Citations

Abstract Introduction Pulmonary Kaposi Sarcoma (KS) is a rare manifestation of human immunodeficiency virus (HIV) infection, predominantly seen in immunocompromised patients and infrequently in the era of antiretroviral therapy (ART). KS is a mesenchymal neoplasm arising from blood and lymphatic vessel endothelial cells, primarily affecting homosexual or bisexual men with HIV. Diagnosis typically relies on a combination of clinical evaluation, radiographic imaging, and histopathological confirmation via biopsy. This case underscores the importance of considering pulmonary KS in the differential diagnosis of acute respiratory failure in patients with advanced HIV, even with ART. Case presentation A 44-year-old male with newly diagnosed HIV/AIDS was admitted to the ICU for acute hypoxic respiratory distress. He had initially presented months prior with skin rashes, an HIV viral load of 1040, and a CD4 count of 148, at which time antiretroviral therapy (Biktarvy) was initiated. A chest CT scan revealed diffuse bronchial wall thickening, ground-glass opacities, interlobular septal thickening in a perihilar and upper lung predominant distribution, and bilateral pleural effusions. Pleural fluid analysis confirmed an exudative profile, with worsening hemorrhagic effusions suggestive of visceral Kaposi sarcoma. Bronchoscopy indicated submucosal changes, especially in the left upper lobe and proximal main stems. Skin biopsy, fine-needle aspiration of an axillary lymph node, and a left upper lobe lung biopsy confirmed Kaposi sarcoma. The biopsy showed elevated EBV-positive cells, HHV8-positive sarcoma cells, CMV-negative status, and mixed T and B cells (CD3 and CD20). Lung immunohistochemistry indicated neoplastic cells positive for FLI1, CD31, and patchy HHV8 staining, but negative for AE1/AE3. With a diagnosis of Kaposi sarcoma involving pleuropulmonary, cutaneous, visceral, and lymph node regions, the patient was started on systemic chemotherapy with doxorubicin. Unfortunately, KS had spread signficantly and patient was made comfort care as he was having respiratory failure despite on mechanical ventilator. Discussion Before the advent of antiretroviral therapy (ART), Kaposi's sarcoma carried a poor prognosis, with pulmonary KS survival averaging 2-10 months. ART alone is generally sufficient for asymptomatic patients, often leading to lesion regression and forming the foundation of HIV-associated KS management. For symptomatic or progressive cases, systemic chemotherapy—typically pegylated liposomal doxorubicin—is recommended, as anthracyclines offer effective, lower-toxicity treatment. Paclitaxel may be used in patients unresponsive to anthracyclines. Although less common for KS, localized radiation therapy can provide symptomatic relief in cases of airway obstruction, hemoptysis, or pleuritic chest pain.

Abstract Background. Sarcopenia (i.e. skeletal muscle loss) and physical frailty are significant contributors to adverse clinical outcomes in lung cancer patients. Nutritional intake and physical activity influence skeletal muscle mass and strength. We determined the impact of lung cancer on clinical outcomes in hospitalized patients with sarcopenia, frailty, or sarcopenia+frailty. Design. The Nationwide Inpatient Sample (NIS) (years 2018-2020) from the United States was analyzed to study adult hospitalized patients with a diagnosis of lung cancer. Sarcopenia and frailty were defined by ICD10 codes that have been previously validated. Multivariate regression models were generated to determine the clinical impact of sarcopenia, frailty, or sarcopenia+frailty in patients with a diagnosis of lung cancer as compared to a general medical population (GMP) without lung cancer. Age was restricted to >40 years old for both cohorts because lung cancer is rare in those less than 40 years old. Models were adjusted for age, race, sex, and comorbidities (cardiovascular disease, anemia, coagulopathy, HIV, depression, diabetes mellitus, and COPD). Results. Compared to the GMP (n=126,099), patients with lung cancer (n=241,913) were older (mean+SD age: 69.6+10.0 vs. 67.6+13.3 years, p<0.001), and had a higher prevalence of sarcopenia (22.5% vs 9.0%, p<0.001), frailty (53.4% versus 49.8%, p<0.001), and sarcopenia+frailty (15.3% versus 6.8%, p<0.001). COPD was common and found in 52.3% of lung cancer patients and 20.2% of the GMP. In lung cancer patients, the most common medical reasons for admission were sepsis, pneumonia, and COPD exacerbation. In GMP patients, the most common medical reasons for admission were sepsis, congestive heart failure, and acute kidney injury. In lung cancer patients, frailty had the greatest association with mortality (unadj OR 3.12, 95% CI: 3.02-3.23; adj OR 3.04, 95% CI: 2.91-3.17). Sarcopenia+frailty was most associated with greater healthcare utilization including greater healthcare cost (unadj OR 1.31, 95% CI: 1.29-1.32; adj OR 1.28, 95% CI: 1.26-1.30) and length of stay (unadj OR 1.57, 95% CI: 1.55-1.58; adj OR 1.50, 95% CI: 1.48-1.52). Sarcopenia+frailty were more likely to require additional healthcare facilities upon discharge and were the least likely to be discharged to home (unadj OR 0.32, 95% CI: 0.32-0.33; adj OR 0.35, 95% CI: 0.33-0.36). (see Table 1). Conclusion. While frailty was most associated with in-hospital mortality in lung cancer patients, sarcopenia+frailty was most associated with greater healthcare utilization. Our findings highlight the need to develop targeted interventions to improve clinical outcomes in lung cancer patients with sarcopenia and/or frailty.

Abstract RATIONALE: Mesenchymal progenitor cells (MPCs) in the lungs of individuals with Idiopathic Pulmonary Fibrosis (IPF) show intrinsic fibrogenic properties, possessing a distinct transcriptomic profile and maintaining fibrogenic activity, which contributes to the fibroblast population in IPF. We hypothesize that IPF MPCs are distinguished from control MPCs by a unique gene interaction network. METHODS: We analyzed bulk RNA-seq data, available on the Gene Expression Omnibus (GEO) under accession numbers GSE97038 and GSE276568. In these experiments, CD44hi MPCs were isolated through flow cytometry from mesenchymal cell lines derived from IPF patients (explanted lungs from live IPF patients after lung transplant) and control subjects (lobectomy for clinical reasons) using antibodies against CD44 and SSEA4. The pooled dataset comprises nine IPF and nine control MPC lines. We identified differentially expressed genes (DEGs) in IPF MPCs compared to controls using DESeq and performed pathway enrichment analysis on DEGs using Gene Ontology (GO). We also conducted Gene Set Enrichment Analysis (GSEA) with gene sets related to stemness, pluripotency, and self-renewal. Weighted gene co-expression network analysis (WGCNA) identified functional modules specifically associated with IPF MPCs. RESULTS: Applying an adjusted p-value threshold of 0.05, we identified 134 DEGs in IPF MPCs compared to controls. GO analysis showed significant enrichment in pathways associated with leukocyte migration, extracellular matrix organization, and cell differentiation and growth. GSEA highlighted significant enrichment in two gene sets related to stemness, with adjusted p-values of 0.002 and 0.048. Using WGCNA, we identified 16 functional modules, one of which reached significance based on an adjusted p-value threshold of 0.05 and a correlation coefficient cutoff of 0.45. This significant module demonstrated a positive correlation with IPF status (correlation coefficient of 0.69, adjusted p-value 0.0085). CONCLUSION: This study is the first to characterize a distinct gene expression profile in IPF MPCs compared to controls, highlighting enriched biological processes relevant to IPF pathogenesis. GSEA results further support the hypothesis that IPF MPCs display stem cell-like gene expression patterns, including genes associated with pluripotency and self-renewal. Additionally, we identified functional gene modules that significantly correlate with the fibrogenic properties of IPF MPCs, including hub genes that may play critical roles in promoting fibrosis in IPF. These findings deepen our understanding of IPF MPC biology and identify potential targets for future research. We plan to expand this approach by increasing the sample size to enhance statistical power, aiming to identify more robust functional modules and their highly connected hub genes.

Abstract RATIONALE: Vascular dysfunction contributes to pathological tissue remodeling in aging-associated disease such as Idiopathic Pulmonary Fibrosis (IPF). IPF is an incurable lung disease characterized by progressive accumulation of scar-forming fibroblasts and several vascular alterations, including endothelial transcriptional changes leading to a pro-fibrotic endothelial secretory phenotype. To date, the mechanisms governing these transcriptional changes remain largely unexplored. To fill this gap, we sought to investigate whether microRNAs (miRNAs), small non-coding RNA that function as key gene expression regulators, modulate the transcriptional changes of the endothelium associated with progressive pulmonary fibrosis. METHODS AND RESULTS: miRNA expression profiling of lung ECs (LECs) sorted from aged mice with persistent lung fibrosis revealed upregulation of miR-205-5p. Further analysis demonstrated that endothelial miR-205-5p was strongly upregulated in an additional mouse model of progressive lung fibrosis induced by repetitive bleomycin dose as well as in human LECs purified from IPF lungs. RNA-seq analysis of normal human LECs overexpressing miR-205-5p revealed reduction of genes associated to endothelial identity (e.g. PECAM1, ERG, NOS3), and an increase of genes encoding for soluble pro-inflammatory and pro-fibrotic molecules, including TGFBI, TGFB2, TGFB3, CXCL10, CCL5, IL1B and FAS compared to normal LECs transfected with a control mimic. Consistently, conditioned medium from miR-205-5p overxpressing LECs exerted a pro-fibrotic activity on quiescent human lung fibroblasts, as demonstrated by upregulation of a panel of profibrotic transcripts (e.g. COL1A1, CTHRC1, FN1 and TNC) and elevated Collagen I deposition compared to human lung fibroblasts exposed to conditioned medium generated by human LECs transfected with a control mimic. CONCLUSION: Altogether, our findings suggest that lung endothelail miR-205-5p induces loss of endothelial cell identity and drives the secretion of pro-fibrotic molecules that promote the transition of quiescent fibroblasts into scar-forming fibroblast through paracrine signal. Our data set the stage for further investigations into the role of miR-205-5p and associated pathways in lung vascular injury responses, with the long term goal of targeting endothelial dysfunction for slowing the progression of pulmonary fibrosis.

Abstract Lung transplant recipients are at high risk for pleural complications following transplantation. Pleural effusions are nearly universal immediately after transplant, but most resolve spontaneously in the following weeks. For persistent effusions, there is no consensus on the optimal management strategy, and risks of potential procedures must be balanced with long-term complications. A 58-year-old male presented with 3 months of severe fatigue, brain fog, chills without fever, poor appetite, and weight loss. His medical history included bilateral redo lung transplant 7 months prior for chronic lung allograft dysfunction, type II diabetes mellitus, chronic kidney disease stage IIIb, and heart failure with preserved ejection fraction. His immunosuppression regimen included tacrolimus, prednisone, and mycophenolate, with prophylaxis of trimethoprim/sulfamethoxazole and posaconazole. At the follow up visit, spirometry revealed a significant decline in lung function (FVC 2.31 to 1.97; FEV1 1.84 to 1.51). He was admitted for urgent evaluation. A CT scan revealed a large (20 cm) multiseptated left-sided empyema or hematoma causing mass effect on the spleen and distal pancreas. A 12 French locking loop pigtail catheter was placed into the left pleural space, and fluid analysis showed a total nucleated cell count of 23,306/mcL (100% neutrophils), LDH >9000 U/L, total protein of 1.3 g/dL, glucose <2 mg/dL, and pH <6.80, consistent with empyema. Fungal cultures identified Scedosporium species. The patient received six doses of intrapleural lytics, yielding 3.3 liters of serosanguinous drainage. However, repeat CT showed residual thick fibrinous peel surrounding the pleura. Video-assisted thoracoscopic decortication revealed extensive pleural infection with minimal healthy mucosa, allowing only limited decortication due to bleeding risk. He then underwent open-window thoracostomy (Clagett window) for ongoing drainage, followed by three additional debridement procedures and antifungal therapy with liposomal amphotericin B and voriconazole. This case illustrates the insidious onset of empyema in immunocompromised hosts, such as lung transplant patients, and highlights the rare need for open-window thoracostomy in severe pleural infections.

Abstract RATIONALE: Understanding co-isolation patterns between fungi and other potentially pathogenic microorganisms in the airways of bronchiectasis patients is important for uncovering possible microbial interactions and informing treatment. Although numerous organisms have been identified in respiratory cultures, the specific patterns of their co-isolation are underexplored. OBJECTIVES: To examine the patterns of co-isolation between fungi and bacteria or mycobacteria in respiratory samples from patients with bronchiectasis across a large national health system. METHODS: We reviewed 58,170 respiratory culture tests from 8,194 patients with bronchiectasis (identified using ICD-10-CM codes J47.0, J47.1, and J47.9) across Mayo Clinic. These tests were analyzed for fungal, bacterial, and mycobacterial growth, focusing on co-isolation from the same sample. Chi-square statistics were used to compute p-values. RESULTS: Of all 18,983 samples cultured for fungi, 59% were positive. Of these, 72% yielded yeasts and 40% molds. Among the 11,372 samples cultured for both fungi and bacteria, 681 (6%) showed co-isolation, representing 54% of positive bacterial cultures. The odds of bacterial co-isolation with fungi were 1.4 (95% CI: 1.3-1.6; p < 0.01), driven by yeasts (OR: 1.5, 95% CI: 1.3-1.7; p < 0.01), rather than molds (OR: 1.0, 95% CI: 0.9-1.2; p = 0.8). Pseudomonas species, the most common bacterial isolate, had a higher likelihood of co-isolation with fungi (OR: 1.6, 95% CI: 1.3-1.9; p < 0.01), particularly yeasts (OR: 1.6, 95% CI: 1.4-2.0; p < 0.01). Molds, including those from genera such as aspergillus and penicillium, did not show a significant association with the isolation of pseudomonas. On the other hand, among the 15,859 samples cultured for both fungi and mycobacteria, 1352 (9%) showed co-isolation, representing 62% of positive mycobacterial cultures. Odds of co-isolation were 1.7 (95% CI: 1.5-1.8; p < 0.01). Molds showed a stronger association with isolation of mycobacteria (OR: 1.7, 95% CI: 1.5-1.9; p < 0.01) compared to bacteria, while yeasts also had elevated odds (OR: 1.4, 95% CI: 1.2-1.5). CONCLUSIONS: Distinct patterns of fungal co-isolation with bacteria and mycobacteria have been observed in bronchiectasis, which may influence key aspects of the disease, such as inflammation and mucociliary dysfunction. Advanced metagenomic and immunoprofiling techniques could provide deeper insights into these co-isolation patterns while considering other factors like clinical demographics, previous antibiotic exposure, and disease severity. Understanding whether altering the mycobiome could modify these aspects and improve outcomes remains an important avenue for research.

Abstract Rationale Pulmonary artery pulsatility index (PAPi) is defined as pulmonary artery pulse pressure divided by right atrial pressure and has been identified as a predictor of mortality in pulmonary hypertension. Portopulmonary-hypertension (POPH), a subset associated with portal hypertension, lacks a clear prognostic association with PAPi. This study aimed to assess whether perioperative PAPi values correlate with outcomes in liver transplant patients with POPH. Methods This single-center, retrospective study included POPH patients undergoing liver transplantation at Mayo Clinic Florida from June 2003 to December 2023. 69 patients were categorized based on the lower PAPi quartile in our dataset (>0.9 or ≤ 0.9), measured via catheterization within one day of transplantation, comparing baseline characteristics and outcomes. Categorical variables were analyzed using chi-square or Fisher's exact tests, while continuous variables were compared with independent t-tests or Mann-Whitney U tests. Unadjusted and adjusted odds ratios (ORs) for 1-year mortality were calculated using logistic regression for baseline comorbidities and univariate significance. Results Most patients were white (91.3%) and non-Hispanic (82.6%), with a mean BMI of 29.3 kg/m² and MELD score of 20.3. Mean hemodynamic data included heart rate of 75.8 bpm, pulmonary artery pressure of 29.9 mmHg, right atrial pressure of 15.1 mmHg, and PAPi of 1.25. Mortality rates were 7.2% at 30 days, 10.1% at 90 days, and 11.6% at 1 year. Patients with PAPi >0.9 (n=50) were older (mean age 58.2 vs. 52.9) than those with PAPi ≤0.9 (n=19). The PAPi >0.9 group was predominantly white (94% vs. 84.2%, p=0.04), with no significant differences in BMI, MELD scores, or ethnicity. Mortality at 30 and 90 days was higher in the PAPi >0.9 group (10% and 14%, respectively) compared to the PAPi ≤0.9 group (0% for both); however, differences were not statistically significant. At 1 year, mortality was 14% in the PAPi >0.9 group and 5.3% in the PAPi ≤0.9 group, with no statistical significance. Multivariate analysis indicated no association between PAPi and 1-year mortality (OR 0.12-0.24, p=0.2-0.3), and PAPi as a continuous variable showed no link with 1-year mortality. Conclusions PAPi was not significantly associated with 1-year mortality in liver transplant patients with POPH, suggesting that it should not be used alone to decide listing for transplantation. Further studies with larger cohorts are needed to confirm these findings or identify alternative hemodynamic markers or PAPi values predictive of long-term outcomes in this high-risk group.

Abstract Rationale: Heart failure (HF) is often characterized by elevated left ventricular filling pressures (LVFP) and pulmonary congestion. However, LVFP may not always predict congestion. Pulmonary congestion can be quantified by computed tomography (CT) imaging. We hypothesized that extravascular lung water quantified by CT may differ in HF groups such as HF with preserved ejection fraction (HFpEF) vs HF with reduced ejection fraction (HFrEF), inpatients with acute decompensated heart failure (ADHF) vs stable and this would be related to echocardiography (echo) derived estimates of LVFP. Methods: We enrolled and studied 83 patients with HF who were either admitted or had a clinic visit at Mayo Clinic, Rochester, MN from May 2018 through March 2019. All subjects underwent comprehensive echo and supine thoracic CT scans. CT lung fluid was quantified and reported as proportion (%) of total lung volume. CT attenuation in lung tissue was also measured. LVFP was evaluated according to standardized echo diagnostic algorithms. Patients were stratified based on clinical diagnosis of HF as inpatients with HFpEF (n=26, 75.6±8.5yrs, M=50%, BMI=36.2±8.9kg/m2) inpatients with HFrEF (n=33, 75.6±14yrs, M=79%, BMI=31.1±9.1kg/m2), inpatients with ADHF (n=14, 72.6±14.5yrs, m=64.2%, BMI= 32.2±7.6Kg/m2) and stable outpatient HF controls (n=10, 65±13 yrs, m=90%, BMI= 29.5±5.2Kg/m2). All four groups were compared using one-way ANOVA followed by a post-hoc analysis. A correlation between lung fluid % and LVFP was performed using Spearman's correlation test. Results: When HF groups were compared according to CT % lung fluid, significant differences were found between HF groups (p=0.004). Post-hoc analysis revealed a significant difference in % lung fluid as HFrEF group had higher mean value in % lung fluid compared to HF control group (p=0.004). Similarly, ADHF group had higher mean % lung fluid compared to HF control group (p= 0.007). However, we found no correlation between LVFP and % lung fluid. The rightward shift in CT attenuation for HFpEF, HFrEF, and ADHF subjects, as displayed in figure 1, suggests greater levels of % lung water in these subjects compared to controls. Conclusion: These data suggest that CT measures of lung water differ in subgroups of HF patients and may not correlate with LVFP.

Abstract RATIONALE: Significant sex differences exist in the prevalence and severity of asthma across the lifespan. Asthma is more prevalent and severe in pubescent boys compared to girls but worse in girls and women after puberty. The transition to menopause brings significant reductions in estrogen and progesterone levels. In this study, we test the hypothesis that the effect of menopause on asthma prevalence and outcomes is modified by the use of female sex hormones. METHODS: We used data from nine two-year cycles (1999-2000 to 2015-2016) from NHANES to determine the association between menopause and asthma outcomes. We defined severe asthma based on GINA treatment classes 4&5. We used analytic sample weights to compute national estimates according to NHANES guidelines. Adult (age >18 years) women were considered to be menopaused if (1) they reported to be menopaused during the NHANES survey, (2) they had bilateral oophorectomy, or (3) they were ≥52 years. Weighted logistic regression analyses were used to adjust for age, race, body mass index (BMI), smoking, blood eosinophil count, female hormone therapy, and oral contraceptives. Analyses were performed using the SURVEY package in R. RESULTS: The cohorts’ clinical characteristics are listed in table 1. Compared to pre-menopause (weighted n=60,394,897), menopause (weighted n=52,364,594) was associated with higher rates of active asthma (9.2 vs. 8.9%, p=0.004) and severe asthma (5% vs. 1.8%, p<0.001), but not lifetime asthma (15.1 vs. 16.3%, p=0.063). Notably, postmenopausal women had higher BMIs (weighted median [IQR]: 28.1 [24.2-33.1] vs. 26.1 [22.6-32.1], p<0.001), longer asthma durations (weighted median [IQR]: 20.0 [7.0-41.0] vs. 15.0 [8.0-24.0], p<0.001), and lower lung functions (p<0.001) (table 1). Adjusted analysis did not show significant associations between menopause and lifetime asthma (adjusted OR, 1.074; 95% CI, 0.901-1.280), active asthma (adjusted OR, 1.072; 95% CI, 0.865-1.328), or severe asthma (adjusted OR, 1.369; 95% CI, 0.958-1.954). Interestingly, a history of female hormone therapy and oral contraceptives use was associated with a higher risk of lifetime asthma (adjusted OR, 1.191; 95% CI, 1.031-1.375 and adjusted OR, 1.287; 95% CI, 1.169-1.417 respectively). Among women with active asthma, menopause was not associated with non-severe exacerbations (adjusted OR, 1.335; 95% CI, 0.883-2.021) or with severe exacerbations requiring ER visits (adjusted OR, 1.416; 95% CI, 0.818-2.451). Conclusion: The increased prevalence of active asthma and severe asthma among menopausal women can largely be attributed to age-related changes, comorbidities, and hormone therapy use rather than menopause alone.

Abstract RATIONALE: Women are more likely to develop asthma after puberty, and their symptoms can fluctuate during the menstrual cycle, pregnancy, and menopause. Menopausal women with asthma face unique challenges, as hormonal fluctuations during this stage can impact respiratory health. About one-third of women undergo hysterectomy before age 60, with most procedures occurring before natural menopause. While half of these surgeries preserve the ovaries, the other half include oophorectomy, creating distinct hormonal environments. Despite the traditional view of the uterus as hormonally inactive, there remains a critical gap in our understanding of the potential impact of hysterectomy on respiratory health.METHODS: We used data from nine two-year cycles (1999-2000 to 2015-2016) from NHANES to determine the association between hysterectomy and asthma phenotypes. Severe asthma was defined based on GINA treatment classes 4&5. Analytic sample weights were used according to published NHANES guidelines to create national estimates. Asthma status (lifetime, active, severe) was obtained for women without (weighted n=90,348,593) or with a history of hysterectomy (weighted n=22,310,898). Weighted logistic regression analyses were used to determine the impact of hysterectomy on asthma prevalence, severity, exacerbations, and asthma-related emergency room (ER) visits adjusting for age, race, body mass index (BMI), smoking history, blood eosinophil count, a history of unilateral or bilateral oophorectomy, female hormone therapy, and oral contraceptive use. Analyses were performed using the SURVEY package in R.RESULTS: Clinical characteristics of women with and without a history of hysterectomy are listed in Table 1. Overall, hysterectomy was associated with higher asthma prevalence (18.1 vs. 15.1%) and severity (5.1 vs. 2.9%). For all women, hysterectomy was associated with a higher risk for lifetime asthma (adjusted OR, 1.262; 95% CI, 1.1079-1.477) but not for active asthma (adjusted OR, 1.146; 95% CI, 0.93-1.412) or severe asthma (adjusted OR, 0.996; 95% CI, 0.748-1.325). Interestingly, oophorectomy was associated with a higher risk for lifetime asthma (adjusted OR, 1.228; 95% CI, 1.102-1.368 for unilateral; adjusted OR, 1.232; 95% CI, 1.232-1.513 for bilateral) and active asthma (adjusted OR, 1.417; 95% CI, 1.232-1.629 for unilateral; adjusted OR, 1.507; 95% CI, 1.143-1.986 for bilateral). Among women with active asthma, hysterectomy was associated with severe exacerbations requiring ER visits (adjusted OR, 1.845; 95% CI, 1.157-2.941) but not with non-severe exacerbations (adjusted OR, 1.176; 95% CI, 0.811-1.705).CONCLUSIONS: This study highlights the influence of hysterectomy on asthma risk and severity and emphasizes the role of female hormones in asthma pathogenesis.