The Lung Transplant GO (LTGO) randomized controlled trial evaluated the efficacy of a telerehabilitation behavioral exercise program after lung transplantation compared to enhanced usual care (EUC). We hypothesized that the LTGO treatment condition would show significantly greater improvements in change scores from baseline to 3 and 6 months for outcomes of physical function, physical activity, and blood pressure control compared to the EUC condition. The sample included 88 lung transplant recipients (LTRs) randomized 1:1 to either LTGO or EUC. No statistically significant differences in change scores for physical function, physical activity, and blood pressure control were found between treatment groups at 3 and 6 months. While no statistically significant difference in outcomes were found between groups, null findings are not uncommon. These findings and the discussion of post-trial considerations are important for the design of future trials to inform the field of telerehabilitation.

Chronic Obstructive Pulmonary disease (COPD) and Idiopathic Pulmonary Fibrosis (IPF) are chronic pulmonary disorders with distinct pathologies but shared risk factors. Metabolomics may provide insights into mechanisms. To identify metabolites associated with COPD and IPF, and to characterize shared and disease-specific signatures. Plasma metabolomic profiling was conducted in the Lung Tissue Research Consortium (LTRC). Logistic regression identified metabolites associated with COPD and IPF, and results were replicated in an external cohort, COPDGene. We applied Weighted Gene Co-expression Network Analysis (WGCNA) to explore disease-associated metabolite modules. We further evaluated relationships between significant metabolites and risk genes of interest. Of 1131 metabolites in LTRC, 246 (21.8

RATIONALE: Type 2 (T2) inflammation in patients with chronic obstructive pulmonary disease (COPD) is evidenced by elevated blood eosinophil counts (BEC), often correlating with higher risk for exacerbations. In the BOREAS and NOTUS trials, add-on dupilumab 300 mg every 2 weeks (q2w) vs placebo significantly reduced exacerbation rates and improved lung function in patients with COPD and T2 inflammation. This post-hoc analysis of pooled data from BOREAS and NOTUS evaluated efficacy of dupilumab in patients stratified by baseline BEC of ≥150 cells/µL or ≥300 cells/µL. METHODS: BOREAS (NCT03930732) and NOTUS (NCT04456673), both phase 3, randomized, placebo-controlled trials, enrolled 1,874 patients (40-85 years) with COPD, moderate-to-severe airflow limitation, and T2 inflammation. The inclusion criterion was screening BEC ≥300 cells/µL (at Visit 1, 1-4 weeks before randomization). Baseline BEC was measured at day of randomization. Patients were randomized to dupilumab 300 mg or placebo q2w for 52 weeks. This analysis included patients from the intention-to-treat (ITT) population of BOREAS and NOTUS, stratified by baseline BEC ≥150 cells/µL, 150-300 cells/µL or ≥300 cells/µL (at randomization). Endpoints assessed included annualized moderate-to-severe exacerbation rate, change from baseline to Week 52 in pre- and post-bronchodilator forced expiratory volume in 1 second (FEV1) and St. George's Respiratory Questionnaire (SGRQ) total score. RESULTS: Of 1,873 patients, 1,703 (dupilumab n = 855; placebo n = 848) had baseline BEC ≥150 cells/µL, and 1,135 (dupilumab n = 573; placebo n = 562) still had baseline BEC ≥300 cells/µL. Dupilumab vs placebo reduced annualized exacerbation rates by up to 36.9%. At Week 52, dupilumab vs placebo improved pre-bronchodilator FEV1 by (least squares [LS] mean difference [95% CI]) 0.07 (0.04, 0.11) L in the ITT population, 0.08 (0.04, 0.11) L in patients with baseline BEC ≥150 cells/µL, and 0.09 (0.05, 0.13) L in those with baseline BEC ≥300 cells/µL. Similar results were observed for changes in post-bronchodilator FEV1. Dupilumab also reduced SGRQ total scores at Week 52 by (LS mean [95% CI]) −3.37 (−4.95, −1.78) (ITT population), −3.07 (−4.7, −1.44) (baseline BEC ≥150 cells/µL), and −3.98 (−6.01, −1.95) (baseline BEC ≥300 cells/µL). Overall study safety of BOREAS and NOTUS was consistent with known dupilumab profile. CONCLUSIONS: In patients with COPD and T2 inflammation, dupilumab reduced annualized exacerbation rates, and improved lung function and quality of life in patients in ITT and across baseline BEC of ≥150 cells/µL and ≥300 cells/µL, with slightly greater treatment effects observed in patient with higher baseline BEC.

Background Mepolizumab and dupilumab are monoclonal antibodies targeting type 2 inflammation that are both approved as add-on maintenance treatment in patients with inadequately controlled chronic obstructive pulmonary disease (COPD) and an eosinophilic phenotype. Research Question What is the comparative efficacy of mepolizumab and dupilumab in reducing the risk of exacerbations and improving health-related quality of life in patients with COPD and an eosinophilic phenotype? Study Design and Methods This study used a robust matching-adjusted indirect comparison (MAIC) approach to compare pooled efficacy data from three Phase III, randomized, placebo-controlled COPD trials of mepolizumab (METREX [NCT02105948], METREO [NCT02105961], and MATINEE [NCT04133909]) with two trials of dupilumab (BOREAS [NCT03930732] and NOTUS [NCT04456673]). An indirect comparison was performed using MAIC, reweighting individual patient data from mepolizumab trials using propensity score-based methods to match the aggregate baseline characteristics of the dupilumab trial populations. To match the more restrictive eligibility criteria of the dupilumab trials, patients from the mepolizumab studies were included in this MAIC if they had blood eosinophil counts ≥300 cells/μL at screening, modified Medical Research Council scale grade ≥2, moderate-to-severe airflow limitation, and chronic bronchitis (CB) (defined by investigator assessment or St George’s Respiratory Questionnaire for COPD [SGRQ-C]). Outcomes included rate/risk of exacerbations and health-related quality of life (SGRQ-C). Results No statistically significant differences were observed in the reduction of the annualized rate of moderate/severe exacerbations (rate ratio [95% confidence interval]: 0.91 [0.60, 1.37] using investigator-assessed CB and 1.13 [0.80, 1.58] using SGRQ-C CB definition). No statistically significant differences were observed in SGRQ-C changes. Interpretation In this MAIC study, there were no statistically significant differences between mepolizumab and dupilumab in the magnitude of effect in reducing moderate/severe exacerbations and improving health-related quality-of-life outcomes.

INTRODUCTION:The dysregulation of both reduced (IL-33red) and oxidised (IL-33ox) interleukin (IL)-33 has been implicated in chronic obstructive pulmonary disease (COPD) inflammation and remodelling processes. Tozorakimab, an anti-IL-33 monoclonal antibody, inhibits both IL-33red and IL-33ox activity. METHODS AND ANALYSIS:The tozorakimab LUNA programme comprises four ongoing, multicentre, randomised, double-blind, parallel-group, placebo-controlled, phase III studies evaluating the efficacy and safety of tozorakimab in participants with symptomatic COPD and a history of exacerbations receiving optimised inhaled therapy. In OBERON (NCT05166889) and TITANIA (NCT05158387), 1132 and 1172 participants, respectively, were randomised to receive tozorakimab 300 mg every 4 or 8 weeks or placebo for 52 weeks. In MIRANDA (NCT06040086), 1454 participants were randomised 3:2 to tozorakimab 300 mg every 2 weeks or placebo for ≥52 weeks. In PROSPERO (NCT05742802), participants who completed treatment with tozorakimab in OBERON or TITANIA will continue treatment for an additional 28 weeks or 52 weeks; participants recruited from the placebo arm will be re-randomised 1:1 to tozorakimab or placebo. The primary endpoint in OBERON, TITANIA and MIRANDA is the annualised rate of moderate-to-severe COPD exacerbations; the primary endpoint in PROSPERO is the annualised rate of severe COPD exacerbations. For all studies, the primary endpoint will be first assessed in former smokers, then in current and former smokers. Secondary key endpoints include measures of lung function, respiratory symptoms, health status and safety. The tozorakimab LUNA programme is assessing the efficacy and safety of tozorakimab in participants with COPD. It is the largest pivotal programme of any biologic therapy in COPD to date. ETHICS AND DISSEMINATION:The protocols were approved by independent ethics committees and institutional review boards. Results of the studies will be submitted to the EU Clinical Trials Information System within a year from the global end of trial data in all participating countries and will be published or presented at scientific meetings. TRIAL REGISTRATION NUMBER:OBERON: NCT05166889; TITANIA: NCT05158387; MIRANDA: NCT06040086; PROSPERO: NCT05742802.

BACKGROUND:Age-associated decline in mitochondrial oxidative capacity is associated with increased risk of disease, frailty, and disability. Oral nitrite and nitrate supplementation have been demonstrated to improve mitochondrial energetics and physical function in younger adults, but effects in older adults (age ≥70 years) remain unclear. METHODS:We conducted a randomized, placebo-controlled, double-blind, two-arm trial with a parallel group design to examine the effect of 20 mg sodium nitrite supplements administered three times a day for 12 weeks versus placebo in older (age ≥70 years) sedentary adults. Change in muscle mitochondrial respiration (complex I and II supported maximal oxidative phosphorylation [CI&II MaxOXPHOS]) was the primary outcome. Platelet bioenergetics, cardiorespiratory fitness, and other physical function measures were also assessed. RESULTS:Sixty-four adults (75.7 ± 5.7 years) completed the trial. Nitrite supplementation was not associated with improvements in skeletal muscle mitochondrial respiration, nor improvements in exercise capacity and physical function. However, platelet mitochondrial respiration changed significantly following an acute dose of oral nitrite. Notably, while nitrite levels increased 16- to 30-fold in plasma following an acute dose, levels increased only 1.6-fold in skeletal muscle. CONCLUSIONS:The divergent response of skeletal muscle versus platelet mitochondrial respiration in response to nitrite supplementation suggests tissue-specific pharmacokinetics and pharmacodynamics that likely impact the efficacy of nitrite supplementation. Results also suggest there may be age-related changes in drug delivery, metabolism, and mitochondrial responsiveness compared to the effects of nitrite/nitrate previously demonstrated in younger adults. Clinical Trial Registration Number: ClinicalTrials.gov NCT04405180.

RATIONALE:Excess weight contributes to impaired physical function among individuals with chronic obstructive pulmonary disease (COPD) and sleep apnea. Self-directed lifestyle-based weight management programs are an accessible option to promote weight loss and improve physical function, but their effectiveness has not been clearly demonstrated. OBJECTIVE:To test whether a self-directed lifestyle program improves 6-minute walk test (6MWT) distance among individuals with COPD and comorbid sleep apnea. STUDY DESIGN AND METHODS:We performed a subset analysis of participants previously enrolled in the INSIGHT-COPD randomized clinical trial (low-intensity lifestyle intervention vs usual care) who self-reported a diagnosis of sleep apnea. Our primary outcome was between-group differences for change in 6MWT distance (minimally important difference [MID] 30 m). Secondary outcomes included between-group differences in weight (a loss of 3% defines meaningful reduction) and quality of life (SF-12 Physical Component Score [PCS], MID 3-3.5 points). We also tested whether sleep apnea modified the effect of the intervention across the entire INSIGHT-COPD population. MEASUREMENTS AND MAIN RESULTS:Among 285 participants with sleep apnea (141 randomly allocated to intervention, 144 to usual care), those randomized to intervention could walk further (difference in 6MWT distance of 25.5 m, 95% CI 8.2 m to 42.9 m; 23.4% vs 20.1% had a MID increase in 6MWT distance) and had a greater reduction in weight (difference in weight of -2.4 kg, 95% CI -3.9 to -0.9 kg; 36.2% vs 23.6% had a 3% reduction in weight) at 12 months. The intervention group also reported a greater physical-function-related quality of life (difference in SF-12 PCS of 1.78 pts, 95% CI 0.10 to 3.49) in comparison to usual care at 12 months. CONCLUSIONS:Among patients with COPD and sleep apnea, a self-directed video-based weight management program led to favorable changes in 6MWT distance compared to usual care, though this did not meet the threshold of a clinically important improvement. However, fewer participants in the intervention group saw a decline in 6MWT distance, and more achieved meaningful weight loss. To effectively improve function in this population, additional interventions beyond self-directed weight management will be necessary.Clinical trial registered with www.clinicaltrials.gov (NCT02634268).

Chronic obstructive pulmonary disease (COPD) is a lung disease that makes it hard to breathe and gets worse over time. People with COPD have damaged airways with swelling and increased mucus production. Ensifentrine is a novel agent that inhibits phosphodiesterase (PDE) 3 and PDE4, two enzymes that affect airway muscles, inflammation, and mucus removal from the lungs. This summary of research provides an overview of a previously published article on the results from the phase 3 ENHANCE trials, which studied the effect of ensifentrine in people with moderate to severe COPD who may have already been taking standard maintenance medications. Ensifentrine improved breathing, symptoms, and quality of life. It also reduced the rate and risk of flare-ups (called exacerbations) and was well tolerated. These results support the use of ensifentrine as an effective and well-tolerated treatment for people with COPD.

Rationale: Excess weight contributes to impaired physical function among individuals with chronic obstructive pulmonary disease (COPD) and comorbid sleep apnea. Self-directed lifestyle-based weight management programs are an accessible option to promote weight loss and improve physical function, but their effectiveness in this population is unclear. We sought to test whether a self-directed lifestyle program improves 6-minute walk test (6MWT) distance among individuals with COPD and comorbid sleep apnea. Methods: INSIGHT-COPD was a randomized trial to test whether a self-directed video-based lifestyle intervention would lead to better physical function in participants with excess weight and COPD. We performed a retrospective subset analysis restricted to participants with a self-reported clinician-diagnosis of sleep apnea. Our primary outcome was between-group differences for change in 6MWT distance, which we measured using a linear mixed effects model. We also assessed secondary outcomes including weight and SF-12 physical function related quality of life. Finally, we assessed whether participants met meaningful thresholds for improvement and decline in 6MWT distance (30m) and weight loss (5% total body weight) using generalized linear regression models for binary outcomes. Results: Among the 684 participants randomized in INSIGHT-COPD, 285 had self-reported sleep apnea (141 randomized to intervention, 144 to control). At 12 months, those randomized to intervention could walk further relative to those randomized to control (adjusted between group difference for 6MWT distance +25.5 m [95% CI 8.2-42.9 m] for individuals with OSA in the intervention group compared to the control group). We did not observe a between-group difference in the likelihood of achieving meaningful improvement in 6MWT distance, though fewer intervention participants experienced a meaningful decline in 6MWT (Figure). Intervention participants also experienced a greater reduction in weight, (adjusted between-group difference of -2.4 kg, 95% CI -3.9 to -0.9 kg) and were more likely to experience meaningful weight loss (Figure). Participants in the intervention arm also experienced greater improvements in physical-function related quality-of-life (adjusted between-group difference: SF-12 PCS 1.78 pts, 95% CI 0.10 to 3.49. Conclusions: Among individuals with COPD and self-reported sleep apnea, a self-directed video-based weight management intervention did not lead to clinically meaningful improvements in 6MWT distance relative to usual care. However, fewer participants experienced a meaningful reduction in 6MWT distance, and a greater proportion of participants in the intervention group experienced clinically meaningful weight loss. Additional interventions beyond self-directed weight management will be needed to meaningfully improve function among patients with COPD and comorbid sleep apnea.

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with clusters of co-occurring conditions contributing to a multimorbid syndrome. A disease of aging, COPD is higher in people over 60 years of age and is marked by increased cellular senescence and abnormal tissue repair. Markers associated with cellular senescence and inflammageing are present in individuals with COPD as senescence-associated secretory phenotype (SASP) mediators. We hypothesized that an aging endotype characterized by distinct SASP mediator expression associates with multiorgan dysfunction in COPD. Methods: We analyzed data from the University of Pittsburgh tobacco-exposed cohort, a single-center, prospective observational cohort of adults over 40-years with a 10-pack-year smoking history minimum. We measured 23 plasma SASP mediators with Luminex and plasma levels of intestinal fatty acid binding protein (IFABP), a protein released by damaged enterocytes indicative of impaired intestinal epithelial barrier function, with ELISA. Using automated in-house AI algorithms, we quantified emphysema, coronary and aortic calcifications, muscle volume and density, intramuscular adipose tissue volume, and bone density on CT scans. We used Principal Component Analysis to derive Principal Components (PCs) from the SASP panel to identify distinct patterns of protein expression. Using linear regression modeling, we then examined the association between PCs with lung function, clinical outcomes, and CT measures of emphysema, cardiovascular, and musculoskeletal disease. Results: Of 273 tobacco-exposed individuals (median age 66, IQR 63-70 years; 49% male; 37% current smoker; median FEV1% predicted 87%, IQR 71-100%), 124 individuals had COPD (FEV1/FVC<0.70), 137 had emphysema, and 87 had both. PC1 associated with radiographic emphysema (ß=-0.01; p<0.001) but not spirometric airflow obstruction (ß=0.004; p=0.34) and correlated with chronologic age (r=0.3; p<0.001)—consistent with an emphysema-predominant aging endotype. Conversely, PC2 associated with airflow obstruction (ß=-0.02; p<0.001) but not emphysema (ß=0.003; p=0.16) and did not correlate with chronologic age. PC1 associated with IFABP levels (ß=0.04; p=0.01); muscle density (ß=-0.82; p<0.001); bone density (ß=-2.4; p=0.02); aorta and coronary artery calcification volume (ß=0.57; p=0.01); and intramuscular adipose tissue volume (ß=0.02; p<0.001). PC2 associated with IFABP (p=0.04), with significant expression of SASP proteins CCL5, Myeloperoxidase, VEGFA, Stanniocalcin, IL-7, and MMP-9. PC1 significantly expressed SASP proteins TNF-RSF1A, TNF-RSF1B, GDF-15, MMP-7, Fas, CCL18, RAGE, IL-15, and TNF-alpha (Figure 1). Conclusion: PC1 and PC2 are distinct endotypes, and PC1 is consistent with an emphysema-predominant aging endotype characterized by increased gut permeability, musculoskeletal abnormalities, and vascular calcifications. Understanding how cellular senescence and aging drive multimorbidity in COPD could identify future novel therapies.

RATIONALE: There is evidence of type 2 inflammation in a subset of patients with COPD. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation. In BOREAS (NCT03930732) and NOTUS (NCT04456673), patients with COPD, moderate-to-severe airflow limitation, and type 2 inflammation (≥300 cells/µL blood eosinophils at screening) on background triple therapy, who received dupilumab 300 mg every 2 weeks or placebo for 52 weeks, had a statistically significant reduction in exacerbations and improved lung function. Safety was consistent with the known dupilumab safety profile. This analysis examined multiple lung function parameters in the pooled population and current and former smokers from both trials. METHODS: Change in pre- and post-bronchodilator forced expiratory volume in 1 second (FEV1), post-bronchodilator FEV1/forced vital capacity (FVC) ratio, and post-bronchodilator forced expiratory flow 25-75% of vital capacity (FEF25-75%) over time were analyzed. RESULTS: In the intention-to-treat (ITT) population, patients received dupilumab (n = 938) or placebo (n = 936); 830 patients from each group had the opportunity to reach Week 52. The ITT population was used for subgroup (current and former smokers) analysis. In the pooled ITT population who had the opportunity to reach Week 52, the baseline mean (standard deviation) pre-bronchodilator FEV1 was 1.32 (0.47) and 1.35 (0.48) L; post-bronchodilator FEV1 was 1.41 (0.47) and 1.44 (0.49) L; post-bronchodilator FEV1/FVC ratio was 0.49 (0.12) and 0.49 (0.12); and post-bronchodilator FEF25-75% was 0.56 (0.33) and 0.56 (0.33) L/s for dupilumab and placebo, respectively. By Week 12, dupilumab vs placebo improved pre-bronchodilator FEV1 (least squares [LS] mean difference [95% CI] 83 [51, 114] mL), post-bronchodilator FEV1 (LS mean difference [95% CI] 72 [40, 105] mL), post-bronchodilator FEV1/FVC (LS mean difference [95% CI] 16 [9, 23]), and post-bronchodilator FEF25-75% (LS mean difference [95% CI] 80 [44, 116] mL/s). Improvements were sustained up to Week 52. In the ITT population, the LS mean difference (95% CI) vs placebo in pre-bronchodilator FEV1 at Week 12 was 89 (52, 127) in former smokers (n = 661 dupilumab; n = 654 placebo)and 64 (20, 109) mL in current smokers (n = 275 dupilumab; n = 282 placebo). CONCLUSIONS: In 2 pivotal phase 3 trials in patients with COPD and type 2 inflammation, dupilumab improved lung function by Week 12 and sustained the improvement throughout the study period.

Background: Small airway disease (SAD) is associated with FEV1 decline. This study aimed to assess the association between SAD and the progression to COPD in high-risk individuals. Methods: We analyzed data from COPDGene participants with ≥10 pack-years of cigarette smoking who had normal spirometry or preserved ratio impaired spirometry (PRISm). Normal spirometry was defined as both post-bronchodilator FEV1 and FEV1/FVC≥ lower limit of normal (LLN); PRISm was defined as FEV1 < LLN with FEV1/FVC ≥ LLN. Participants underwent inspiratory and expiratory chest CT. Using Parametric Response Mapping (PRM), we quantified SAD as the percent of voxels (%PRMfSAD) with non-emphysematous gas trapping (≥ -950 Hounsfield units (HU) at inspiration and < -856 HU at expiration). %Emphysema was defined as the percentage of voxels with ≥ -950 Hounsfield units (HU) at inspiration and < -856 HU at expiration. We used logistic regression models to examine the association of %PRMfSAD and %emphysema at enrollment, as well as changes between enrollment and the 5-year follow-up visit with progression to moderate COPD (outcome), defined as both FEV1 and FEV1/FVC

Introduction Post-Acute Sequelae of COVID-19 (PASC) is a significant complication of SARS-CoV-2 infection, leading to persistent symptoms and diminished functional status. Long-term QoL data, particularly in relation to therapeutic interventions like P2Y12 inhibitors, SGLT2 inhibitors, and crizanlizumab, remain limited. This study aimed to evaluate the effect of these treatments on one-year QoL outcomes in critically ill COVID-19 patients. Methods: This analysis is part of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4a) randomized controlled platform trial, conducted at 34 hospitals in the United States and Spain from September 2020 to June 2021. Participants were randomized to receive standard care or one of the following interventions: P2Y12 inhibitors, SGLT2 inhibitors, or crizanlizumab. QoL outcomes were assessed one year after hospitalization using the Patient-Reported Outcomes Measurement Information System (PROMIS), which measured domains such as physical and mental health, sleep disturbance, and neurological QoL. Univariate and multivariable analyses were conducted to evaluate treatment effects and identify independent predictors of QoL. Results: In total, 750 participants completed PROMIS questionnaires one year post-trial (n=258 SGLT2 inhibitor, n=191 crizanlizumab, n=19 P2Y12 inhibitor). Subject characteristics including age, sex, race, and baseline comorbidities were not significantly different between treatment and control groups. There were no significant differences in the PROMIS t-scores for physical and mental health, sleep disturbance, and neurological QoL (all p>0.05) based on receipt of P2Y12 inhibitors, SGLT2 inhibitor, or crizanlizumab. Average PROMIS t-scores for mental health were consistently lower than the reference score, and physical health across all groups approached 1 standard deviation below the U.S. general public. Pre-infection respiratory disease was associated with lower physical health (difference = -4.99, p < 0.0001), lower mental health (difference = -4.09, p = 0.0001), and higher sleep disturbance t-scores (difference = 4.38, p < 0.0001). Severe disease status was associated with higher physical health t-scores (difference = 4.06, p = 0.0302). Female sex was associated with lower neurological QoL score (difference = -3.02, p = 0.0175), while Hispanic ethnicity (difference = 6.15, p = 0.0005) and pre-infection immunosuppressive disease were associated with higher neurological QoL scores (difference = 3.88, p = 0.0077). Conclusion: In this secondary analysis of a randomized controlled platform trial, P2Y12 inhibitors, SGLT-2 inhibitors, and crizanlizumab were not associated with significant improvement in one-year QoL outcomes among hospitalized COVID-19 patients. Reduced physical and mental health scores were observed across multiple groups, with predictors of diminished QoL including pre-infection respiratory disease, female sex, and ethnicity.

INTRODUCTION:Ensifentrine, recently approved by the FDA for chronic obstructive pulmonary disease (COPD) maintenance treatment, is a novel inhaled therapy with a dual mechanism of action targeting phosphodiesterase (PDE)3 and PDE4. While long-acting bronchodilators and inhaled corticosteroids remain initial guideline-based COPD treatments, persistent symptoms and disease exacerbations highlight an existing unmet need. Ensifentrine offers both bronchodilator and anti-inflammatory benefits, offering the potential to address this treatment gap. AREAS COVERED:This article reviews the mechanism of action of ensifentrine, details supporting preclinical evidence, and summarizes key clinical studies. It further explores ensifentrine's potential impact on the COPD treatment landscape and its potential applicability in other pulmonary diseases. EXPERT OPINION:Ensifentrine's dual bronchodilator and anti-inflammatory action offer a promising adjunct to standard COPD treatments, particularly for patients with persistent symptoms despite conventional therapy. It improves lung function, meaningfully reduces exacerbation frequency, reduces symptoms, and enhances quality of life. Its inhaled delivery minimizes systemic exposure and side effects commonly observed with oral PDE inhibitors. Furthermore, its anti-inflammatory properties suggest potential applications in other chronic respiratory diseases, such as asthma and non-cystic fibrosis bronchiectasis.

RATIONALE. The overall goal of this study is to improve access to high quality specialist care for people with Long-COVID. The priority is to reach populations who may not be aware of the disease or the specialty Long-COVID Recovery clinic. We are using a learning health system approach to co-design a new consultation and referral pathway for patients in primary care in collaboration with Family Medicine providers. In addition, we are working closely with a network of community health workers. As part of this effort, we conducted qualitative key informant interviews and focus groups to gain an in-depth understanding of provider and community perspectives of Long-COVID. METHODS. An initial round of 17 open-ended interviews were conducted with key informants from participating family practice clinics. The results of these interviews informed focus groups with family practice providers, office staff, and community health workers. Transcripts of each interview and focus group were coded thematically to address familiarity with Long-COVID, approaches to diagnosing and managing the disease, access to care, and preferred approaches to professional and community education. RESULTS. Both providers and community health workers recognized that Long-COVID is a real phenomenon among people who have had COVID-19. Community health workers were less familiar with the term and reported that many of their constituents would benefit from being able to put a label on the constellation of symptoms they are experiencing. Providers and office staff reported that Long-COVID is not common, and that they typically manage their patients symptomatically and did not have a clinical pathway or best practice model. Awareness of the specialty Long-COVID Recovery Clinic was low. Providers expressed that access to a trusted referral center would be valuable, but also raised the concern about whether patients would return to primary care. There was interest among providers in asynchronous, on-demand training that would fit in their already busy schedules. Community health workers expressed that patient or public facing materials must be prepared at a low level of literacy and use trusted intermediaries to reach vulnerable, disenfranchised individuals who are distrustful of the local health system. CONCLUSIONS. Formative, qualitative research was conducted to support the design of provider and patient facing materials on Long-COVID. The implementation team used this process to engage with primary care clinicians and office staff to develop an approach that will be easy to implement, provides enhanced access to specialty care, and has a high potential for sustainability.

BACKGROUND:Mepolizumab is a humanized monoclonal antibody that targets interleukin-5, a cytokine that plays a central role in eosinophilic inflammation, which is present in 20 to 40% of patients with chronic obstructive pulmonary disease (COPD). METHODS:In a phase 3, double-blind, randomized, placebo-controlled trial, patients with COPD, a history of exacerbations, and a blood eosinophil count of at least 300 cells per microliter who were receiving triple inhaled therapy were assigned, in a 1:1 ratio, to receive mepolizumab (at a dose of 100 mg) or placebo subcutaneously every 4 weeks for 52 to 104 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Secondary end points, tested hierarchically to control for multiplicity, were moderate or severe exacerbation as assessed in a time-to-first-event analysis, measures of health-related quality of life and symptoms, and the annualized rate of exacerbations leading to an emergency department visit, hospitalization, or both. RESULTS:Of the 804 patients who underwent randomization, 403 were assigned to receive mepolizumab and 401 to receive placebo. The annualized rate of moderate or severe exacerbations was significantly lower with mepolizumab than with placebo (0.80 vs. 1.01 events per year; rate ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.01). The time to the first moderate or severe exacerbation was longer with mepolizumab than with placebo (Kaplan-Meier median time to the first moderate or severe exacerbation, 419 vs. 321 days; hazard ratio, 0.77; 95% CI, 0.64 to 0.93; P = 0.009). Between-group differences in measures of health-related quality of life and symptoms were not significant; thus, no statistical inferences regarding subsequent secondary end points in the statistical testing hierarchy were made. The incidence of adverse events was similar in the mepolizumab and placebo groups. CONCLUSIONS:Treatment with mepolizumab led to a lower annualized rate of moderate or severe exacerbations when added to background triple inhaled therapy among patients with COPD and an eosinophilic phenotype. (Funded by GSK; MATINEE ClinicalTrials.gov number, NCT04133909.).