RATIONALE: Chronic cough and sputum production are prevalent in patients with chronic obstructive pulmonary disease (COPD) and are associated with increased risk of exacerbations and morbidity. 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 and NOTUS trials, add-on dupilumab reduced exacerbations and improved lung function in patients with COPD and type 2 inflammation. Safety was consistent with the known dupilumab safety profile. This post-hoc pooled analysis investigated dupilumab efficacy based on baseline cough and sputum scores in patients with COPD from BOREAS and NOTUS. METHODS: BOREAS (NCT03930732) and NOTUS (NCT04456673) both were phase 3 randomized, double-blind, placebo-controlled trials of patients with COPD, moderate-to-severe airflow limitation, and type 2 inflammation (blood eosinophils ≥300 cells/µL at screening) on triple therapy (inhaled corticosteroids, long-acting β2-agonists, and long-acting muscarinic antagonists) unless contraindicated, with investigator reported chronic cough/chronic bronchitis (emphysema not excluded). Patients were randomized 1:1 to receive dupilumab 300 mg or placebo subcutaneously every 2 weeks for 52 weeks. The Evaluating Respiratory Symptoms in COPD tool (E-RS:COPD) was used to evaluate baseline cough and sputum scores (range 0−11, with lower scores indicating less severe symptoms). Assessed endpoints included the moderate or severe exacerbation rates and pre-bronchodilator forced expiratory volume in 1 second (FEV1) at Week 12, in patients dichotomized by median baseline cough and sputum score. RESULTS: Median baseline cough and sputum score was 3.4 points. Of 1,851 patients with cough and sputum scores at baseline, 914 (dupilumab n=449; placebo n=465) had a baseline score equal to median or higher, and 937 (dupilumab n=475; placebo n=462) scored below the median. Compared with placebo, dupilumab reduced moderate or severe exacerbations by 29% (relative risk, RR [95% CI]: 0.71 [0.59, 0.87]) in patients with baseline cough and sputum score equal to median or higher, and by 33% (RR [95% CI]: 0.67 [0.54, 0.83]) in those who scored below the median. Dupilumab improved pre-bronchodilator FEV1 at Week 12 compared with placebo by least squares mean difference (95% CI) of 91 (51, 131) mL (baseline score equal to median or higher) and 81 (36, 125) mL (below median baseline score). CONCLUSION: In this pooled analysis of BOREAS and NOTUS, dupilumab significantly reduced exacerbation rates and improved lung function compared to placebo irrespective of high or low E-RS:COPD cough and sputum score at baseline.

BACKGROUND:Clinical risk factors for severe asthma attacks have been identified, but their incremental prognostic values are unclear. Additionally, the incremental contribution of type 2 inflammation, a common, treatable process, is undetermined. We aimed to quantify the prognostic value of baseline characteristics and type 2 inflammatory biomarkers, specifically blood eosinophil count and fractional exhaled nitric oxide (FeNO), to predict asthma attacks. METHODS:In this systematic review and meta-analysis of randomised controlled trials (RCTs), Oxford Asthma Attack Risk Scale 2 (ORACLE2), we searched MEDLINE from Jan 1, 1993, to April 1, 2021, for trials investigating fixed treatment regimen effects on asthma attack rates for at least 6 months with baseline blood eosinophil count and FeNO. Eligible participants were aged 12 years or older with asthma (any severity) who had been randomly assigned to the control group of an RCT. Relevant trials were manually retrieved and reviewed by two independent reviewers (SC and IDP). Disagreements were discussed with five reviewers. Individual patient data (IPD) for meta-analysis were requested from study authors. We investigated the rate of severe asthma attacks (≥3 days of systemic corticosteroids) for at least 6 months and prognostic effects of baseline blood eosinophil count and FeNO in control group participants. Rate ratios (RRs) with 95% CIs were derived for annualised asthma attack rates from negative binomial models adjusted for key variables, including blood eosinophil count and FeNO, and interactions between these type 2 inflammatory biomarkers were explored. Certainty of evidence was assessed using GRADE. The heterogeneity of the included studies and potential for ecological bias were quantified by the concordance statistic (C-statistic). This study was registered with PROSPERO, CRD42021245337. FINDINGS:We identified 976 potentially eligible studies. After automated screening, we manually reviewed 219 full-text articles. Of these, 19 publications comprising 23 RCTs were eligible. 6513 participants (4140 [64%] female; 2370 [36%] male; three missing) spanning 22 RCTs were included for data analysis. 5972 (92%) of 6513 patients had moderate-to-severe asthma. 4615 asthma attacks occurred during 5482 person-years of follow-up (annualised rate 0·84 per person-year). Higher blood eosinophil count or FeNO was linked to higher asthma attack risk (per 10-fold increase, RR 1·48 [95% CI 1·30-1·68] for blood eosinophil count and 1·44 [1·26-1·65] for FeNO; high-certainty evidence). Other prognostic factors were attack history (yes vs no, RR 1·94 [1·61-2·32]); disease severity (severe vs moderate, RR 1·57 [1·22-2·03]); FEV1 percentage predicted (FEV1%; per 10% decrease, RR 1·11 [1·08-1·15]); and 5-item Asthma Control Questionnaire score (ACQ-5; per 0·5 increase, RR 1·10 [1·07-1·13]). High blood eosinophil count and FeNO combined were associated with greater risk than either prognostic factor separately. Bronchodilator reversibility was associated with lower risk of severe asthma attacks (per 10% increase, RR 0·93 [0·90-0·96]), with the reduction observed primarily between 0% and 25%. Regarding heterogeneity of the included studies, the C-statistic ranged from 0·58 to 0·95, indicating major differences in patient and disease characteristics between studies. In the univariable meta-analysis per trial, we found substantial heterogeneity in associations between studies, with I2 statistics ranging from 0·56 to 0·97. INTERPRETATION:Blood eosinophil count, FeNO, asthma attack history, disease severity, low lung function (low FEV1%), and symptoms (ACQ-5 score) are key predictors of asthma attacks. Conversely, we found that moderate bronchodilator reversibility was associated with reduced risk. These findings from high-quality multinational RCTs support incorporation of blood eosinophils and FeNO into clinical risk stratification for targeted risk reduction. More individualised clinical decision-making models should be explored. FUNDING:National Institute of Health and Care Research Oxford Biomedical Research Centre; Association pulmonaire du Québec; Fonds de recherche du Québec-Santé; Québec Air-Intersectorialité-Respiratoire-Son network; Stichting Astma Bestrijding; Leiden University Fund; and Academy of Medical Sciences.

Chronic obstructive pulmonary disease (COPD) is a highly prevalent inflammatory lung condition characterized by chronic respiratory symptoms and airflow obstruction that often leads to diminished quality of life. Nonpharmacologic management for patients with COPD involves smoking cessation and healthy lifestyle changes. Pharmacologic treatments include inhaled bronchodilators with or without the use of inhaled corticosteroids, which can be administered through inhalation or nebulization. In addition, oral medications including macrolide antibiotics and phosphodiesterase (PDE) 4 inhibitors can help reduce exacerbation risk. However, many of these medications provide suboptimal disease control, owing to limited efficacy, increased risk of adverse events with long-term use, or difficulty in administration technique. PDE3 plays an important role in maintaining smooth muscle function, and PDE4 plays a crucial role in the inflammatory response in airway smooth muscle. Direct molecular inhibition of PDE3 or PDE4 has been shown to provide benefit in COPD. Dual PDE3 and PDE4 inhibition may, therefore, have synergistic anti-inflammatory and bronchodilator effects. These results have been observed in clinical trials of nebulized ensifentrine, a novel, dual-action PDE3 and PDE4 inhibitor that is the first in its class to be approved by the U.S. Food and Drug Administration for maintenance treatment of COPD in adult patients. In this review, we explore the pathophysiologic mechanisms of COPD, describe current paradigms and methods of drug delivery for the treatment of the disease, and illustrate how dual inhibition of PDE3 and PDE4 may provide additional benefit to current standard-of-care regimens.

e20082 Background: Stereotactic body radiotherapy (SBRT) is an established treatment for early-stage lung cancer, particularly in patients who are medically inoperable or decline surgery. Access to SBRT historically has been challenging for patients with lower socioeconomic status. This study evaluates the demographics, clinical characteristics, and outcomes of lung cancer patients who received SBRT in a safety-net hospital system. Methods: Clinical data were abstracted from all patients with primary lung malignancies who received SBRT from 2014 to 2022 at a single institution. Demographics, medical and social histories, histology, stage, radiation treatment details, ECOG (Eastern Cooperative Oncology Group) performance status at diagnosis and one year after SBRT, local or locoregional failure, development of metastases, date of last contact and cause of death were obtained from the electronic medical record. Nodule size was recorded at time of treatment. Follow-up was calculated from the date of diagnosis based on imaging to the date of last contact. Freedom from local and locoregional progression (FFLP/FFLRP), progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Progression was defined as LP, LRP, distant metastasis, or death. Statistical analyses were conducted using JMP. Results: A total of 106 patients (56% female; median age 64, range: 49-90) received SBRT with an overall median follow-up of 38 months (range: 5-139). Patients were 56% Black, 24% White, 14% Hispanic, and 6% Asian. Most patients (42%) had Medicare, 33% were uninsured and treated on a county-based financial assistance plan, 11% had exchange-based insurance, 8% had employer-sponsored insurance and 6% had Medicaid. Median smoking history was 30 pack years (range: 0-135) with 38% actively smoking and 51% with COPD. Almost a third (28%) of patients began treatment with an ECOG of 2 or greater and 30% of patients were treated without histologic confirmation. Of those with histological confirmation, 65% were adenocarcinoma and 26% squamous cell carcinoma. The median dose and fractionation were 5000 cGy (range: 4000-6000) over 4 fractions (range: 3-15). No grade 3 adverse events or hospitalizations related to SBRT were reported. One year following treatment, 41% of patients maintained their performance status and a post-treatment ECOG of 2 or greater was observed in 15% of patients who began treatment with a score of 0-1. Actuarial three-year FFLP, FFLRP, PFS and OS were 97%, 82%, 63%, and 77%, respectively. Of the 4 patients who experienced local failure, 1 had a prior history of lung cancer and 2 received a biologically effective dose (BED 10 ) of <105Gy. Conclusions: Our real-world experience underscores the practicality, safety and effectiveness of SBRT as a valuable first-line treatment option for early-stage lung cancer in resource-limited settings.

BACKGROUND:Asthma affects over 260 million people globally, with significant health impacts. The Global Initiative for Asthma (GINA) 2024 report recommends inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combinations, including fluticasone propionate/salmeterol (FP/SAL) and budesonide/formoterol (BUD/FOR), for maintenance treatment. Both combinations have demonstrated clinical benefits, with previous clinical trials and real-world studies showing comparable asthma control with FP/SAL and BUD/FOR. This United States (US)-based study compares the real-world effectiveness of FP/SAL and BUD/FOR on asthma control and treatment adherence. METHODS:This retrospective cohort study analyzed data from the US Optum's Market Clarity database (July 1, 2010, to December 31, 2019), with integrated medical, pharmacy claims, and clinical electronic health records. Patients aged ≥18 years with asthma at GINA Steps 3-4, and ≥1 pharmacy claim for FP/SAL or BUD/FOR (index) were included. Patients on other ICS/LABA therapy ≥12 months prior to index were excluded. Inverse probability of treatment weighting adjusted for confounders. Outcomes were stratified by asthma severity. RESULTS:A total of 57,000 patients were included (FP/SAL: 28,639; BUD/FOR: 28,361). Baseline characteristics were balanced post-weighting. Asthma control was similar between cohorts, with no significant differences in Asthma Control Test scores or short-acting β2-agonist fills during the 12-month period following the index. Treatment adherence, assessed using proportion of days covered (≥0.8), was higher in the FP/SAL cohort (5.4 %) versus the BUD/FOR cohort (4.4 %; p < 0.001). CONCLUSIONS:FP/SAL and BUD/FOR were similarly effective for asthma control in real-world settings, while FP/SAL was generally associated with greater medication adherence, a key factor for long-term control.

BACKGROUND:Patient-reported outcomes should be considered alongside clinical assessments to guide therapy for COPD. RESEARCH QUESTION:Does add-on dupilumab treatment improve health-related quality of life and respiratory symptoms in patients with COPD and type 2 inflammation? STUDY DESIGN AND METHODS:In this pooled analysis of two phase 3 trials, patients with COPD and type 2 inflammation receiving triple therapy were randomized 1:1 to receive dupilumab 300 mg (n = 938) or placebo (n = 936) every 2 weeks for 52 weeks. Quality of life and respiratory symptom severity were measured by change from baseline to week 52 in St. George's Respiratory Questionnaire (SGRQ; total [0-100 units, lower scores indicating better quality of life] and domain scores for symptoms, activity, and impacts) and Evaluating Respiratory Symptoms in COPD (E-RS:COPD; total [0-40 units, lower scores meaning less severe respiratory symptoms] and domain scores for breathlessness, cough and sputum, and chest symptoms) scores. RESULTS:In total, 1,660 patients reached week 52 (n = 830 in each treatment arm). At week 52, dupilumab vs placebo reduced SGRQ and E-RS:COPD total scores by least squares mean differences (95% CI) of -3.4 (-5.0 to -1.8; P < .0001) and -0.9 (-1.4 to -0.4; P = .0006), respectively. Similar reductions were observed across SGRQ domain scores of symptoms (-3.5 [-5.5 to -1.5]), activity (-4.0 [-5.9 to -2.1]), and impacts (-2.9 [-4.6 to -1.1]), and E-RS:COPD domain scores of breathlessness (-0.6 [-0.8 to -0.3]), cough and sputum (-0.2 [-0.3 to 0.0]), and chest symptoms (-0.1 [-0.3 to 0.0]). INTERPRETATION:Dupilumab exhibited improvements in SGRQ and E-RS:COPD total and domain scores in patients with COPD and type 2 inflammation. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifiers; Numbers: NCT03930732 and NCT04456673; URL: www. CLINICALTRIALS:gov.

Oral corticosteroids (OCS) have been used for both maintenance and burst treatment of asthma since the 1950s owing to their beneficial effect on symptoms and exacerbations coupled with a historical lack of alternative therapies. Despite the current availability of well-tolerated and effective treatment with biologics, chronic OCS use remains high. This is of great concern because evidence suggests that a lifetime cumulative exposure even as low as 0.5 to 1.0 g prednisolone equivalent (about three to four bursts of OCS) significantly increases the risk of a wide range of acute and long-term adverse effects, some of which may not be fully reversible. Conversely, biologics have demonstrated a more favorable benefit-risk profile compared with OCS, while reducing exacerbations and improving symptom control. Here, we review the current situation, highlight the need for improved stewardship of OCS use, describe the cumulative and potentially irreversible toxicity seen with even short bursts of OCS, and discuss the role of biologics in minimizing their use. Finally, we provide our opinion on how maintenance OCS therapy in asthma can be relegated to history, with early patient risk evaluation to identify and measure biomarkers and/or clinical traits that may predict risk of future exacerbations, enabling proactive preventative intervention.

Introduction: Lebrikizumab, a novel, high-affinity monoclonal antibody selectively targeting interleukin-13, has demonstrated efficacy and safety in moderate-to-severe atopic dermatitis at higher doses than studied in asthma. Clinical trials of lebrikizumab in moderate-to-severe uncontrolled asthma have not demonstrated consistent exacerbation reductions, possibly due to suboptimal patient selection and premature understanding of asthma phenotypes. We describe post-hoc analyses in adults with uncontrolled eosinophilic asthma with a history of ≥1 asthma exacerbation in the past 12 months from 2 phase 3 lebrikizumab clinical trials (LAVOLTA I and II) completed in 2016. Methods: Patients were randomly assigned to receive lebrikizumab (37.5mg or 125mg), or placebo (all N=716) every 4 weeks. Adjusted exacerbation rate (AER) at week 52 (W52), presented as rate reduction, and placebo-corrected mean change in prebronchodilator forced expiratory volume in 1 second (FEV1) at weeks 24 (W24) and 52 were assessed in patients with elevated fractional exhaled nitric oxide (FeNO [≥50 mean parts per billion]; 37.5mg [n=105], 125mg [n=107], placebo [n=109]) and in those with both elevated FeNO and elevated blood eosinophils (≥300 cells/µL; 37.5mg [n=60], 125mg [n=66], placebo [n=62]) at baseline. Results: Lebrikizumab significantly reduced the AER versus placebo at W52 in the elevated FeNO (37.5mg, 47.5%; 125mg, 45.5%) and elevated FeNO and blood eosinophils (37.5mg, 52.3%; 125mg, 52.9%) subgroups. Significant FEV1 improvement was observed in patients with elevated FeNO at W24 (improvement for 37.5mg, 205.4mL; 125mg, 240.9mL) and W52 (37.5mg, 189.8mL; 125mg, 212.0mL). In patients with elevated FeNO and elevated blood eosinophils, FEV1 significantly improved at W24 (37.5mg, 274.8mL; 125mg, 234.1mL) and for the lower dose at W52 (37.5mg, 209.5mL), while a numeric increase was observed for the higher dose (125mg, 139.2mL). Conclusion: Lebrikizumab could be beneficial in patients with uncontrolled asthma with type 2 inflammation (elevated FeNO and/or elevated blood eosinophils) and a history of recent exacerbations.

Clinical and translational observations suggest that repair or new growth of alveolar structures in humans is feasible. The pathways and mechanisms for repairing damaged alveoli have been characterized in in vivo and ex vivo models, and many of these major biological pathways involved in facilitating lung repair have been validated in adult human lung tissue. Improvements in imaging, functional studies, and biomarkers have led to sensitive measures of treatment effects and clinical outcomes that can be used to study emphysema repair in humans with emphysema. Additionally, the development of innovative platform clinical trial designs now allows for the simultaneous testing of multiple drugs and treatment response biomarkers within a heterogenous population, helping to distinguish responders from non-responders. Several approved medications targeting pathways involved in lung repair could be tested to treat emphysema (e.g., all-trans retinoic acid, thiazolidinediones, metformin, non-steroidal anti-inflammatory drugs, and lithium). These advances enable feasible assessment of the scientific premise of lung repair in human emphysema in clinical trials.

Importance:Individuals at risk for chronic obstructive pulmonary disease (COPD) but without spirometric airflow obstruction can have respiratory symptoms and structural lung disease on chest computed tomography. Current guidelines recommend COPD diagnostic schemas that do not incorporate imaging abnormalities. Objective:To determine whether a multidimensional COPD diagnostic schema that includes respiratory symptoms and computed tomographic imaging abnormalities identifies additional individuals with disease. Design, Setting, and Participants:This cohort study included 2 longitudinal cohorts: the Genetic Epidemiology of COPD (COPDGene), which enrolled 10 305 participants between November 9, 2007, and April 15, 2011, with longitudinal follow-up through August 31, 2022; and the Canadian Cohort Obstructive Lung Disease (CanCOLD), which enrolled 1561 participants between November 26, 2009, and July 15, 2015, with follow-up through December 31, 2023. Exposure:Exposure included the new multidimensional COPD diagnostic schema, defined by (1) major diagnostic category: presence of the major criterion (airflow obstruction based on postbronchodilator forced expiratory volume in the first second of expiration [FEV1]/forced vital capacity ratio <0.70) and at least 1 of 5 minor criteria (emphysema or bronchial wall thickening on computed tomography, dyspnea, poor respiratory quality of life, and chronic bronchitis); or (2) minor diagnostic category: presence of least 3 of 5 minor criteria (which must include emphysema and bronchial wall thickening for individuals with respiratory symptoms potentially due to other causes). Main Outcomes and Measures:All-cause mortality, respiratory cause-specific mortality, exacerbations, and annualized change in FEV1. Results:Among 9416 adults in COPDGene (mean [SD] age at enrollment, 59.6 [9.0] years; 5035 [53.5%] were men; 3071 [32.6%] were Black; 6345 (67.4%) were White; 4943 [52.5%] currently smoked), 811 of 5250 individuals (15.4%) without airflow obstruction were newly classified as having COPD by minor diagnostic category, and 282 of 4166 individuals (6.8%) with airflow obstruction were classified as not having COPD. Reclassified individuals with a new COPD diagnosis had greater all-cause mortality (adjusted hazard ratio, 1.98; 95% CI, 1.67-2.35; P < .001) and respiratory-specific mortality (adjusted hazard ratio, 3.58; 95% CI, 1.56-8.20; P = .003), more exacerbations (adjusted incidence rate ratio, 2.09; 95% CI, 1.79-2.44; P < .001), and more rapid FEV1 decline (adjusted β = -7.7 mL/y; 95% CI, -13.2 to -2.3; P = .006) compared with individuals classified as not having COPD. Among individuals with airflow obstruction on spirometry, those no longer classified as having COPD based on this new diagnostic schema had outcomes similar to those without airflow obstruction. Among 1341 adults in CanCOLD, individuals newly classified as having COPD experienced more exacerbations (adjusted incidence rate ratio, 2.09; 95% CI, 1.25-3.51; P < .001). Conclusions and Relevance:A new COPD diagnostic schema integrating respiratory symptoms, respiratory quality of life, spirometry, and structural lung abnormalities on computed tomographic imaging newly classified some individuals as having COPD. These individuals had an increased risk of all-cause and respiratory-related death, frequent exacerbations, and rapid lung function decline compared with individuals classified as not having COPD. Some individuals with airflow obstruction without respiratory symptoms or evidence of structural lung disease were no longer classified as having COPD.

INTRODUCTION: Preventing attacks is a key goal in asthma management. The type-2 inflammatory biomarkers blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO) are established and modifiable risk factors. Given the complexity and multifaceted nature of asthma, we hypothesized that their prognostic value might vary based on interactions with clinical risk factors. METHODS: We analyzed data from the OxfoRd Asthma attaCk risk scaLE (ORACLE2) patient-level meta-analysis, which includes placebo participants from 22 randomized controlled trials (RCTs) investigating the effects of fixed treatment regimens on severe asthma attack rates over a minimum of 24 weeks. Multiple imputation by chained equations was used for missing values in 10 iterations. Multivariable negative binomial models were fit to assess interactions between inflammatory biomarkers (FeNO and BEC) and other key risk factors, such as the Global Initiative for Asthma (GINA) treatment step, Asthma Control Questionnaire (ACQ)-5 score, attack history, and forced expiratory volume in 1 second (FEV1). A Benjamini-Hochberg procedure adjusted for multiplicity of testing (false discovery rate (FDR)<0.05 significant). Spline curves were plotted to visualize significant interactions. As an exploratory analysis, other potential interactions between asthma attacks risk factors and baseline characteristics were evaluated (FDR<0.05). RESULTS: The 6,513 analysed participants experienced 4615 attacks over 5482 person·years. BEC (per 10-fold increase) was found to interact with FEV1 (per 10% decrease) (interaction term: 1.11 [1.03; 1.21], p-value = 0.01). FeNO (per 10-fold increase) negatively interact with a low treatment step (GINA step 1-2 versus GINA step 3-5) (0.28 [0.11; 0.68], p-value = 0.005) and positively interact with a history of severe attacks in the last 12 months (2.42 [1.51; 3.87], p-value = 2×10⁻⁴). The spline curves illustrated the prognostic value of these inflammatory biomarkers according to subgroups based on the identified interactions (Figure A-C). In an exploratory analysis, a strong positive interaction between Immunoglobulin E (IgE) (per 10-fold increase) and a positive history of nasal polyposis was identified (1.58 [1.25; 1.98], p-value = 9×10⁻⁵). The spline curve illustrated the dichotomous prognostic value of IgE on asthma attack risk according to the presence (n=584) or absence (n=3522) of nasal polyposis (Figure D). CONCLUSIONS: This analysis underscores the complex interactions between inflammatory biomarkers and other asthma attack risk factors. The prognostic value of BEC is stronger in those with reduced lung function, while FeNO's prognostic value depends on recent attack history and treatment step. A potential prognostic interaction between IgE and nasal polyposis was also identified. Registration:PROSPERO-CRD42021245337

Over the past 70 years, oral corticosteroids (OCS) have played an important role in the management of acute and chronic asthma; however, their use is associated with an increased incidence of adverse events, chronic diseases such as osteoporosis and diabetes, and mortality, as well as increased healthcare resource utilization and costs. Despite a consensus that the use of OCS should be minimized in asthma treatment strategies, many patients still routinely receive long-term or frequent short courses of OCS. Add-on biologics can help to improve asthma control in patients with severe asthma and evidence of type 2 inflammation; in clinical trials and real-world studies, both short- and long-term OCS-sparing effects have been demonstrated. In this review, we discuss the benefits and burdens of OCS in patients with severe asthma from the perspective of both patients and healthcare providers and outline potential methods for reducing reliance on OCS. Given the risk of adrenal insufficiency or crisis upon cessation of OCS, we discuss the need for clear guidance and algorithms for the tapering of OCS together with the requirement for multidisciplinary patient-provider interactions as part of an effective OCS stewardship scheme.

Frailty is associated with respiratory exacerbations and mortality in individuals with Chronic Obstructive Pulmonary Disease (COPD). Among those with a smoking history and normal spirometry, frailty's association with respiratory outcomes is less defined. COPDGene is a cohort study of individuals aged 45-80 with a minimum 10 pack-year smoking history. A modified Fried Frailty Phenotype was performed at 10-year follow-up; participants were categorized as frail, prefrail, or robust. Primary outcomes were respiratory exacerbations, epigenetic pace of aging, and all-cause mortality. Among 2665 participants, 401 (15%) were frail and 1352 (51%) were prefrail. Adjusting for smoking and lung function, frailty was associated with prospective respiratory exacerbation rate (IRR 3.4, 95% CI 2.4-4.8), severe exacerbations (OR 2.8(1.8-4.2)), and frequent exacerbations (OR 5.5(3.2-9.3)). Prefrailty was also associated with exacerbation outcomes (rate IRR 1.8(1.4-2.3); severe OR 1.6(1.1-2.2); frequent OR 2.6(1.7-4.1)). Frailty and prefrailty were associated with increased all-cause mortality (AHR: frailty 4.5(2.4-8.5); prefrailty 2.5(1.5-4.2)). All frailty (and most prefrailty) findings persisted in those with normal spirometry. Baseline DunedinPACE of aging was associated with prospective frailty at 10-year follow-up. Frailty associated with respiratory exacerbations and mortality; findings persisted among individuals with normal spirometry, highlighting the relevance of evaluating for frailty in people with a history of smoking.

BACKGROUND:Asthma disproportionately affects vulnerable populations. Safety net hospitals (SNHs) manage a significant proportion of these patients. Despite the assumption that patients in SNHs have more severe asthma, little is known about how their outcomes compare to the general population. METHODS:Asthma patients from Harris Health System (HHS), a large SNH system in Texas, were compared to a representative national cohort of patients from Epic Cosmos (EC), a US-wide aggregated electronic health record database. Asthma was defined by ≥ 2 outpatient diagnoses and prescription for asthma medications from 2021 to 2022. Demographics, comorbidities, and asthma outcomes were analyzed. Comparisons between groups were made using standardized mean differences (SMD). Logistic regression was used to standardize exacerbation rates. RESULTS:We identified 2644 HHS and 602,460 EC patients. HHS patients were more likely to identify as Hispanic (55.7 % vs. 7.6 %) and non-White (79.4 % vs. 30.2 %) and had higher rates of obesity and metabolic comorbidities. Despite more intensive asthma medication use and a higher proportion with elevated blood eosinophils and serum IgE, patients with asthma treated within HHS had a similar prevalence of severe asthma exacerbations as compared to EC (28.0 % vs. 27.5 %), which was not statistically different (SMD = 0.01). Direct standardization to EC showed a numerically but not statistically lower rate of exacerbations among patients seen at HHS (24.3 % vs 27.5 %). CONCLUSIONS:Patients treated at a large SNH had comparable asthma outcomes to the general asthma population. These findings emphasize the critical role of resourcing SNHs to improve asthma management and reduce health disparities.

Background:The burden of chronic obstructive pulmonary disease (COPD) is well established, but opportunities for earlier diagnosis and improved management are still missed. Compared to the general COPD population, patients with a history of exacerbations and suboptimal treatment ("modifiable high-risk") are at greater risk of future exacerbations and adverse health outcomes. To date there is no systematic approach for identifying and treating this patient group. Method:Two cluster randomized controlled trials (CRTs) in the United Kingdom and United States will assess the impact of a primary care-based quality improvement program (COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care [CONQUEST]), compared to routine care. In each trial, 126 primary care clusters will be randomized 1:1 to intervention or control arms. Three groups of modifiable high-risk patients will be identified using electronic medical records: undiagnosed with potential COPD, newly diagnosed COPD, and already diagnosed COPD. Eligible patients will be aged ≥40 years, have experienced ≥2 moderate/≥1 severe exacerbation(s) in the prior 24 months, including ≥1 in the last 12 months, and not be prescribed inhaled triple therapy. Patients in the undiagnosed group will also be required to have a positive smoking history. Primary trial outcomes will be the annual rate of exacerbations and the annual rate of major adverse cardiac or respiratory events, comparing the quality improvement program against routine care. Discussion:These will be the first CRTs assessing such a comprehensive primary care-based COPD quality improvement program. Intention-to-treat analysis of trial outcomes after 24 months will inform its effectiveness in targeting the identification, assessment, treatment, and follow-up of patients with modifiable high-risk COPD. Trial registration:UK trial: ISRCTN15819828; US trial: NCT05306743.

BACKGROUND:Quality improvement programmes (QIPs) are designed to enhance patient outcomes by systematically introducing evidence-based clinical practices. The CONQUEST QIP focuses on improving the identification and management of patients with COPD in primary care. The process of developing CONQUEST, recruiting, preparing systems for participation, and implementing the QIP across three integrated healthcare systems (IHSs) is examined to identify and share lessons learned. APPROACH AND DEVELOPMENT:This review is organized into three stages: 1) development, 2) preparing IHSs for implementation, and 3) implementation. In each stage, key steps are described with the lessons learned and how they can inform others interested in developing QIPs designed to improve the care of patients with chronic conditions in primary care.Stage 1 was establishing and working with steering committees to develop the QIP Quality Standards, define the target patient population, assess current management practices, and create a global operational protocol. Additionally, potential IHSs were assessed for feasibility of QIP integration into primary care practices. Factors assessed included a review of technological infrastructure, QI experience, and capacity for effective implementation.Stage 2 was preparation for implementation. Key was enlisting clinical champions to advocate for the QIP, secure participation in primary care, and establish effective communication channels. Preparation for implementation required obtaining IHS approvals, ensuring Health Insurance Portability and Accountability Act compliance, and devising operational strategies for patient outreach and clinical decision support delivery.Stage 3 was developing three IHS implementation models. With insight into the local context from local clinicians, implementation models were adapted to work with the resources and capacity of the IHSs while ensuring the delivery of essential elements of the programme. CONCLUSION:Developing and launching a QIP programme across primary care practices requires extensive groundwork, preparation, and committed local champions to assist in building an adaptable environment that encourages open communication and is receptive to feedback.

BACKGROUND:The body mass index, airflow obstruction, dyspnea, and exercise capacity (BODE) index predicts 5-year mortality risk in chronic obstructive pulmonary disease (COPD); higher scores predict worse outcomes. Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4/13, reduced exacerbations and improved lung function in patients with COPD in the phase 3 BOREAS trial (NCT03930732). We assessed dupilumab efficacy in patients with COPD and type 2 inflammation by baseline BODE index. METHODS:Patients with COPD, moderate-to-severe airflow limitation, screening blood eosinophils ≥300 cells/μL, and high exacerbation risk, on triple therapy, received 300 mg add-on dupilumab or placebo every 2 weeks for 52 weeks. Annualized moderate or severe COPD exacerbation rate and change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV1) at Weeks 12 and 52 were assessed by baseline BODE index, categorized as low (≤4) or high (>4). RESULTS:Of 934 patients with reported baseline BODE index scores (dupilumab: 470; placebo: 464), 61.8 % had scores ≤4. Dupilumab reduced exacerbations versus placebo, regardless of baseline BODE index group. Exacerbation reductions were similar by BODE index group; relative risk (95 % confidence interval) for patients with BODE index >4 versus ≤4 was 0.656 (0.496-0.868) versus 0.718 (0.547-0.944). At Weeks 12 and 52, dupilumab consistently improved pre-bronchodilator FEV1 versus placebo, regardless of baseline BODE index group. CONCLUSION:Dupilumab reduced exacerbations and improved lung function in patients with COPD and type 2 inflammation irrespective of baseline BODE index score. CLINICAL TRIAL REGISTRATION NUMBER:BOREAS trial NCT03930732.

Asthma is a chronic airway inflammatory disorder, affecting over 350 million people worldwide, with allergic asthma being the most common form of the disease. Allergic asthma is characterized by a type 2 (T2) inflammatory response triggered by numerous allergens beginning in the airway epithelium, which acts as a physical barrier to allergens as well as other external irritants including infectious agents, and atmospheric pollutants. T2 inflammation is propagated by several key cell types including T helper 2 (Th2) cells, eosinophils, mast cells, and B cells. Immunoglobulin E (IgE), produced by B cells, is a key molecule in allergic airway disease and plays an important role in T2 inflammation, as well as being central to remodeling processes within the airway epithelium. Blocking IgE with omalizumab has been shown to be efficacious in treating allergic asthma however, the role of IgE on airway epithelial cells is less communicated. Developing a deeper explanation of the complex network of interactions between IgE and the airway epithelium will facilitate an improved understanding of asthma pathophysiology. This review discusses the indirect and direct roles of IgE on airway epithelial cells, with a focus on allergic asthma disease.