Citations

Abstract Introduction: Obesity's increasing prevalence significantly impacts Intensive Care Unit (ICU) patient outcomes, especially for those requiring prolonged mechanical ventilation. This study investigates the effect of Body Mass Index (BMI) on mortality and complications—such as acute respiratory distress syndrome (ARDS), pulmonary embolism (PE), and deep vein thrombosis (DVT)—in ICU patients intubated for over 96 hours. Methods: We conducted a retrospective cohort study using the TriNetX database to identify patient populations with relevant ICD codes. Patients who had received anticoagulation and had been on mechanical ventilation for more than 96 hours were included. Cohort 1 consisted of patients with a BMI of 30-44.9 kg/m² (n = 70,379), and Cohort 2 included patients with a BMI of 18.5-29.9 kg/m² (n = 111,054). Both cohorts were matched using propensity score matching (PSM), resulting in balanced groups of 47,233 patients. The mean age was 64.3 ± 15.1 years in Cohort 1 and 64.5 ± 16.5 years in Cohort 2, with a male predominance of 57.9% in both cohorts after matching. Outcomes (mortality, PE, DVT, and ARDS) were identified using ICD-10 codes and analyzed on Days 14, 30, and 90. Results: Higher BMI was associated with increased all-cause mortality across all measured time points. By Day 14, mortality was 23.0% in Cohort 1 versus 19.2% in Cohort 2 (RiskRatio [RR]: 1.196; 95% CI: 1.166-1.226). By Day 90, mortality reached 37.6% in Cohort 1 compared to 32.6% in Cohort 2 (RR: 1.151; 95% CI: 1.132-1.171). Additionally, the risk of developing ARDS was higher in Cohort 1, with statistically significant risk ratios observed on Day 14 (RR: 1.117; 95% CI: 1.020-1.222) and Day 30 (RR: 1.094; 95%CI: 1.010-1.186). PE risk in Cohort 1 significantly increased by Day 30 (RR: 1.119; 95% CI: 1.008-1.243), while DVT risk was also elevated in Cohort 1 at both Day 14 (RR:1.140; 95% CI: 1.037-1.253) and Day 30 (RR: 1.129; 95% CI: 1.040-1.224). Conclusion: Higher BMI in mechanically ventilated ICU patients intubated for more than 96 hours is associated with increased mortality and a higher incidence of complications, including ARDS, PE, and DVT. This study contributes to our understanding of BMI's impact on ICU outcomes, highlighting critical areas for improved clinical management in this population and the need for targeted interventions in obese ICU patients, such as optimized respiratory support and monitoring for thromboemboliccomplications.

Abstract RATIONALE: 4G4G/4G5G SERPINE1 genotypes produce high concentrations of plasminogen activator inhibitor-1 and are associated with worse asthma outcomes. A secondary analysis of the American Lung Association (ALA) SOYA trial showed that soy isoflavones significantly reduced asthma exacerbations versus placebo among patients with 4G4G/4G5G SERPINE1 genotypes. We hypothesized that baseline characteristics predict optimal responders to soy isoflavones among this subgroup. METHODS: ALA-SOYA was a randomized controlled trial that tested the efficacy of soy isoflavones vs. placebo for reducing asthma exacerbations among adolescents and adults with symptomatic asthma. In this responder analysis among participants with 4G4G/4G5G SERPINE1 genotypes, baseline demographic and clinical characteristics were tested for effect modification of the treatment assignment (soy/placebo) on the primary outcome of annualized number of asthma exacerbations using interaction terms in negative binomial regression models, with a significance threshold of p-interaction=0.15. RESULTS: Data were available for n=168 participants. Soy reduced the annualized number of asthma exacerbations relative to placebo among patients with 4G4G/4G5G SERPINE1 genotypes (incident rate ratio (IRR)=0.37, 95% confidence interval (CI): 0.15-0.90, p=0.028). Self-reported adherence to baseline controller therapy was the only significant effect modifier of this association (interaction p=0.115), with those using inhaled corticosteroid (ICS)/long-acting beta-agonist (LABA) controller therapy at least twice weekly experiencing reductions in asthma exacerbations with soy versus placebo (IRR = 0.25, 95% CI: 0.09-0.69; p= 0.007) but not among those using ICS/LABA controller therapy less frequently (IRR = 1.33, 95% CI: 0.22-8.02; p= 0.757). CONCLUSION: Soy isoflavones reduce asthma exacerbations among patients with the 4G4G/4G5G SERPINE1 genotypes and are most effective in those with greater adherence to asthma controller therapy regimens.

Abstract RATIONALE: Albuterol-budesonide 180/160 µg is indicated in the US for as-needed treatment or prevention of bronchoconstriction and to reduce risk of exacerbations in patients ≥18 years old with asthma. The objective of the ALbuterol-budesonide Treatment in Acute airway obstruction (ALTA) study (NCT05555290) is to assess comparative efficacy, safety, and mechanisms of action of albuterol-budesonide 180/160 µg versus albuterol 180 µg in treating and preventing bronchoconstriction. This report describes the clinical profiles of patients meeting criteria for randomization into the trial. METHODS: ALTA is a phase 3b, multicenter, randomized, double-blind, 2-period, cross-over study evaluating the effects of repetitive dosing of albuterol-budesonide 180/160 µg versus albuterol 180 µg for treating adults treated as intermittent asthma and experiencing acute airway obstruction induced by repeated mannitol challenges. Inclusion criteria evaluated during screening include asthma diagnosis ≥6 months, prescribed and utilizing albuterol as the only asthma treatment for ≥4 weeks, pre-bronchodilator FEV1 ≥1.50 L and FEV1 ≥60% to <90% predicted, and positive response to a mannitol challenge (decrease in FEV1≥15% at ≤635 mg cumulative mannitol dose). Exclusion criteria include clinically significant lung disease other than asthma; any smoking in the prior 6 months or ≥10 pack-year smoking history; or a clinical encounter for asthma worsening within the past 4 weeks. RESULTS: Thus far, 84 patients have met the criteria for randomization into ALTA. Mean(SD) age=44.9(13.7) years, 56.0% female, 40.5% African American, 9.5% Hispanic/Latino. Clinical characteristics include 10.7% with 1 prior-year severe exacerbation; mean(SD) fractional exhaled nitric oxide=37.0(37.4) ppb; mean(SD) baseline pre-bronchodilator FEV1=2.464(0.538) L; mean(SD) baseline percent predicted FEV1=76.7(7.9)%; mean(SD) % fall in FEV1 with mannitol challenge=22.1(7.3)% at a mean(SD) cumulative mannitol dose of 146.4(176.3) mg. Despite being treated for intermittent asthma, based upon symptoms, lung function, and exacerbation history, no patients met NAEPP 2007 criteria for intermittent disease, and 13.1% fell into the mild, 78.6% moderate, and 8.3% severe persistent asthma categories (Figure). With respect to asthma control, as measured by Asthma Impairment and Risk Questionnaire scores, 60.7% had well-controlled, 20.2% not well-controlled, and 19.1% very poorly controlled disease. CONCLUSION: The baseline characteristics of patients in the ALTA study reveal that patients treated as intermittent asthma exhibit heterogeneity in clinical characteristics, airway hyper-reactivity, T2 inflammation, and disease severity and control. Additional genomic and biomarker data are forthcoming and altogether will provide an opportunity to address the mechanism of albuterol and budesonide interactions in a broad spectrum of asthma phenotypes.

Abstract RATIONALE: Many ICU patients experience physical, psychological, and cognitive impairments following resolution of critical illness, collectively referred to as post-intensive care syndrome (PICS). PICS has become widely recognized within the critical care field, but how to screen for PICS does not currently have consensus. Development of a validated, concise PICS screening tool would allow for rapid identification of this vulnerable and understudied population. Therefore, this study's goal was to develop and evaluate a screening tool to identify patients at risk for PICS. METHODS: We performed a prospective cohort study in a quaternary academic hospital. We included adults ≥ 18 years old with ≥48 hours spent in an ICU. Exclusion criteria were admission for suicide attempt, severe cognitive impairment/dementia, life expectancy <3 months, and non-English speaking. We assessed mental, cognitive, and physical function following ICU discharge and at 3 months using Hospital Anxiety and Depression Scale, Impact of Event Scale-Revised, Montreal Cognitive Assessment-blind, and Barthel Index. Our team, including critical care physicians, psychiatrists, psychologists, physical and occupational therapists, and nurses, developed a brief 15-item PICS screening tool (5 questions/domain). This tool was administered after patients were discharged from ICU stay to general care to assess its effectiveness in predicting impairments in all 3 domains at discharge and again at three months after hospital discharge, in comparison to previously mentioned validated questionnaires. Youden index statistical methods were used to determine potential “cutoff” values (scores) for the tool to maximize sensitivity and specificity. RESULTS: A total of 194 patients from 6 ICUs were recruited and completed the initial questionnaire, and 109 (56%) patients completed 3-month follow-up. Median age was 65 years (IQR 57-72) and 49% (95/194) were female. Screening tool is depicted in Figure 1. Overall, the screening tool weakly-to-moderately correlated with continuous outcomes of the validated measures upon ICU discharge and 3-month follow-up. When evaluating sensitivity and specificity for individual domains, the tool had an area under the receiver operating curve of >0.7 for the following domains: cognitive, anxiety, and physical impairments, indicating moderate-to-good sensitivity and specificity. CONCLUSIONS: This PICS screening tool was correlated with validated measures of PICS upon ICU discharge and at 3-month follow-up for all three domains. The tool's strength lies in its concise nature, making it easier for those caring for this patient population to screen for long-term effects of an ICU stay. Our proposed next step is validation of the PICS screening tool in an external cohort.

Abstract Rationale: Airway-stenosing disease is a significant clinical problem in multiple populations. While the immediate endoscopic and clinical response to bronchoscopic interventions are high, rates of clinically significant recurrence are elevated, and often require multiple and frequent reinterventions. Newer strategies to prevent recurrence of central and proximal airway stenosis are needed. Methods: Retrospective review of bronchoscopic balloon bronchoplasties performed at the Mayo Clinic utilizing paclitaxel coated balloons (PCB) in 2023-2024 for recurrent airway stenosis. IN.PACT Admiral and AV balloons (sizes 5-12 mm, 3.5 mcg/mm2 paclitaxel dose) were used with an inflation time of 2-3 minutes. Procedural success was defined as <50% airway stenosis or resolution of the procedural indication. Reintervention was considered only if a therapeutic bronchoscopy was subsequently required to address the same lesion treated with PCB. Only patients with follow-ups >90 days were included in the reintervention inter-procedural time analysis. Results: Thirty-three procedures were performed in 18 patients. Seventeen (51%) for lung transplantation-associated stenosis (29% anastomotic/perianastomotic, 76% lobar and segmental stenoses), 8 (24%) for granulomatous polyangiitis-associated stenosis, 3 for postintubation tracheal stenosis and 2 for chemical/pill injury. Eighteen cases (54%) utilized an additional dilation modality (12 non-coated balloon dilation, 4 rigid dilation), 5 spray cryotherapy, 6 other ablative therapies (4 CO2-laser, 2 electrocautery cuts), and 6 received an airway stent during the same procedure. 57% percent of interventions occurred in the lobar, 27% mainstem/bronchus intermedius, 9% tracheal, 7% segmental airways. Thirty-one (93%) cases had a satisfactory initial endoscopic result. The median number of bronchoscopic therapeutic interventions required before the use pf PCB was 5 (IQR 2.5-11.5), which significantly decreased to 0.1 (IQR 0-1, range 0-9) after PCB (p <0.001). The reintervention-free survival significantly increased after PCB dilation from a median 35 days (IQR 28.7-80.5) to 132 days (IQR 64-197; p=0.004). Twenty-one cases required subsequent bronchoscopies, sixteen (76%) of which demonstrated improvement in lesion severity when compared to the results of prior interventions. Only 16 (48%) required therapeutically addressing the same lesion. Only 2 minor complications occurred (6%, self-limited bleeding and unplanned admission), none related to paclitaxel use. Six-month mortality was 3% from an unrelated cause. Conclusions: The locoregional antiproliferative effects of paclitaxel show promise in preventing recurrence, minimizing the need for repeat procedures, and extending intervals between interventions in patients with recurrent, predominantly benign airway stenosis. Its use is feasible, safe, and future research is warranted, particularly comparing PCB with the currently available strategies.

Abstract Background: Lymphangioleiomyomatosis (LAM) is a rare, female-predominant, low-grade neoplasm that can lead to progressive diffuse cystic lung disease. Pregnancy has been associated with accelerated disease progression and increased risk of spontaneous pneumothoraces in women with LAM. Sirolimus is the current first line treatment for LAM and has demonstrated benefit in stabilizing lung function decline and reducing the risk of spontaneous pneumothoraces; however, there is unclear evidence regarding the risk benefit ratio of the use of sirolimus during pregnancy. Methods: We queried physicians across the LAM Clinic Network and obtained information regarding demographics, baseline characteristics, LAM related complications, lung function, sirolimus dosing, and pregnancy outcomes in women with LAM who took sirolimus during pregnancy. Results: We identified 9 women with LAM who had used sirolimus during pregnancy for a total of 12 pregnancies. All women had sporadic LAM with moderate lung function impairment prior to pregnancy: median FEV1 56% predicted, median DLCO 43% predicted, and 2 patients on supplemental oxygen. Sirolimus was used throughout pregnancy in most instances (10/12 (83.3%)). Sirolimus was held prior to pregnancy in 2 patients; both these patients experienced a spontaneous pneumothorax in the first trimester and resumed sirolimus in the second trimester with no further pneumothoraces during the rest of the pregnancy. The median sirolimus dose during pregnancy was 1 (range 1-2) mg daily with a median trough level of 2.95 (range: 1 – 6.7) ng/ml. Ten pregnancies (83.3%) resulted in live births, 1 pregnancy was terminated due to molar pregnancy, and 1 pregnancy resulted in miscarriage. Spirometry and DLCO were available in 8 pregnancies and tended to be stable (Figure 1). None of the 10 pregnancies that resulted in live births reported any fetal health issues. Seven out of these 10 children (70%) were breastfed with continued sirolimus use. At the time of submission of this report, the median age of these children is 3.5 years (range: 1 – 6.5 years) with no reported adverse health outcomes from sirolimus exposure during pregnancy. Conclusions: The use of sirolimus during pregnancy in women with LAM appears to be safe for both mother and fetus and might help reduce the pregnancy associated risks of accelerated lung function decline and spontaneous pneumothoraces.

Abstract RATIONALE: Allogeneic hematopoietic stem cell transplant (alloHSCT) is the only curative therapy for multiple hematological malignancies and bone marrow failure syndromes. Graft versus host disease (GvHD), remains one of the leading causes of morbidity and mortality. Bronchiolitis obliterans syndrome (BOS) is the canonical manifestation of chronic GvHD of the lungs, occurring in 3-10% of alloHSCT recipients and conferring poor prognosis. There has been a recent paradigm shift towards using post-transplant cyclophosphamide (PTCy) for GvHD prophylaxis resulting in dramatic decreases in both acute and chronic GvHD compared to traditional regimens using methotrexate and tacrolimus. The effect of PTCy on the development of BOS is not well-studied. METHODS: We performed a retrospective cohort study comparing the cumulative incidence of BOS between 93 patients receiving PTCy and 154 patients receiving non-PTCy containing regimens for GvHD prophylaxis between 2015 and 2023 at a single center (Mayo Clinic, Rochester, MN). Patients were included if they were ever diagnosed with BOS or if they survived and were followed for at least 1 year. BOS was diagnosed using 2014 National Institutes of Health criteria. Patients who met 3 of 4 diagnostic criteria were included if a clinical diagnosis of BOS was made. We performed a competing risks time-to-event analysis to compare the incidence of BOS (or death) between the two cohorts. Outcomes were not adjusted for HSCT type (related, unrelated, or haploidentical [HID]) due to a high degree of collinearity with GvHD prophylaxis strategy. RESULTS: Combined cohorts were median age 55 (40-63), 56% male, and 43% ever smokers. Transplants involved HID donors (59% of PTCy cohort, zero non-PTCy), matched related (10% of PTCy, 44% of non-PTCy), matched unrelated (20% of PTCy, 51% of non-PTCy), and mismatched unrelated donors (11% of PTCy, 5% of non-PTCy). Three-year cumulative incidences of BOS among PTCy and non-PTCy recipients were 7% and 14%, respectively (subdistribution HR 0.52 [95% CI 0.21-1.29], P=0.159). For those who received PTCy, incidence of GvHD was smaller (subdistribution HR 0.64 [95% CI 0.46-0.99], P=0.006) with fewer organs involved (1 versus 2, P=<0.0001) and fewer immunosuppressive therapies employed for treatment (2.0 versus 2.5, P=0.01). CONCLUSION: PTCy may reduce risk of BOS among patients undergoing HSCT. Findings are limited by important differences between the cohorts, such as HCT type, and by small sample size. As PTCy is now increasingly used for non-HID transplants, future studies are needed to examine the effect of PTCy on the development of BOS.

Abstract Introduction: The data on outcomes comparing lung transplantation with ABO-identical versus ABO-compatible blood group is limited. Composite Allocation Score(CAS) was introduced on March 9th, 2023, and has considered additional points for the difficult-to-match blood group. We aimed to study the trend and outcomes of patients who underwent lung transplants with ABO identical versus compatible blood groups. Methods: We queried the United Network of Organ Sharing (UNOS) database of those who underwent lung transplantation between 10/1/1987 to 3/31/2024 and compared the outcomes between those who had ABO-identical vs ABO-compatible blood groups. Combined organ transplants and recipients age <18 were excluded. Results: A total of 50,406 patients were included in our study, out of which 4,111 (8.15%) were ABO-compatible and 47,347 (91.85%) were ABO-identical. Among the recipient demographics, the ABO-compatible group compared to the ABO-identical group showed a lesser lung allocation score (40 ± 16 vs 42 ± 16), but higher A-blood group (59% vs 38%), obstructive lung disease (38% vs 33%), CAS (49 ± 13 vs 47 ± 10), mechanical ventilator support pre-transplant (6.2% vs 5.2%), need for ex-vivo lung perfusion (9.6% vs 5.8%) and listing for single lung transplant (39% vs 34%), all p<0.05. The donors for the ABO-compatible group had a closer distance to the transplant center (205 ± 285 vs 226 ± 265 nautical miles), lesser white race (61% vs 64%), and gender mismatch (30% vs 32%) but higher male gender (64% vs 61%), O-blood group (81% vs 49%) and ethnicity mismatch (45% vs 41%), all p<0.05. The univariate analysis showed a higher 30-day (7.2% vs 5.8%), 1-year (22% vs 19%), and 5-year (54% vs 50%) mortality among patients with ABO-compatible compared to ABO-identical recipients, all p<0.001. However, the adjusted odds ratio of 30-day (0.76, 95% CI 0.36-1.47, p=0.4), 1-year (1.07, 95% CI 0.69-1.66, p=0.7) and 5-year (0.69, 95% CI 0.46-1.05, p=0.081) mortality were not statistically significant with ABO-identical when compared to ABO-compatible group on adjusting to the covariates in the multivariate analysis. The trend of ABO-compatible lung transplantation has been increasing with the introduction of CAS (figure 1). Conclusion: Patients who underwent lung transplantation with the ABO-compatible blood group donor organs had similar outcomes compared to the ABO-identical blood group. The findings of our study reinforce the importance of increasing the use of ABO-compatible organs to enhance the lung transplantation rate, aligning with the observed trend following the introduction of CAS.

Abstract RATIONALE: Airway remodeling, a key characteristic of severe asthma, leads to progressive loss of lung function and incomplete reversibility of airflow obstruction. We examined the effect of benralizumab on lung function in patients from the pooled SIROCCO (Bleecker ER, et al. Lancet 2016; PMID: 27609408) and CALIMA (FitzGerald JM, et al. Lancet 2016; PMID: 27609406) studies, utilizing a new analysis of spirometry to highlight important changes in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) throughout the studies. METHODS: This retrospective analysis pooled data from the randomized, placebo-controlled, double-blind Phase 3 SIROCCO and CALIMA studies. SIROCCO enrolled patients with severe asthma, while CALIMA enrolled patients with moderate-to-severe asthma, both with a planned 2:1 randomization for baseline blood eosinophils ≥300 cells/μL versus <300 cells/μL. All patients (aged 12-75 years) had ≥2 exacerbations in the previous year, despite use of medium- to high-dose inhaled corticosteroids plus additional controllers. Patients in this analysis received subcutaneous benralizumab 30 mg every 8 weeks (Q8W; first three doses given every 4 weeks) for 48 weeks in SIROCCO and 56 weeks in CALIMA. The changes in FEV1 and FVC following bronchodilator (BD) were measured at baseline and study end. Effects on FEV1 and FVC were further stratified by baseline eosinophil count (≥300 cells/μL or <300 cells/μL). Results are reported as mean (standard deviation). RESULTS: Overall, 839 patients received benralizumab Q8W; 557 had a baseline eosinophil count of ≥300 cells/μL and 282 had <300 cells/μL. At baseline, pre- and post-BD FEV1 were 1722 mL (615; n=837) and 2128 mL (755; n=813). At study end, pre- and post-BD FEV1 were 2029 mL (756; n=735) and 2225 mL (800; n=738). At baseline, pre- and post-BD FVC were 2865 mL (905; n=837) and 3285 mL (971; n=813). At study end, pre- and post-BD FVC were 3214 mL (1010; n=735) and 3379 mL (1021; n=738). Pre-BD FEV1 and FVC improved by 307 mL and 349 mL and post-BD FEV1 and FVC improved by 97 mL and 94 mL between baseline and study end, respectively. Stratified by baseline eosinophil count, findings were similar in both groups (Figure). CONCLUSIONS: Benralizumab treatment resulted in both improved FEV1 and FVC while maintaining BD response in patients with uncontrolled, moderate-to-severe asthma. Improvements were seen in patients with baseline eosinophil counts of both ≥300 cells/μL and <300 cells/μL. These results may reflect reduced hyperinflation, potentially due to improved airway inflammation and mucus plugging.

Abstract Hip chondral defects often are encountered at the time of hip arthroscopy and can result in substantial pain and dysfunction. With the evolution of cell‐based techniques, there is growing interest in single‐stage, arthroscopic treatment of such chondral lesions. Arthroscopic orthobiologic delivery remains technically challenging, given the constrained and concave nature of the acetabulum and the need to perform instrumentation taking into account nearby structures such as the articular surface, hip capsule, and labrum. In this Technical Note, we describe our preferred method for arthroscopic delivery of orthobiologics at the time of single‐stage cartilage repair, which allows for needle‐based transcapsular, translabral access of hip chondral defects for both the acetabulum and femoral head. Technique Video video See video under supplementary data.