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Abstract Introduction Sex-based differences in morbidity and mortality for pulmonary hypertension (PH) are insufficiently addressed in current research. However, recognizing these differences is crucial for optimal clinical management and improving outcomes. This study assesses the effect of sex on survival among PH patients, while accounting for disease severity, comorbidities, treatment, and race. Methods We analyzed data from the PVRI GoDeep meta-registry, including all incident patients with complete hemodynamic profiles. Survival was evaluated using Kaplan-Meier and Cox proportional hazards models, adjusted for various confounders. Analyses included both PAH and non-PAH groups and risk assessment by the ESC/ERS 2022, REVEAL lite 2, and COMPERA 4-strata scores. All analyses were performed using R (The R Foundation). Results A total of 19,663 incident PH patients were included in the analysis, with 5,581 patients (28%) diagnosed with Group 1 PH and a median age of 64 years [IQR: 52-73]. Among these, male patients (8,704, 44%) had a significantly higher mortality risk than female patients across the entire cohort and within all PH subtypes. The adjusted hazard ratio for mortality in male versus female patients was 1.391 [95% CI: 1.260-1.536] in the overall population and 1.404 [95% CI: 1.264-1.561] for those with PAH. This survival difference was consistent across various severity levels, age groups, and in the presence of comorbidities such as obesity and cardiovascular diseases, as well as among those receiving PAH-specific therapies as well as patients who remained without treatment during the observation period. Notably, male disadvantage in survival was observed in low, intermediate, and high-risk categories for ESC/ERS 2022, REVEAL lite 2, and COMPERA scores but not within REVEAL 2.0, which includes male sex as a non-modifiable risk factor. Racial analysis revealed a greater mortality risk for males among White patients, with no significant differences noted in Black or Asian populations. Conclusion Our PVRI GoDeep meta-registry analysis demonstrates that male PH patients face higher mortality risk across both PAH and non-PAH groups, independent of disease etiology, age, severity, comorbidities, and treatment factors, with this risk amplified in White patients. These findings suggest that male sex should be further considered as a risk factor to refine predictive models for survival in PH.

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 Rationale: Chronic lung diseases, such as COPD and bronchiectasis (BE), may manifest differently by gender in symptom presentation, time to diagnosis, and overall disease burden. This study aimed to assess perceptions of individuals with self-reported COPD, BE, or non-tuberculous mycobacteria (NTM) regarding healthcare experiences and disease-related symptoms. Methods: This cross-sectional study analyzed data from US-based and international participants with self-reported COPD, BE, or NTM using an online survey. Participants were recruited through the COPD Foundation (COPDF) social media channels and completed a questionnaire developed with input from a steering committee that included COPDF leadership, physician-researchers, and patient stakeholders. The survey explored participants’ experiences with healthcare, disease burden, and self-reported symptoms. A subset of women answered additional questions regarding menopause-related symptom changes. Descriptive statistics were calculated and analyzed across self-identified genders and two disease groups: COPD (with or without BE or NTM) and BE (with or without NTM or COPD). Continuous variables were compared using ANOVA, while categorical variables were analyzed using chi-square or Fisher's exact test. Results: Of 632 respondents included in these analyses (mean age 70±9 years, 74% women), 68% reported COPD and 32% BE (both groups included individuals with or without additional diagnoses). Women with COPD were younger than men (p=0.048) and had a shorter duration between symptom onset and initial healthcare visit (< 6 months) (p<0.01). Compared to men, a higher proportion of women with COPD reported that their diagnosis was not explained by a healthcare provider (p=0.0381) and that they experienced anxiety, depression, or fear related to their diagnosis (p=0.0074). Among participants with BE, men and women were similar in age, though a higher proportion of men had shorter intervals (<6 months) between initial healthcare visit and confirmed diagnosis (p=0.0244) and received their diagnosis during hospitalization (p=0.0244). Both men and women across diagnoses reported similar levels of disease management burden, pulmonologist visit frequency, CAAT scores, numbers of comorbidities, and financial difficulties related to their lung condition. Over 75% of women identified as post-menopausal, with approximately one-third reporting worsening pulmonary symptoms associated with menopause. Conclusions: Despite similarities in disease management and comorbidity burden, women with BE and men with COPD reported longer times to initial healthcare visits and diagnostic delays, respectively. Additionally, over one-third of post-menopausal women experienced symptom exacerbation since menopause. These findings underscore the need to further explore gender-based differences and disparities in healthcare access and pulmonary care to enhance lung health outcomes across genders.

Abstract Introduction:IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition marked by lymphoplasmacytic infiltrates that tend to affect various organs, leading to diverse clinical manifestations. While commonly linked to conditions like pancreatitis and sialadenitis, it can also impact the lungs, causing pulmonary masses, consolidations, or pneumonia. Key histopathological features include IgG4-positive plasma cells and storiform fibrosis, although these may not always be present. Case Presentation: We present a case of an 82-year-old male with a past medical history significant for pulmonary cryptococcal infection and a previous COVID-19 infection, who presented to our pulmonology clinic with fatigue for two months followed by an upper respiratory infection that did not respond to several rounds of antibiotics. A chest CT scan revealed bilateral consolidative airspace opacities and lymphadenopathy. Subsequent bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL) suggested a possible cryptococcal infection; however, his symptoms did not improve after a course of fluconazole. A follow-up PET-CT scan showed increased metabolic activity in the bilateral pulmonary consolidations, thoracic adenopathy, a possible right supraclavicular lymph node, and bilateral inguinal lymph nodes. He underwent a repeat bronchoscopy with EBUS-guided biopsy of the FDG-avid lymphadenopathy, and pathology results indicated granulomatous inflammation. He was evaluated by ophthalmology for uveitis and signs of retinal detachment on brain MRI, as well as nephrology for a progressive decline in kidney function. A renal biopsy showed numerous plasma cells staining for IgG and IgG4, along with storiform interstitial nephritis, consistent with IgG4-related interstitial nephritis. His autoimmune evaluation revealed elevated levels of ANA, double-stranded DNA, RNP antibodies, and various IgG subclasses, including IgG1, IgG3, and IgG4. Considering the biopsy results and the reduced suspicion of an infectious process, he was initiated on immunosuppression treatment with prednisone and rituximab for the IgG4-related disease which resulted in significant improvement in both the patient's symptoms and kidney function. Discussion:In conclusion, this case emphasizes the diagnostic challenges of IgG4-related pulmonary disease, largely due to the nonspecific nature of the respiratory manifestations. In our case, the diagnosis remained unclear despite the patient undergoing both transbronchial and EBUS-guided lymph node biopsies. This highlights the importance of maintaining a high clinical suspicion for this underdiagnosed condition as early treatment can lead to notable recovery.

Abstract Introduction Rheumatoid arthritis (RA) is a systemic autoimmune rheumatic disease (SARD) primarily associated with articular involvement, but is often associated with lung involvement, sometimes preceding articular symptoms. Common pulmonary manifestations include interstitial lung disease (ILD), airway, and serosal involvement. RA-related pleural disease can mimic empyema due to the pleural fluid's green, pus-like appearance, exudative nature, low pH, markedly low glucose, and elevated lactate dehydrogenase (LDH) levels. Empyema sometimes yields negative cultures which can accentuate the diagnostic challenge in such cases. This report presents a patient with RA-related pleural lung disease who was referred to our hospital with trapped lung presumed to be secondary to empyema in the setting of pleural-based pulmonary abscess. Case Report A 66-year-old female with a 22-year history of RA presented with recurrent right-sided pleural effusions and progressive dyspnea over three years. Her initial presentation in 2022 involved a large right-sided pleural effusion, suspected to result from a ruptured pleural-based pulmonary abscess that led to empyema and subsequently a trapped lung. Pleural fluid analysis showed elevated LDH (1364 U/L), low glucose (45 mg/dL), high cholesterol (121 mg/dL), and low triglycerides (79 mg/dL). Due to refractory exudative effusion and a comprehensive negative infectious evaluation (bacterial, mycobacterial, and fungal cultures), RA-related pleural disease was suspected. The patient underwent video-assisted thoracoscopic surgery (VATS), which revealed pleural-based rheumatoid nodules and pleural thickening. (figure1) Lung and pleural biopsies confirmed RA-associated fibrinous pleuritis, RA-associated follicular bronchiolitis, and usual interstitial pneumonitis. Given the complexity of the infection, a thoracotomy with decortication and pleurectomy was planned and conducted in stages. Immunosuppressive regimen was switched from leflunomide to rituximab. Discussion This case underscores the diagnostic complexity in distinguishing RA-associated pleural effusion from empyema. Features such as pleural nodularity resembling a pulmonary abscess, unilateral exudative effusion, grossly purulent pleural fluid, low pH and glucose, and elevated LDH levels led to an initial misdiagnosis of empyema. Characteristic pleural fluid, along with persistent negative cultures and absence of sepsis pointed towards RA-related pleural disease. VATS and biopsy were instrumental in establishing the final diagnosis through characteristic histopathological findings of RA-associated pleural, parenchymal and airway involvement. Conclusion For RA patients with pleural effusion suggestive of empyema, especially in the context of negative cultures and no signs of sepsis, RA-related pleural disease should be a consideration. Early recognition and timely immunosuppressive therapy escalation can prevent complications such as trapped lungs and reduce the necessity for extensive surgical interventions. Figure1:

Abstract Amiodarone is a commonly used class III antiarrhythmic medication with a rare but well-known adverse effect of pulmonary toxicity. This case illustrates the importance of knowing the risk factors for the development of amiodarone-related lung toxicity, particularly in patients with pre-existing lung disease. Additionally, intensivists must remain mindful of non-infectious causes of ARDS, including acute medication-related lung toxicity. A 73-year-old man was admitted to the Medical Intensive Care Unit (MICU) for worsening hypoxic respiratory failure and progressive pulmonary infiltrates. He has a past medical history of vocal cord malignancy, lung cancer s/p left upper lobe lobectomy and had a left mainstem bronchus stent placed a month prior to presentation. Three weeks before coming to our ICU, the patient was being treated in the outpatient setting for pneumonia post stent placement and was started on rate controlling agents for newly diagnosed atrial fibrillation with rapid ventricular rate. He was ultimately loaded with amiodarone and switched to maintenance for rhythm control. During his stay in the MICU, he underwent a bronchoscopy with bronchoalveolar lavage (BAL), ECHO and repeat CT chest imaging to further investigate his hypoxemia. He was empirically being treated with vancomycin and meropenem. His chest CT compared to one month prior had developed diffuse ground glass opacities and his BAL was limited and unrevealing. He ultimately had progression of disease and was transitioned to comfort care. Amiodarone lung toxicity is a diagnosis of exclusion and presents as interstitial lung disease. A lung biopsy with histopathology is the gold standard for diagnosis and would show foamy laden macrophages. BAL findings include elevated cellular count with 50% of the cases showing eosinophilia. Amiodarone can have an acute, subacute and chronic presentation, with acute being the more aggressive subtype. A double-blind controlled study concluded that the incidence of severe lung fibrosis was 1.2% in doses ranging from 300-800mg compared to < 200mg daily [1] Another retrospective study in Japan found that there is an association with higher incidence of amiodarone induced lung toxicity in age greater than 60. [2] This case highlights a patient presenting with worsening hypoxic respiratory failure, and CT changes, shortly after receiving a second loading dose of amiodarone for atrial fibrillation. He continued to decompensate despite being on appropriate antibiotics and lack of improvement with diuretics. His chest CT was revealing new bilateral ground glass opacities with restrictive physiology on ventilator mechanics, and other causes were ruled out.

Abstract IntroductionPatients with interstitial lung disease (ILD) who are admitted to the intensive care unit (ICU) face significant challenges, with high rates of morbidity and mortality. Despite the severity of outcomes in this population, the potential impact of gender disparities on ICU outcomes in ILD has not been well studied.MethodsWe analyzed data from the NIS spanning 2016 to 2018, focusing on adults (≥18 years) hospitalized with ILD (J84), and defined ICU stays using ICD codes for central line placement and mechanical ventilation. The NIS, part of the Healthcare Cost and Utilization Project, provides a weighted, nationally representative sample of U.S. hospitalizations. Demographic, clinical, and hospital characteristics were collected, with race/ethnicity categorized per NIS classifications. Multivariable logistic and linear regression models adjusted for potential confounders to evaluate gender differences in outcomes.ResultsOur study identified 810,295 adult hospitalizations with ILD, of which 42,080 required ICU-level care. Of these, 46.7% were female. Female ICU patients were younger (mean age 66.9 ± 13.8 vs. 69.1 ± 12.7, p<0.001), more likely to be African American (17.0% vs. 10.9%, p<0.001), and less likely to be Caucasian (63.7% vs. 69.2%, p<0.001). Females were more often from lower-income ZIP codes (33.2% vs. 38.3%, p<0.001) and had lower rates of tobacco use disorder (35.0% vs. 43.9%, p<0.001). Mortality was significantly lower in females (40.5% vs. 48.1%, p<0.001). After adjusting for confounders, female gender was independently associated with reduced mortality risk (adjusted odds ratio 0.77, 95% CI 0.70-0.84, p<0.001) and a shorter length of hospital stay (adjusted difference 1.15 days, 95% CI 0.54-1.77).ConclusionOur study highlights notable gender differences in outcomes for patients with ILD admitted to the ICU. Female patients had a significantly lower risk of mortality and shorter hospital stays than male patients, even after adjusting for key clinical and socioeconomic confounders. These findings are consistent with emerging evidence that biological sex and gender-related factors play a critical role in disease expression and outcomes in ILD.Several mechanisms may explain these gender disparities. Sex hormones, such as estrogen, have been shown to exert protective effects in pulmonary fibrosis models, potentially influencing the disease course in women. Incorporating these considerations into clinical practice and future research will be vital for advancing individualized, patient-centered medicine in ILD.

Abstract Introduction: Endobronchial optical coherence tomography (EB-OCT) imaging has unique potential to diagnose and quantify early, microscopic disease changes and assess therapeutic responsivity in interstitial lung disease (ILD). However, training and time requirements for interpretation and quantitative evaluation of large volumetric EB-OCT datasets need to be optimized to facilitate clinical adoption. We develop and validate a computationally-efficient, rapid EB-OCT quantitative image analysis framework using artificial intelligence (AI) with deep learning architecture for 2D feature segmentation, 3D feature burden and spatial distribution mapping, and computer-aided diagnosis in early ILD subjects. Methods: Volumetric EB-OCT datasets, consisting of 2D cross-sectional images, were acquired from multiple locations in the bilateral lungs of ILD and healthy control subjects. EB-OCT features were manually segmented from cross-sectional images by an expert EB-OCT reader, including fibrosis, microscopic honeycombing, traction bronchiolectasis, normal parenchyma, and emphysema. EB-OCT images with corresponding feature segmentations were used to train and validate a multiclass convolutional neural network. The 2D AI-based segmentation model was subsequently evaluated against manual ‘ground truth’ segmentations for each feature in a de novo ‘test’ dataset of independent subjects using dice similarity score, precision, recall/sensitivity, specificity, and balanced accuracy. To generate 3D AI-based quantitative feature burden and spatial distribution maps, AI-based feature segmentation was performed on each EB-OCT 2D cross-sectional image within a volumetric imaging site. Three external pathologist readers independently interpreted 3D AI-based features maps for each EB-OCT imaging site acquired for a subject (without access to EB-OCT images) and provided a single diagnosis of usual interstitial pneumonia (UIP) or non-UIP ILD. Performance of computer-aided ILD diagnosis was compared against independently evaluated histopathology, clinical diagnosis, and prior EB-OCT image interpretation. Results: EB-OCT was acquired in 51 subjects: 30 in vivo early ILD, 5 in vivo non-ILD controls, and 16 ex vivo end-stage ILD. Overall pixel similarity between 2D manual and AI-based segmentation demonstrated high accuracy for each ILD feature (mean balanced accuracy 0.9). 3D quantitative AI-based feature maps demonstrated strong agreement (Spearman ρ0.87, p<0.001) between manual and AI-based segmentation. AI-based computer-aided diagnosis demonstrated 100% sensitivity/specificity for histologic UIP and clinical IPF for all pathologist readers, with improved diagnostic accuracy and significantly reduced training (45-minute training, 75% reduction) and interpretation time (<1 minute per subject for computer-aided diagnosis, 88% reduction) compared to EB-OCT image interpretation. Conclusion: The AI-based EB-OCT image analysis framework could expedite computer-aided diagnosis of early ILD and robust, quantitative assessment of microscopic disease burden, progression, and therapeutic responsivity.

Abstract RATIONALE: Pulmonary fibrosis is recognized as the end result of multiple and recurrent pathways of lung injury. However, the role of chronic inflammation in non-idiopathic pulmonary fibrosis fibrotic interstitial lung disease (non-IPF f-ILD) remains inconclusive, as acute responses to anti-inflammatory treatment may vary. A reliable predictor for identifying patients who stand to benefit from treatment may be helpful for improving or sustaining lung function and avoiding adverse treatment effects. Our study aims to assess whether initial serum inflammatory markers, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), in the absence of clinically suspected infection or other causes of inflammation, are predictive of therapeutic response to anti-inflammatory medications in non-IPF f-ILD. METHODS: We performed a retrospective study comparing treatment response to anti-inflammatory therapy in non-IPF f-ILD stratified by initial CRP or ESR levels. Treatment was defined as corticosteroid or steroid-sparing agent for three months or more with lung function response defined as: 1) relative increase in percent predicted forced vital capacity (FVC%) > 5% in 6 months or > 10% or greater in 12 months; or 2) no change or any increase in FVC% if FVC% was declining prior to treatment initiation (relative decline in FVC% > 5% in the prior 6 months or > 10% in the prior 12 months). Logistic regression was used to predict treatment response as stratified by high vs low-to-normal inflammatory markers, with a mixed model for repeated measures for comparing FVC% change while treated. RESULTS: One hundred sixty-seven non-IPF f-ILD pts received anti-inflammatory therapy with baseline inflammatory markers stratified by high (N = 104) vs low-to-normal (N = 63) prior to treatment. Median age was 64 years with systemic rheumatic disease diagnosed in 58%. Treatment response was higher in patients with elevated inflammatory markers (55.77% vs. 34.92%, P = 0.011), even after adjustment for age, sex, baseline FVC%, and treatment duration (OR 2.45 [1.243-4.828], P = 0.010). FVC% slope from treatment initiation to discontinuation appeared to be increasing in patients with higher baseline inflammatory markers compared to those with low to normal marker levels (P = 0.003) (Figure1). CONCLUSION: Patients with non-IPF f-ILD and high initial inflammatory markers appear to be more acutely responsive to anti-inflammatory therapy with slower FVC decline or improvement over time while on treatment. These findings suggest baseline serum CRP and ESR may be reliable predictors of treatment response and direct treatment duration and intensity for efficacy or reducing adverse effects.