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Abstract RATIONALE. Significant sex-differences exist in asthma across the lifespan. Asthma prevalence and severity are greater in pre-pubescent boys compared to girls but greater in women after puberty. In women, asthma may improve after menopause when sex hormones wane. To address potential mechanisms underlying these changes, we compared the airway transcriptomics signatures of post-menopausal vs. premenopausal women. METHODS. We used bulk RNA seq data from bronchial epithelial cells from three different cohorts (SARP III, GEO-GSE85567, GEO-GSE201955) to perform a comprehensive analysis of differential gene expression and regulation. Data were combined into a meta-analysis, to compare pre-menopausal (n=114 cases with asthma, 48 controls) to post-menopausal women (n=52 cases with asthma, 13 controls). Differential gene expression between pre- and postmenopausal women was analyzed separately for asthma (Figure 1A) and control groups (not shown). Significant differentially expressed genes (DEGs) were identified by contrasting effect sizes (log fold-changes) between asthma and control groups using a Z-score interaction test. Accordingly, a scatter plot (Figure 1B) was created to represent whether differential gene expression between pre- and post-menopausal conditions is modified by disease status (asthma vs. control). The scatter plot also highlights that these findings are related to asthma per. se. and not to normal aging and menopausal transition. Pathway enrichment analysis was conducted using the differential expression data, followed by differential regulation analysis of the identified pathways. Statistical significance was assessed using a false discovery rate (FDR) threshold of 5%. RESULTS. Out of 15,468 genes that passed quality control, 19 genes were differentially expressed in bronchial epithelial cells from pre- and post-menopausal women with asthma (as compared to controls) (Figure 1A). Of these, 5 genes were down-regulated (ITLN1, POSTN, FCRL3, CCL22, PCSK6), and 14 genes were up-regulated (SPP1, S100A9, A2ML1, TNFRSF10C, CSF3R, OLFM1, C1QL2, NLRP3, HAL, PI3, RNASE1, TMEM178B, TNNI3, RNF175) when comparing pre- and post-menopausal women with asthma (Figure 1A). Of these 19 DEGs, 14 were differentially expressed in pre- as compared to post-menopausal women with asthma, but not in controls (Figure 1B). Comparing pre- to post-menopausal women with asthma, biologic pathways related to the innate and adaptive immune system activation and mitochondrial function (Electron transport Chain oxidative phosphorylation and ATP production) were both differentially regulated and expressed. CONCLUSIONS. This analysis highlights several DEGs and pathways that characterize asthma pathogenesis when comparing pre- and post-menopausal women, and emphasize the role of female sex hormones on the immune system response and mitochondrial function in asthma pathogenesis.

Abstract Introduction: Erdheim-Chester disease (ECD) is an exceptionally rare non-Langerhans cell histiocytic malignant disorder but presents a unique diagnostic challenge due to its diverse clinical manifestations from mild symptoms to severe, life-threatening multiorgan disease. Here, we report a case of ECD that presented with pleuro-pulmonary and vascular involvement rather than skeletal lesions. Case description: A 75-year-old man with a history of systemic lupus erythematosus, rheumatoid arthritis, and chronic obstructive pulmonary disease presented with syncope, anorexia, fatigue, and weight loss. He was noted to be in atrial fibrillation. Subsequent imaging studies, including. The CTA of chest and PET-CT scans showed hyperdense wall thickening in multiple arteries and veins, including the pulmonary arteries and veins, aortic arch, thoracic and abdominal aorta, and iliac arteries as well as pulmonary nodules suggestive of a large vessel vasculitis associated with systemic inflammation. The patient underwent a pleural biopsy which only demonstrated nonspecific inflammation. He subsequently underwent surgical wedge biopsy of a superior right lower lobe and multiple pleural biopsies showed atypical histiocytic infiltrate suspicious for a histoplasmic neoplasm with the atypical histiocytes characterized by plump to spindled nuclei with focal emperipolesis. Atypical histiocytes were positive for CD163, factor 13a, cyclin D1 suggestive of ECD. As further testing demonstrated a negative BRAFV600E mutation, the patient was initiated on cobimetinib 40 mg daily. He responded to therapy with subjective and objective improvement. There has been no radiographic evidence of recurrence. Discussion: The diagnosis of ECD relies on clinical presentation, imaging studies, and distinctive pathological findings. Overall, the prognosis depends on the degree of histiocytic damage before initiation of treatment; degree of inflammation; age; digestive tract involvement. A biopsy revealing non-Langerhans cell histiocytosis, supported by immunohistochemistry exams, is essential for confirming the diagnosis. Diagnosing ECD is challenging due to its rarity and multisystem involvement necessitating a multidisciplinary approach. Pulmonary involvement, seen in 43% of cases, often presents with features of interstitial lung disease but does not significantly impact overall prognosis. Recent evidence implicates the BRAFV600E mutation in ECD pathogenesis, suggesting new therapeutic possibilities.

Abstract Rationale: Volatile organic compounds (VOCs) in exhaled breath change significantly after ultramarathons and could help monitor athletes’ physiological status to optimize training. While VOCs can reflect metabolic changes, the connection between VOCs and clinical blood and respiratory data remains unknown. In this study, we investigated how breath VOCs are linked to clinical variables that reflect the cardiovascular and respiratory system. Methods: Correlation analysis was performed between respiratory data collected in pre- and post-race samples from 24 runners who participated in the 2019 Ultra-Trail du Mont Blanc (UTMB®) ultra-marathon. Correlation analysis was then performed between these clinical data and previously published breath VOC data collected from the same individuals. Results: Clinical data indicated a slight decrease in runner's lung function post-race. Interestingly, in post-race samples, respiratory parameters vital capacity (VC) and forced expiratory volume in one second (FEV1) formed a moderate positive correlation with 2,3-butanediol (r = 0.53, r = 0.63, respectively), a compound produced by bacterial metabolism. We hypothesize that production of 2,3-butanediol results from the effect of exhaustive exercise on the gut microbiome, which may provide protection to ameliorate lung injury. Additionally, a strengthened correlation from moderate (r = 0.5 – 0.7) to strong (r > 0.7) between VC and FEV1 (r = 0.67 to r = 0.84), forced vital capacity (FVC) and maximal expiratory pressure (MEP) (r = 0.57 to r = 0.75), was observed from pre-race to post-race samples. Finally, FEV1 and MEP shifted from no correlation (r < 0.5) in pre-race to a strong correlation (r = 0.73) in post-race. Conclusion: The strengthened correlation between respiratory data in post-race samples suggests that the gut microbiome, under the effect of exercise, may have an indirect impact on both lung function and respiratory muscle function changes. Our findings support the notion that there is an intricate relationship between exhaustive exercise, altered gut microbiome activity, and lung function, and together they can influence athlete performance.

Abstract IntroductionFungal infections, particularly in the Midwest, can often be asymptomatic and may mimic primary lung cancer. This case illustrates pulmonary histoplasmosis in an 80-year-old woman with a history of lung cancer highlighting the diagnostic challenges presented when both conditions coexist.Case SummaryAn 80-year-old woman (prior smoking history of 47-pack-years) with synchronous lung cancers (poorly differentiated non-small cell carcinoma with squamous differentiation in the left lower lobe and squamous cell carcinoma in the right lower lobe) previously underwent radiation therapy to both lesions. She was admitted for shortness of breath and cough and was initially diagnosed with pneumonia based on CT findings. Despite multiple courses of antibiotics, her symptoms persisted over 2 months, improving only temporarily with a short course of prednisone. A follow-up CT revealed increasing confluent thick-walled cavitation in the posterior right upper lobe and superior segment of the right lower lobe concerning for cavitating/necrotizing pneumonia versus possible cancer progression. A PET-CT scan (Fig.1A) showed significant FDG uptake in the right upper lobe lesion and mild uptake in mediastinal lymph nodes complicating the differentiation between cancer and infection. Bronchoscopy with biopsy of an endobronchial lesion in the posterior segment of right lower lobe revealed necrotizing granulomatous inflammation (Fig.1B) with GMS stain showing the presence of fungal organisms suggestive of histoplasmosis. Histoplasma PCR from bronchoalveolar lavage was also positive. She was subsequently started on antifungal therapy for a planned one-year treatment course. DiscussionHigh positron emission tomography (PET) avidity in chest imaging is often linked to aggressive tumors but can also indicate benign conditions such as fungal infections. A “flip-flop sign” on PET imaging, where nodal activity surpasses that of a lung nodule, is typically seen in benign lung lesions, particularly fungal infections. However, infections and inflammatory conditions may also show high PET avidity mimicking malignancy. Endobronchial lesions, common in lung cancer, are less frequently associated with infections. In patients with a history of cancer, active lung infection, and PET-avid lesions without the flip-flop sign, invasive testing is usually required to differentiate between infection and malignancy. In this case, our patient with a history of lung cancer and a PET-avid lung lesion was found to have pulmonary histoplasmosis after invasive testing highlighting the need for comprehensive evaluation.ConclusionThis case emphasizes the importance of considering fungal infections in the differential diagnosis of PET-avid pulmonary lesions, particularly in patients with a history of malignancy.

Abstract Fibrosing mediastinitis is an infiltrative disease which may develop secondary to a variety of causes, including autoimmune, infectious, and malignant processes. Here, we present a case of fibrosing mediastinitis, with initial concerns for IgG4-related disease. A 36-year-old man presented to his primary provider with three months of intermittent dyspnea. CT chest was significant for a large, infiltrative mediastinal and left hilar mass with calcifications and involvement of the left upper and lower lobe bronchi, lingular bronchus, and left main pulmonary artery. Subsequent autoimmune and fungal studies were negative. The patient underwent bronchoscopy, with biopsy of a lymph node at station 11L showing increased IgG4 on immunostain (30 cells/hpf), though IgG immunostaining was not completed for comparison. Despite initial concerns for fibrosing mediastinitis, the patient was diagnosed with IgG4-related disease and initiated on rituximab and mycophenolate. Notably, the patient's serum IgG4 concentrations were consistently within normal limits before and after initiation of rituximab. The patient was referred to our clinic after lack of response to therapy on imaging. Laboratory evaluation redemonstrated a normal serum IgG4 concentration and fungal studies were consistent with previous histoplasma infection, suggesting fibrosing mediastinitis secondary to histoplasmosis. IgG4-related disease was determined to be unlikely considering repeatedly normal IgG4 levels and weakly positive IgG4 staining. Repeat CT chest demonstrated fibrosis of the left upper lobe; compression of the left atrial appendage; and occlusion and severe obstruction of the left superior pulmonary vein and left lower lobe pulmonary artery, respectively. VQ scan demonstrated significantly reduced perfusion of the left lung and the patient was referred for stenting of the affected vasculature. PET-CT revealed moderate FDG avidity of the left hilar nodes, concerning for ongoing active fibrosing mediastinitis, for which he was continued on rituximab. The indolent nature of fibrosing mediastinitis often leads to advanced disease at the time of presentation. Hilar structures are commonly involved, as in the case of this patient with a severe perfusion defect secondary to obstruction of the pulmonary vessels. A diagnosis of fibrosing mediastinitis merits careful investigation of the underlying cause. Fungal infections, specifically histoplasmosis in North America, are a leading cause of this condition. IgG4-related disease is also associated with fibrosing mediastinitis, and both conditions are driven by fibroinflammatory processes. However, it is important to note that IgG4 immunostaining is non-specific, and diagnosis of IgG4-related disease requires the meeting of rigorous criteria. Differentiation between these diagnoses is important given potential differences in management.

Abstract INTRODUCTION: Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis (PVOD/PCH) is a rare subgroup of pulmonary arterial hypertension (PAH). Unfortunately, there is significant overlap between PVOD and PAH, making differentiation difficult. Thus, a constellation of investigations is necessary to suggest such a diagnosis. CASE PRESENTATION: A 65-year-old female with a history of smoking was diagnosed with idiopathic PAH following 2 months of worsening dyspnea. Right heart catheterization (RHC) revealed a mean PA pressure (mPAP) 58mmHg, pulmonary artery wedge pressure (PAWP) 14mmHg, cardiac output/index (CO/CI) 5.5/2.6, and pulmonary vascular resistance (PVR) 8 Wood units. Further workup excluded other causes of pulmonary hypertension (Table 1). Tadalafil was initially started followed by macitentan, which were associated with worsening hypoxemia and dyspnea. Computed tomography (CT) scan of the chest revealed mediastinal lymphadenopathy and small bilateral pleural effusions. This development in relation to the initiation of PAH-directed therapies raised concern for possible PVOD. Medical therapy was downtitrated, but worsening hypoxemia in the setting of worsening edema led to the cessation of all therapies. Due to clinical concern, the patient was admitted for a repeat RHC and close supervision during a trial of epoprostenol. RHC revealed a mPAP of 57mmHg, PAWP 5mmHg, CO/CI 3.4/1.6 and PVR 15 Wood units. She had been on metoprolol for hypertension which was discontinued. Low-dose epoprostenol was started at 1ng/kg/min. Her oxygen requirements increased slightly which improved with diuresis. Epoprostenol was slowly titrated with improvements in CI. Repeat chest CT showed mild diffuse centrilobular nodular opacities more prominent compared to prior scans, and adenopathy. After a steady dose of epoprostenol (4ng/kg/min), the patient improved with lower oxygen requirements. She was discharged with plans to continue low dose outpatient epoprostenol and start sotatercept. Lung transplant evaluation is on hold pending response to this approach. Genetic testing is pending. DISCUSSION: Despite challenges of definitive diagnosis where lung biopsy is risky, a diagnosis of PVOD can be supported from a spectrum of strongly suggestive clinical, hemodynamic and radiographic features. Though genetic testing for the EIF2AK4 mutation may confirm the presence of heritable PVOD, its absence does not exclude its possibility as most cases do not have an identifiable genetic cause. Management is challenging given ineffective or potentially harmful responses to PAH-directed therapies, though some do respond to a variable extent. As suggested here, close supervision during epoprostenol infusion adds to the limited body of evidence supporting such endeavors when initiating vasodilatory therapies in patients with suspected PVOD.

Abstract Introduction Extramedullary hematopoiesis (EMH) is the production of blood cells outside of bone marrow. It is associated with myeloproliferative neoplasms such as myelofibrosis and chronic myeloid leukemia. Most common sites for EMH are liver and spleen, but other sites may be involved. Pulmonary EMH is extremely rare. It is associated with symptoms of dyspnea, cough or chest pain. Chest imaging may demonstrate pulmonary nodules or masses, alveolar septal thickening, ground glass opacities, and/or patchy consolidations. We present a case of a woman with primary myelofibrosis who developed pulmonary hypertension (PH) in the setting of pulmonary EMH. Case description 73-year-old woman with history of primary myelofibrosis (diagnosed via bone marrow biopsy, grade 3 fibrosis, being treated with hydroxyurea) presented with progressive exertional dyspnea for 1.5 years. Exam was notable for elevated jugular venous pressure and mild peripheral edema. Labs revealed anemia with hemoglobin 8.2 g/dL, thrombocytosis with platelets 549K/dL and no leukocytosis. Brain natriuretic peptide was elevated at 1361 ng/L. Chest CT demonstrated few peripheral wedge-shaped opacities in the bilateral lower lobes were noted. Pulmonary function tests revealed normal spirometry and lung volumes but moderately reduced diffusion capacity. Echocardiogram showed normal left ventricular (LV) size and function with ejection fraction 60%, moderately enlarged right ventricle (RV) and RV systolic pressure 63 mmHg. Right heart catheterization showed RA pressure:14 mmHg, PA: 49/26/36 mmHg, PCWP 15mmHg, thermodilution CO 5.5 L/min, CI 3.1L/min/m2, Fick CO 4.6 L/min, CI 2.6 L/min/m2, pulmonary vascular resistance 3.8-4.6 Woods Units. Given her history of myelofibrosis, Tc-99m bone marrow scan was performed which showed diffuse radiotracer uptake in both lungs suggestive of pulmonary EMH. She subsequently underwent radiation therapy with 100cGy to bilateral lungs. On a follow-up visit two months later, she reported symptomatic improvement. Repeat NM bone scan showed decreased tracer uptake in the lungs. Discussion PH associated with myeloproliferative neoplasia is classified as group 5 in the latest clinical classification. It can be due to thrombocytosis, hypercoagulability, left ventricular failure, portal hypertension and/or hematopoietic infiltration of the pulmonary parenchyma. Tc-99m sulfur colloid scanning can be used to detect hematopoietic tissue in the lung. Treatment is usually radiation-therapy to the lungs to control the hematopoiesis. In patients with myeloproliferative neoplasms presenting with dyspnea, consider screening for PH with echocardiogram.

Abstract Rationale: SARS-CoV-2 infection may be associated with new or worsening respiratory symptoms that, if persistent, may contribute to “Long COVID.” Research is needed on the prevalence and risk determinants of Long COVID and related respiratory symptoms in adults with and without pre-existing obstructive lung disease or smoking history. Methods: C4R is a prospective, observational study that collected information on SARS-CoV-2 infection using standardized methods across 14 NIH-funded cohorts. The third wave of C4R questionnaires, administered June 2023 to January 2025, assessed self-reported Long COVID via the question, “Do you think that you are experiencing, or have ever experienced, what has been called “long COVID,” or symptoms related to COVID at least a month after your infection?” Questionnaires also assessed the presence (vs absence) of 22 symptoms that have been linked to Long COVID, including cough, shortness of breath, and post-exertional malaise. Pre-pandemic obstructive lung disease (COPD or asthma) and smoking status (ever/never) were harmonized from self-reported data collected at the most recent pre-pandemic cohort exam. Poisson regression was used to assess prevalence ratios (PRs) adjusting for age, sex, BMI, education, and pre-pandemic hypertension, diabetes, cardiovascular disease, and depressive symptoms. PRs for respiratory symptoms were tested according to self-reported Long COVID and history of non-hospitalized or hospitalized infection; effect modification by pre-pandemic lung disease and smoking was assessed by multiplicative interaction terms and in fully stratified models. Results: Among 23,434 questionnaire respondents, 1,484 (6.3%) self-reported Long COVID, including 246/1,262 (19.5%) with pre-pandemic lung disease and 664/4,018 (16.5%) with smoking history. The adjusted PR for Long COVID was 1.17 (95%CI:0.99-1.39;P=0.06) comparing participants with/without lung disease and 1.17 (95%CI:1.04-1.32;P=0.01) comparing participants with/without smoking history. Respiratory symptoms were more prevalent in those with self-reported Long COVID, as well as in those with a history of hospitalized or non-hospitalized infection (Table). Associations were generally stronger in participants without pre-pandemic lung disease (p-interaction<0.05 for all comparisons). Respiratory symptoms were also more prevalent with a history of repeated, and pre-Omicron infections, and were less prevalent among participants vaccinated prior to their first infection; findings were similar even after excluding participants with self-reported Long COVID. Conclusions: Long COVID is common, particularly in adults with pre-existing COPD or asthma or smoking history. Long COVID and history of SARS-CoV-2 infection, including non-hospitalized infections, was associated with greater respiratory symptom burden. Whether SARS-CoV-2 infection or Long COVID are associated with development or progression of obstructive lung diseases warrants future studies.

Abstract RATIONALE: Chronic kidney disease (CKD) is common in the general population and is associated with inflammation and compromised immune function. Since these mechanisms are hypothesized to promote severe COVID-19, we tested associations of pre-pandemic CKD with incident COVID-19 hospitalization or death in a large, multi-ethnic, US general population-based meta-cohort of adults. METHODS: Data were harmonized and pooled from 9 NIH-funded longitudinal cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R). CKD was classified by KDIGO 2024 CKD guideline (Low Risk, Moderately Increased Risk, High Risk, Very High Risk) using pre-pandemic urinary albumin-to-creatinine ratio (uACR) and estimated glomerular filtration rate using creatinine (eGFRcr). Incident COVID-19 hospitalization or death was ascertained over 2020−2023 via self-report and active surveillance, with medical record adjudication in a subset. In our primary analysis, we assessed associations between CKD stages and incident COVID-19 hospitalization or death. A secondary analysis examined joint association of CKD stages and the number of comorbidities (obesity, hypertension, diabetes, and cardiovascular disease) with the severe COVID-19. Multivariable hazard ratios (HRs) were estimated by cause-specific Cox regression, adjusting for socio-demographics and smoking. RESULTS: Among 26,039 multi-ethnic adult participants (mean age 66.1±14.8, 60.6 % female, 28.6% Whites, 3.2% Asians, 20.6% Blacks, 41.3% Hispanics, 6.3% American Indians) with a median follow-up of 550 days since the onset of the pandemic (baseline: March 1, 2020), there were 734 incident COVID-19 hospitalizations or deaths. The mean time since CKD markers were measured before the baseline was 6.5 years. The cumulative incidence of severe COVID-19 was 2.3, 3.5, 6.5, and 7.3% across CKD risk stages, and similar patterns were observed within variant types (Figure 1). Compared to participants with Low Risk of CKD, there was a graded increased hazards of severe COVID-19 across CKD stages, with HRs (95% CIs) of 1.27 (1.03−1.55) for Moderately Increased Risk, 2.33 (1.77−3.06) for High Risk, and 2.72 (1.89−3.92) for Very High Risk. In a joint analysis, both increased CKD risk and a higher number of comorbidities were associated with a higher risk of severe COVID-19, showing the highest HR of 12.29 (5.75−26.27) in Very High Risk individuals with four comorbidities compared to Low Risk individuals with none. CONCLUSIONS: Higher CKD stages were associated with a greater risk of COVID-19 hospitalization or death and the risk is substantially heightened with additional comorbidities. These results suggest that adults with CKD and related comorbidities may merit enhanced COVID-19 risk mitigation.

Abstract Introduction Endometriosis is when endometrial glands and stroma develop outside of the uterus and the most common extra-pelvic site is the involvement of the thoracic cavity. Thoracic endometriosis most commonly presents with catamenial pneumothorax, which refers to a temporal association with menstruation. The pathophysiology is unknown, but thoracic endometriosis should be suspected in any female of reproductive age presenting with catamenial pneumothorax. Case Description A 35 year-old female with a history of a total abdominal hysterectomy for uterine leiomyoma presented with chest pain, scapular pain, and shortness of breath. Her past medical history was notable for recurrent bilateral spontaneous pneumothoraces with prior pleurodeses. Chest x-ray on admission confirmed bilateral pneumothoraces. She was hemodynamically stable and saturating well on room air. There was no tension physiology. She underwent bilateral chest tube placement with successful lung re-expansion followed by bilateral pleurodesis. Pelvic MRI revealed endometriosis involving the vaginal cuff, ovaries, and tethering of the rectosigmoid colon with findings suspicious for bowel invasive disease. Previous imaging had failed to provide evidence for thoracic endometriosis, nor was endometriosis identified on previous VATS procedures. There was no evidence of cystic lung disease on prior imaging or other cause to explain recurrent pneumothoraces. She was started on hormonal suppressive therapy per gynecology for thoracic endometriosis syndrome. Discussion The diagnosis of thoracic endometriosis is usually made clinically; histopathologic confirmation is ideal but not required. The clinical characteristics that set thoracic endometriosis apart from other diseases that present similarly include temporal association with menstruation, right lung predominance, and demographics (i.e. young, female with recurrent disease). Patients with thoracic endometriosis may have higher serum carbohydrate antigen (CA) 125 and CA 19-9, however, these markers are poorly sensitive and non-specific. At times, pleural fluid is sent for evaluation of endometrial cells, but the diagnostic yield is thought to be low. Hormone suppressive therapy should be used to treat the majority of patients with pneumothoraces related to endometriosis, however, even with the combined strategy of hormonal suppression and surgery, recurrence can still occur.