, he continued to require no supplemental oxygen. Discussion While shunt physiology is commonly part of the differential for hypoxemia, it is rarely described as an oncologic complication. This appears to be the first report of such pathology in a sarcoma patient, and the first to report shunt resolution through arterial embolization rather than surgical resection or systemic anti-tumor therapy. In addition, previous cases typically describe shunt detection via selective pulmonary arterial occlusion by Swan-Ganz catheter, whereas here the noninvasive TTE with agitated saline was sufficient. While the few existing reports highlight good response to lobectomy or pneumonectomy, this case highlights the potential for minimally invasive vascular intervention. Despite the metastatic nature of this patient’s disease, he received significant, rapid physiologic and functional benefit from a procedure with less morbidity. Maintaining suspicion of intra-tumoral shunt physiology is appropriate for patients with vascular pulmonary masses and hypoxemia. This abstract is funded by: None