Citations

Abstract Introduction Obstructive sleep apnea (OSA) is effectively treated with continuous positive airway pressure (CPAP), but access remains a challenge. The COVID-19 pandemic accelerated telehealth, offering a convenient alternative to in-person visits for OSA evaluation and treatment initiation. This study compares patients managed entirely via video telehealth to those managed entirely in person. We hypothesize that virtual are as effective as in-person evaluations in managing most OSA patients. Methods The study is approved by the Mayo Clinic IRB. We retrospectively studied adult patients diagnosed with OSA requiring CPAP initiation between June 2020–2023. Data collected included baseline demographics, home sleep apnea testing (HSAT) results, polysomnography (PSG) results, Epworth Sleepiness Scale (ESS) scores, OSA severity, compliance results, other relevant comorbidities (i.e. cardiovascular diseases). Visit type categorized as “in-person” for patients who had both initial and follow-up appointments in-person, while “telehealth” group included patients who had both appointments virtually. Results Of 59 patients, 33 had telehealth (56%). The groups had similar medians in age (66 vs 62), sex (73% vs 67% male), and BMI (30 vs 32). There was no significant difference in median ESS scores (8 vs 7, p=0.7). However, the severity of OSA (moderate to severe) was higher in the in-person group (73% vs 45%, p=0.03). When baseline sleep study data was investigated, there were no differences in AHI and average SpO2 values measured by HSAT or PSG between the two groups (p>0.05 for all). CPAP compliance was significantly higher in the telehealth group compared to in-person (78% vs 40%, OR: 5.5, 95% CI: 1.7-17.1, p=0.003). Virtual visit type was the only independent predictor of compliance (p=0.006), after adjusting for age, BMI, comorbidities and OSA severity in multivariate analysis. However, there was no difference in average daily CPAP usage (6:39 vs 7:18, p=0.5) and percentage of days with usage >4 hours (91% vs 95, p=0.5). Median AHI after treatment improved in both groups, with no significant difference between groups (1.7 vs 2.4, p=0.8). Conclusion Telehealth offers a successful alternative to in-person visits for OSA evaluation, with similar outcomes and significantly better compliance, enhancing OSA management. Support (if any)

Abstract Introduction Adherence with mask-based therapies remains a significant challenge for optimal treatment of patients with sleep disordered breathing. Transvenous phrenic nerve stimulation (TPNS) to treat central sleep apnea offers a novel, automated approach to enhance nightly adherence by initiating therapy based on patient-specific programmed conditions such as sleep schedule, activity, and body position. Therapy automatically pauses when the patient sits up or changes position, facilitating re-initiation of sleep. This research aimed to determine the degree of adherence achieved with TPNS’s automated activation approach. Methods Device data from 128 remedē® System Pivotal Trial participants were analyzed to calculate hours of therapy activation. Daily use from device data within the 14 days prior to scheduled visits were used to calculate median daily hours of therapy per patient, and subsequently the overall median daily use for all patients. Therapy duration was defined as the sum of time of delivered therapy when all conditions to activate therapy were met between the first time therapy came on to the last time off during the night, excluding time when activity or body position did not meet the programmed criteria for therapy activation. Results The median [Q1-Q3] nightly therapy duration at 6, 12, 18, and 24 months was 5.9 [4.9-6.6], 5.7 [5.0-6.8], 6.0 [5.3-6.8], and 5.9 [4.9-6.5] hours, respectively. Using a definition for adequate therapy as the percentage of patients with usage ≥4 hours/night for at least 70% of nights, 86%, 82%, 83%, and 90% of patients met the criteria at these visits. Only two patients (< 2%) who had therapy activated discontinued treatment prior to 6 months due to stimulation intolerance. Patients with median delivered therapy ≥4 hours/night reported more quality of life improvement than patients with < 4 hours of therapy. Conclusion The automatic activation of TPNS therapy resulted in a higher duration of nightly usage and higher rate of adequate delivered therapy than generally are reported for mask-based therapies. This high usage may yield a greater overall reduction in central sleep apnea burden over the whole night compared to therapies that require the patient to initiate the therapy. Support (if any) ZOLL Respicardia, Inc.

Abstract Introduction Residual excessive daytime sleepiness (RES) despite effective positive airway pressure (PAP) therapy for obstructive sleep apnea (OSA) is a clinical problem impacting quality of life and daily function. Wake-promoting agents (WPAs) such as modafinil, armodafinil, and solriamfetol have demonstrated efficacy in reducing RES in randomized controlled trials (RCTs); however, their effectiveness in typical sleep clinic populations remains underexplored. This study aimed to evaluate the efficacy, safety, and tolerability of these WPAs in real-world clinical settings. Methods This retrospective study analyzed electronic health records of 69 randomly selected, consenting patients with OSA who are on PAP therapy and a WPA at Mayo Clinic from 9/19/2019 to 9/19/2024. Researchers reviewed charts for treatment indication, duration, adverse effects, and response (categorized as “complete,” “partial,” or “poor”). Therapy longevity was assessed using initiation, refill, and discontinuation data. Outcomes were analyzed with paired t-tests, chi-square tests, and regression models. Results Of 69 patients, 45 were excluded because: WPA use before observation period (24), off-label WPA use (13), WPA use before CPAP (3), or other (5). Off-label reasons included neurologic-condition-related fatigue (6), depression augmentation (5), and autoimmune-condition-related fatigue (2). 24 patients were on WPAs for RES with PAP-treated OSA, including 3 with mixed indications, and were included in analyses. The median age was 65 (IQR 11). BMI at OSA diagnosis was 33.6 (IQR 6.4). Most subjects were male (75%). Initial Epworth Sleepiness Scale scores (ESS) were 12.3±1.1. ESS at the first WPA prescription were 15.4±0.9 (p=0.04). Most patients (83.3%) started on modafinil. Of the 4 patients who started on armodafinil or solriamfetol, chart review showed a previous trial of modafinil without benefit. After optimizing the initial WPA dosage, ESS improved by 3.3±1.4 points (p=0.04) to 12.1 ±1.2. Side effects limited WPA use in 20.8% of patients. Median first WPA duration was 141 days (IQR 53-280) with no significant difference between these WPAs (p=0.81). Conclusion Although WPAs have narrowly defined approved indications, they are often prescribed off-label for comorbidities. Unlike straightforward use in RCTs, real-life use is more complicated. Patients prescribed WPAs for the targeted approved indication show statistically significant benefits, although adverse effects limited their use for some. Support (if any)

Abstract Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

Summary The eosinophilic esophagitis (EoE) Endoscopic Reference Score (EREFS) measures endoscopic severity. While a score of ≤2 has been proposed for endoscopic response, it is unknown whether achieving this threshold results in clinically important outcomes. We aimed to determine whether an EREFS response to topical steroids (tCS) is associated with a decreased need for future esophageal dilation. In this retrospective cohort study, we included patients with a new diagnosis of EoE who underwent esophageal dilation, were then treated with tCS, and had at least two follow-up endoscopies. Endoscopic response was defined as EREFS ≤2. Histological and global symptom responses were recorded. We compared patients with and without endoscopic response and calculated the number of subsequent dilations in each group. Of 113 EoE patients, 55 (49%) had endoscopic response post-tCS. Compared to endoscopic non-responders, responders were older (43.4 vs 34.4 years; p = 0.001) and had lower EREFS (4.4 ± 1.6 vs. 6.3 ± 1.5; p < 0.001) at baseline. EREFS responders required fewer dilations on their initial post-treatment endoscopy (65% vs 90%; p = 0.002) and had greater symptom (92% vs 64%; p = 0.005) and histologic responses (82% vs 24% <15 eos/hpf; p < 0.001). Over the median follow-up time of 1106 days, EREFS responders required fewer dilations than non-responders (4.5 ± 2.9 vs 6.2 ± 4.5; p = 0.03). Endoscopic responders to tCS required fewer esophageal dilations compared to non-responders. Responders also had better symptom and histologic responses. These results provide evidence that endoscopic response is associated with important clinical outcomes including a reduction in future esophageal dilations.

Abstract RATIONALE: Chronic lower respiratory diseases (CLRD) confer higher risks from respiratory viral infections, hence CLRD patients are prioritized for influenza, pneumococcal, and COVID-19 vaccination. Nonetheless, vaccine deferral and declination remain common. Given that COVID-19 vaccination is particularly polarizing, and attitudes toward it may differ from other vaccines, we assessed COVID-19 vaccination behaviors and attitudes in adults with versus without CLRD and/or smoking history, which is strongly associated with CLRD risk. METHODS: We pooled data from 10 cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) that collected pre-pandemic data on self-reported physician diagnosis of asthma or COPD. C4R assessed COVID-19 vaccination status through three waves of standardized questionnaires (2020-2022, 2021-2023, 2023-2024). Prompt COVID-19 vaccination was defined as self-report of receiving at least one COVID-19 vaccine by May 1, 2021. Cumulative COVID-19 vaccine count was self-reported on the Wave 3 Questionnaire. Vaccine attitudes and receipt of influenza and/or pneumococcal vaccines were self-reported on the Wave 1 or 2 Questionnaire. Age-adjusted Poisson regression was used to test associations of vaccination behaviors with CLRD and smoking status at the most recent pre-pandemic exam. RESULTS: Of 20,034 participants (pre-pandemic COPD, 9.3%; asthma, 11.7%; current smoking, 13.4%; former smoking, 36.3%), 64.2% reported prompt COVID-19 vaccination. Among the subset of 10,626 participants completing the Wave 3 Questionnaire in 2023-24, the median COVID-19 vaccine count was 3 (Q1:2, Q3:4). Compared to participants without CLRD, prompt vaccination was more likely in those with asthma (RR=1.04, 95%CI:1.01-1.07, p=0.008) and less likely with COPD (RR=0.94, 95%CI:0.91-0.98, p=0.001), but there were no differences in doses for asthma and COPD. Compared to never smokers, former smoking participants were more likely to receive prompt vaccination (RR=1.11, 95%CI:1.08-1.13, p<0.0001) and more vaccine doses (RR=1.03, 95%CI:1.01-1.05, p=0.015); conversely, current smoking was inversely associated with prompt vaccination (RR=0.94, 95%CI:0.91-0.97, p=0.001) and was associated with fewer doses (RR=0.93, 95%CI:0.89-0.96, p<0.0001). Participants with CLRD versus without CLRD were more likely to report receiving influenza and pneumococcal vaccines, but they were more likely to believe that vaccines are unsafe or ineffective (figure). CONCLUSIONS: COPD was associated with lower likelihood of prompt COVID-19 vaccination. Current smoking was associated with both lower likelihood of prompt COVID-19 vaccination and a lower number of COVID-19 vaccine doses by 2023-24. These associations may be partly attributed to negative vaccine attitudes and beliefs. How the COVID-19 pandemic may have influenced vaccine behaviors and attitudes merits additional study.

Abstract Rationale Non-cystic fibrosis bronchiectasis (hereafter bronchiectasis) is a chronic and progressive respiratory disease. Neutrophilic inflammation plays a key role in the pathophysiology of bronchiectasis. Neutrophil serine proteases (NSPs), especially neutrophil elastase, have been associated with disease progression and poorer clinical outcomes. Brensocatib, an oral, selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1, prevents activation of NSPs. In the phase 3, randomized, double-blind ASPEN trial (NCT04594369), treatment with once-daily brensocatib 10- or 25-mg significantly reduced the annualized rate of adjudicated pulmonary exacerbations over 52 weeks vs placebo; brensocatib 25-mg also significantly reduced lung function decline and improved patient-reported symptoms. Here, we further evaluate the impact of brensocatib on lung function in patients with bronchiectasis. Methods ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], ≥2; adolescents [12-<18 years], ≥1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Post-hoc analyses were conducted to evaluate the extent of lung function response to treatment, as measured by change from baseline in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) over the 52-week treatment period in patients who did vs did not have ≥1 on-study pulmonary exacerbation, and the level of change in post-BD FEV1 and forced vital capacity (FVC) at week 52. Results A total of 583 patients received brensocatib 10-mg, 575 received brensocatib 25-mg, and 563 received placebo. Overall, a greater decline in FEV1 was observed among patients with ≥1 on-study pulmonary exacerbation vs those without. Treatment with brensocatib 10-mg or 25-mg led to less FEV1 decline at week 52 vs placebo for patients regardless of on-study exacerbation (no exacerbation: -42mL, -8mL, vs -48mL; ≥1 exacerbation: -59mL, -41mL, vs -70mL, for 10-mg, 25-mg brensocatib and placebo, respectively [Figure]). In the overall population, no change or an improvement (≥0 mL difference vs baseline) in post-BD FEV1 at week 52 was observed in 38.7%, 45.4%, and 31.2% of patients in the brensocatib 10-mg, 25-mg, and placebo groups, respectively. Similar impacts of brensocatib were observed in FVC (no change or improvement, 10-mg: 41.3%; 25-mg: 48.9%; placebo: 31.8%). Conclusions Overall, greater lung function decline was observed in patients who had on-study pulmonary exacerbations vs those who did not. Brensocatib 25-mg reduced lung function decline vs placebo regardless of whether patients had on-study exacerbations, consistent with overall ASPEN results.

Abstract Introduction Persistent dyspnea increases the risk of disability and impairs quality of life in older patients with bronchiectasis. The impact of dyspnea and fatigue on patients with bronchiectasis in long term follow-up has not been adequately established. We sought to determine if fatigue and higher-grade dyspnea are associated with worse clinical outcomes in 5-years of longitudinal follow-up. Methods We analyzed data collected from a prospective cohort of adult patients with bronchiectasis enrolled in the US Bronchiectasis and Nontuberculous Mycobacteria Research Registry. Patients with a modified Medical Research Council (mMRC) dyspnea score collected at baseline and during 3-5 years of follow-up were included and stratified as mMRC<2 versus mMRC ≥2. Kruskal-Wallis, independent sample t-tests and chi-square tests were used to test the differences in medians and means for continuous variables and associations between categorical variables, respectively, between the baseline mMRC groups and bronchiectasis severity index (BSI) components at follow-up. A multivariable logistic regression analysis was performed to determine the association between dyspnea and clinical outcomes (exacerbations and hospitalizations) at follow-up. Results 1185 adult patients with bronchiectasis met the inclusion criteria. The median age (interquartile range) was 76 (68 to 83) years. At baseline, patients with mMRC ≥2 had a higher proportion of co-existing diagnoses such as asthma, chronic obstructive pulmonary disease (COPD), otitis/rhinosinusitis, rheumatologic disease, and pneumonia compared to patients with mMRC <2 (all p<0.05, data not shown). Furthermore, patients with mMRC > 2 compared to patients with mMRC <2 had higher prevalence of fatigue, acute exacerbations and pulmonary related hospitalizations, and lower mean percentage predicted forced expiratory volume in one second (FEV1) at follow-up (all p< 0.05) (Table 1). Interestingly, body mass index was slightly higher among those with baseline mMRC ≥2 compared to mMRC <2 (p=0.02). Among those with mMRC ≥2 at both baseline and follow-up (n=67, 42%), the odds of having ≥1 exacerbation was 2.4 times higher (odds ratio [OR] 2.45, 95% confidence interval [CI] 1.45-4.1) and 2.8 times higher for ≥1 hospitalization (OR 2.8, 95% CI 1.45-5.2) during follow-up after adjusting for fatigue. Conclusion Elevated dyspnea was associated with a greater proportion of patients with bronchiectasis exhibiting acute exacerbations and pulmonary related hospitalizations and lower lung function during follow-up. Research is still needed to understand the causes (drivers) of dyspnea to implement better treatment strategies and reduce adverse outcomes in bronchiectasis patients.

Abstract RATIONALE: Deferral and declination of the COVID-19 vaccine is correlated with many factors, including different health guidelines and difficulties accessing the vaccine. In the US, COVID-19 vaccines were made available in tranches of clinical risk starting in December 2020 and were available to all adults on April 19, 2021. In the post-pandemic period, repeating COVID-19 vaccination with updated formulations is broadly recommended. Given that the public health impact of vaccine allocation strategies depends on public acceptance of vaccination, we aimed to evaluate demographic, clinical and social correlates of (1) receiving at least one COVID-19 vaccine by May 1, 2021 (prompt vaccination) and (2) the total number of vaccine doses received (vaccine count) through 2023-2024. METHODS: The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a prospective observational meta-cohort study comprising 14 extant NIH-funded population-based cohorts. C4R assessed COVID-19 vaccination using three waves of standardized questionnaires (2020-2021, 2021-2023, 2023-2024). Prompt vaccination was defined by participant self-report of vaccination before May 1, 2021; participants vaccinated after May1, 2021 were classified as non-prompt; participants with missing vaccination information were excluded. Vaccine count was defined by self-report on the 2023-2024 wave Questionnaire. Demographic, clinical and social factors were classified by self-report and/or objective measures from the most recent pre-pandemic cohort exam. Poisson models regressed either prompt vaccination or vaccine count on pre-pandemic factors. RESULTS: Of 17,866 participants (mean age, 6713 years; 60.1% female; 42.1% non-Hispanic White, 22.0% Black, 28.9% Hispanic/Latino, 3.4% American Indian, 2.3% South Asian, 1.4% East Asian), 11,481 (64.3%) reported prompt vaccination. Of the subset of 14,529 participants completing the Wave 3 questionnaire, the median vaccine count in 2023-24 was 3 (Q1, 2; Q3 4). Likelihood of prompt vaccination was higher with greater age, income, and education and with history of diabetes and hypertension; prompt vaccination was less likely with male sex, current smoking, and non-White race and ethnicity (table). Similar associations were observed with respect to vaccine count (table). CONCLUSIONS: In a diverse C4R cohort community-based sample, earlier and greater COVID-19 vaccination was associated with older age and several clinical comorbidities; in contrast, later and lesser vaccine uptake was observed among historically marginalized groups. Whether disparities in COVID-19 vaccination could contribute to disparities in post-COVID-19 conditions merits further investigation.