Reliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma.

BACKGROUND: Black and Latinx patients bear a disproportionate burden of asthma. Efforts to reduce the disproportionate morbidity have been mostly unsuccessful, and guideline recommendations have not been based on studies in these populations. METHODS: In this pragmatic, open-label trial, we randomly assigned Black and Latinx adults with moderate-to-severe asthma to use a patient-activated, reliever-triggered inhaled glucocorticoid strategy (beclomethasone dipropionate, 80 µg) plus usual care (intervention) or to continue usual care. Participants had one instructional visit followed by 15 monthly questionnaires. The primary end point was the annualized rate of severe asthma exacerbations. Secondary end points included monthly asthma control as measured with the Asthma Control Test (ACT; range, 5 [poor] to 25 [complete control]), quality of life as measured with the Asthma Symptom Utility Index (ASUI; range, 0 to 1, with lower scores indicating greater impairment), and participant-reported missed days of work, school, or usual activities. Safety was also assessed. RESULTS: Of 1201 adults (603 Black and 598 Latinx), 600 were assigned to the intervention group and 601 to the usual-care group. The annualized rate of severe asthma exacerbations was 0.69 (95% confidence interval [CI], 0.61 to 0.78) in the intervention group and 0.82 (95% CI, 0.73 to 0.92) in the usual-care group (hazard ratio, 0.85; 95% CI, 0.72 to 0.999; P = 0.048). ACT scores increased by 3.4 points (95% CI, 3.1 to 3.6) in the intervention group and by 2.5 points (95% CI, 2.3 to 2.8) in the usual-care group (difference, 0.9; 95% CI, 0.5 to 1.2); ASUI scores increased by 0.12 points (95% CI, 0.11 to 0.13) and 0.08 points (95% CI, 0.07 to 0.09), respectively (difference, 0.04; 95% CI, 0.02 to 0.05). The annualized rate of missed days was 13.4 in the intervention group and 16.8 in the usual-care group (rate ratio, 0.80; 95% CI, 0.67 to 0.95). Serious adverse events occurred in 12.2% of the participants, with an even distribution between the groups. CONCLUSIONS: Among Black and Latinx adults with moderate-to-severe asthma, provision of an inhaled glucocorticoid and one-time instruction on its use, added to usual care, led to a lower rate of severe asthma exacerbations. (Funded by the Patient-Centered Outcomes Research Institute and others; PREPARE ClinicalTrials.gov number, NCT02995733.).

Activated sputum eosinophils associated with exacerbations in children on mepolizumab.

BACKGROUND: MUPPITS-2 was a randomized, placebo-controlled clinical trial that demonstrated mepolizumab (anti-IL-5) reduced exacerbations and blood and airway eosinophils in urban children with severe eosinophilic asthma. Despite this reduction in eosinophilia, exacerbation risk persisted in certain patients treated with mepolizumab. This raises the possibility that subpopulations of airway eosinophils exist that contribute to breakthrough exacerbations. OBJECTIVE: We aimed to determine the effect of mepolizumab on airway eosinophils in childhood asthma. METHODS: Sputum samples were obtained from 53 MUPPITS-2 participants. Airway eosinophils were characterized using mass cytometry and grouped into subpopulations using unsupervised clustering analyses of 38 surface and intracellular markers. Differences in frequency and immunophenotype of sputum eosinophil subpopulations were assessed based on treatment arm and frequency of exacerbations. RESULTS: Median sputum eosinophils were significantly lower among participants treated with mepolizumab compared with placebo (58% lower, 0.35% difference [95% CI 0.01, 0.74], P = .04). Clustering analysis identified 3 subpopulations of sputum eosinophils with varied expression of CD62L. CD62Lint and CD62Lhi eosinophils exhibited significantly elevated activation marker and eosinophil peroxidase expression, respectively. In mepolizumab-treated participants, CD62Lint and CD62Lhi eosinophils were more abundant in participants who experienced exacerbations than in those who did not (100% higher for CD62Lint, 0.04% difference [95% CI 0.0, 0.13], P = .04; 93% higher for CD62Lhi, 0.21% difference [95% CI 0.0, 0.77], P = .04). CONCLUSIONS: Children with eosinophilic asthma treated with mepolizumab had significantly lower sputum eosinophils. However, CD62Lint and CD62Lhi eosinophils were significantly elevated in children on mepolizumab who had exacerbations, suggesting that eosinophil subpopulations exist that contribute to exacerbations despite anti-IL-5 treatment.

Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell-derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire-6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]). RESULTS: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P<0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P<0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV1 (0.23 vs. 0.09 liters; difference, 0.13 liters; 95% CI, 0.08 to 0.18; P<0.001) and scores on the ACQ-6 (-1.55 vs. -1.22; difference, -0.33; 95% CI, -0.46 to -0.20; P<0.001), AQLQ (1.49 vs. 1.15; difference, 0.34; 95% CI, 0.20 to 0.47; P<0.001), and ASD (-0.71 vs. -0.59; difference, -0.12; 95% CI, -0.19 to -0.04; P = 0.002). The frequencies and types of adverse events did not differ meaningfully between the two groups. CONCLUSIONS: Patients with severe, uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo. (Funded by AstraZeneca and Amgen; NAVIGATOR ClinicalTrials.gov number, NCT03347279.).

Asthma control in the United States: relationships between short-acting ß2-agonist and systemic corticosteroid use.

BACKGROUND: Asthma control assessment is based on impairment (current symptoms) and risk (exacerbation history). OBJECTIVE: To understand the extent of uncontrolled asthma, we assessed relationships between prescription fills for systemic corticosteroids (SCS) and short-acting ß2-agonists (SABA) as risk and impairment markers, respectively. METHODS: Annual SCS and SABA fills among US patients with asthma were evaluated by a retrospective analysis of IQVIA Longitudinal Access and Adjudication Data. Patient severity was assigned based on GINA step-therapy level. Exacerbations were evaluated by SCS fills within 12 months of a first asthma prescription fill. Uncontrolled asthma was defined as ≥2 SCS and/or ≥3 SABA fills annually. Individual patient relationships between SCS and SABA fills were assessed by Pearson's correlation coefficient. RESULTS: 4,506,527 patients were included: 15% had ≥2 SCS fills, 29% had ≥3 SABA fills, 37% fulfilled either or both criteria. If only SCS were assessed, 22% treated as mild-to-moderate and 27% as severe asthma would have been misclassified as controlled. If only SABA use was evaluated, 8% treated as mild-to-moderate and 11% as severe asthma would have been misclassified. Overall, 81% of uncontrolled asthma occurred in patients treated for mild-to-moderate disease. Among patients with ≥2 SCS fills, mean SABA fills were 2.9; the correlation between SCS and SABA fills per patient was significant but weak (r=0.18; p<0.001). CONCLUSION: High symptom burden and SCS exposures are not limited to severe asthma but are also characteristic in patients treated for mild-to-moderate disease. Both impairment and risk assessments are required to understand the full extent of uncontrolled asthma across disease severities.

Adoption and Implementation of Maintenance and Reliever Therapy for Adults with Moderate to Severe Asthma.

BACKGROUND: The use of single combination inhaled corticosteroid (ICS) and long-acting bronchodilator for maintenance and relief (MART) significantly reduces asthma exacerbations and has been incorporated into asthma guidelines since December 2020, but there is limited data regarding the implementation of this approach to asthma management. OBJECTIVE: Determine how often MART was prescribed to patients with moderate to severe asthma being seen at subspecialty pulmonary and allergy practices at an academic health care system, and the patient and clinician characteristics associated with the use of MART. METHODS: We conducted a retrospective cross-sectional study of the EMR of an academic health care system in the Northeastern US between January 2021 and October 2023. Patient demographic and clinician data was collected, and MART recommendation was confirmed by chart review. We assessed the relationships between patient demographics, clinician characteristics, and MART recommendation. RESULTS: Of 2,016 patients reviewed, 293 (14.5%) were recommended MART, with 255 (87%) concurrently prescribed short acting bronchodilators. Patients on ICS/formoterol at baseline were significantly more likely to be recommended MART, while older patients and those on Medicare were significantly less likely to be recommended MART. Twenty-two (44%) of 50 clinicians did not recommend MART ever and only three clinicians recommended MART to 30-60% of their patients. Clinicians who were part of the asthma group and those with less than 16 years in practice were significantly more likely to recommend MART. CONCLUSION: Among academic subspecialty clinicians, there has been limited implementation of MART, with a small number of clinicians adopting MART routinely and over 40% of clinicians not recommending it.

Efficacy of Tezepelumab in Severe, Uncontrolled Asthma: Pooled Analysis of the PATHWAY and NAVIGATOR Clinical Trials.

Rationale: Tezepelumab reduced exacerbations in patients with severe, uncontrolled asthma across a range of baseline blood eosinophil counts and fractional exhaled nitric oxide levels, and irrespective of allergy status, in the phase 2b PATHWAY (Study to Evaluate the Efficacy and Safety of MEDI9929 [AMG 157] in Adult Subjects With Inadequately Controlled, Severe Asthma; NCT02054130) and phase 3 NAVIGATOR (Study to Evaluate Tezepelumab in Adults & Adolescents With Severe Uncontrolled Asthma; NCT03347279) trials. Objectives: To examine the efficacy and safety of tezepelumab in additional clinically relevant subgroups using pooled data from PATHWAY and NAVIGATOR. Methods: PATHWAY and NAVIGATOR were randomized, double-blind, placebo-controlled trials with similar designs. This pooled analysis included patients with severe, uncontrolled asthma (PATHWAY, 18-75 years old; NAVIGATOR, 12-80 years old) who received tezepelumab 210 mg or placebo subcutaneously every 4 weeks for 52 weeks. The annualized asthma exacerbation rate over 52 weeks and secondary outcomes were calculated in the overall population and in subgroups defined by inflammatory biomarker levels or clinical characteristics. Measurements and Main Results: Overall, 1,334 patients were included (tezepelumab, n = 665; placebo, n = 669). Tezepelumab reduced the annualized asthma exacerbation rate versus placebo by 60% (rate ratio, 0.40 [95% confidence interval, 0.34-0.48]) in the overall population, and clinically meaningful reductions in exacerbations were observed in tezepelumab-treated patients with type 2-high and type 2-low disease by multiple definitions. Tezepelumab reduced exacerbation-related hospitalization or emergency department visits and improved secondary outcomes compared with placebo overall and across subgroups. The incidence of adverse events was similar between treatment groups. Conclusions: Tezepelumab resulted in clinically meaningful reductions in exacerbations and improvements in other outcomes in patients with severe, uncontrolled asthma, across clinically relevant subgroups. Clinical trials registered with www.clinicaltrials.gov (NCT02054130 [PATHWAY], NCT03347279 [NAVIGATOR]).

iDESC: identifying differential expression in single-cell RNA sequencing data with multiple subjects.

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) technology has enabled assessment of transcriptome-wide changes at single-cell resolution. Due to the heterogeneity in environmental exposure and genetic background across subjects, subject effect contributes to the major source of variation in scRNA-seq data with multiple subjects, which severely confounds cell type specific differential expression (DE) analysis. Moreover, dropout events are prevalent in scRNA-seq data, leading to excessive number of zeroes in the data, which further aggravates the challenge in DE analysis. RESULTS: We developed iDESC to detect cell type specific DE genes between two groups of subjects in scRNA-seq data. iDESC uses a zero-inflated negative binomial mixed model to consider both subject effect and dropouts. The prevalence of dropout events (dropout rate) was demonstrated to be dependent on gene expression level, which is modeled by pooling information across genes. Subject effect is modeled as a random effect in the log-mean of the negative binomial component. We evaluated and compared the performance of iDESC with eleven existing DE analysis methods. Using simulated data, we demonstrated that iDESC had well-controlled type I error and higher power compared to the existing methods. Applications of those methods with well-controlled type I error to three real scRNA-seq datasets from the same tissue and disease showed that the results of iDESC achieved the best consistency between datasets and the best disease relevance. CONCLUSIONS: iDESC was able to achieve more accurate and robust DE analysis results by separating subject effect from disease effect with consideration of dropouts to identify DE genes, suggesting the importance of considering subject effect and dropouts in the DE analysis of scRNA-seq data with multiple subjects.

Dupilumab improves long-term outcomes in patients with uncontrolled, moderate-to-severe GINA-based type 2 asthma, irrespective of allergic status.

BACKGROUND: Previous research has shown greater efficacy of dupilumab in patients with uncontrolled asthma and type 2 inflammation. We analyzed dupilumab's efficacy in patients from the TRAVERSE study with or without evidence of allergic asthma and type 2 inflammation per current GINA guidelines (≥150 eosinophils/µL or FeNO ≥20 ppb). METHODS: All patients aged ≥12 years who rolled over from the placebo-controlled QUEST study (NCT02414854) to TRAVERSE (NCT02134028) received add-on dupilumab 300 mg every 2 weeks for up to 96 weeks. We assessed annualized severe asthma exacerbation rates (AERs) and changes from parent-study baseline (PSBL) in pre-bronchodilator FEV1 and 5-item asthma control questionnaire (ACQ-5) score in patients with moderate-to-severe type 2 asthma with and without evidence of allergic asthma at PSBL. RESULTS: In TRAVERSE, dupilumab consistently reduced AER across all subgroups. By Week 96, dupilumab increased pre-bronchodilator FEV1 from PSBL by 0.35-0.41 L in patients receiving placebo during QUEST (placebo/dupilumab) and 0.34-0.44 L in those receiving dupilumab during QUEST (dupilumab/dupilumab) with an allergic phenotype at baseline. In patients without evidence of allergic asthma, pre-bronchodilator FEV1 improved by 0.38-0.41 L and 0.33-0.37 L, respectively. By Week 48, ACQ-5 scores decreased from PSBL by 1.63-1.69 (placebo/dupilumab) and 1.74-1.81 (dupilumab/dupilumab) points across subgroups with allergic asthma, and 1.75-1.83 (placebo/dupilumab) and 1.78-1.86 (dupilumab/dupilumab) in those without. CONCLUSIONS: Long-term treatment with dupilumab reduced exacerbation rates and improved lung function and asthma control in patients with asthma with type 2 inflammation as per current GINA guidance and irrespective of evidence of allergic asthma.

Effect of tezepelumab on healthcare utilization in patients with severe, uncontrolled asthma: The NAVIGATOR study.

BACKGROUND: Tezepelumab, a human monoclonal antibody, blocks thymic stromal lymphopoietin. In the phase 3 NAVIGATOR study, tezepelumab reduced exacerbations and improved lung function, asthma control, and health-related quality of life compared with placebo in patients with severe, uncontrolled asthma. However, little is known about the impact of tezepelumab on healthcare utilization (HCU) in these patients. OBJECTIVE: To evaluate to what extent tezepelumab reduces patients' HCU. METHODS: In NAVIGATOR, patients were randomized to receive subcutaneous tezepelumab 210 mg or placebo, every 4 weeks for 52 weeks. For this analysis, the main outcomes of interest were asthma-related HCU. A blinded, systematic analysis of the symptoms and HCU recorded in the investigator-reported narratives describing exacerbation-related hospitalizations was also conducted; the narratives included blinded ratings of event intensity, recorded as mild, moderate, or severe. RESULTS: Recipients of tezepelumab (n = 528) required fewer asthma-related unscheduled specialist visits (tezepelumab, 285 events; placebo, 406 events), telephone calls with a healthcare provider (tezepelumab, 234; placebo, 599), ambulance transports (tezepelumab, 5; placebo, 22), emergency department visits (without subsequent hospitalization; tezepelumab, 16; placebo, 37), hospitalizations (tezepelumab, 14; placebo, 78), and intensive care days (tezepelumab, 0; placebo, 31) than did recipients of placebo (n = 531). Among patients with asthma exacerbation-related hospitalizations, 38% of those hospitalized and receiving tezepelumab (5/13) had an event rated as severe, compared with 82% of those hospitalized and receiving placebo (32/39). CONCLUSION: Tezepelumab substantially reduced HCU across all outcomes measured compared with placebo, in addition to the severity of asthma exacerbations requiring hospitalization. Tezepelumab can reduce the overall burden of disease of severe, uncontrolled asthma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home), identifier: NCT03347279.

Inhibition of ABCC1 Decreases cAMP Egress and Promotes Human Airway Smooth Muscle Cell Relaxation.

In most living cells, the second-messenger roles for adenosine 3',5'-cyclic monophosphate (cAMP) are short-lived, confined to the intracellular space, and tightly controlled by the binary switch-like actions of Gαs (stimulatory G protein)-activated adenylyl cyclase (cAMP production) and cAMP-specific PDE (cAMP breakdown). Here, by using human airway smooth muscle (HASM) cells in culture as a model, we report that activation of the cell-surface ß2AR (ß2-adrenoceptor), a Gs-coupled GPCR (G protein-coupled receptor), evokes cAMP egress to the extracellular space. Increased extracellular cAMP levels ([cAMP]e) are long-lived in culture and are induced by receptor-dependent and receptor-independent mechanisms in such a way as to define a universal response class of increased intracellular cAMP levels ([cAMP]i). We find that HASM cells express multiple ATP-binding cassette (ABC) membrane transporters, with ABCC1 (ABC subfamily member C 1) being the most highly enriched transcript mapped to MRPs (multidrug resistance-associated proteins). We show that pharmacological inhibition or downregulation of ABCC1 with siRNA markedly reduces ß2AR-evoked cAMP release from HASM cells. Furthermore, inhibition of ABCC1 activity or expression decreases basal tone and increases ß-agonist-induced HASM cellular relaxation. These findings identify a previously unrecognized role for ABCC1 in the homeostatic regulation of [cAMP]i in HASM that may be conserved traits of the Gs-GPCRs (Gs-coupled family of GPCRs). Hence, the general features of this activation mechanism may uncover new disease-modifying targets in the treatment of airflow obstruction in asthma. Surprisingly, we find that serum cAMP levels are elevated in a small cohort of patients with asthma as compared with control subjects, which warrants further investigation.

New Therapies for Emerging Endotypes of Asthma.

The presentation, pathobiology, and prognosis of asthma are highly heterogeneous and challenging for clinicians to diagnose and treat. In addition to the adaptive immune response that underlies allergic inflammation, innate immune mechanisms are increasingly recognized to be critical mediators of the eosinophilic airway inflammation present in most patients with asthma. Efforts to classify patients by severity and immune response have identified a number of different clinical and immune phenotypes, indicating that the innate and adaptive immune responses are differentially active among patients with the disease. Advances in the detection of these subgroups using clinical characteristics and biomarkers have led to the successful development of targeted biologics. This has moved us to a more personalized approach to managing asthma. Here we review the emerging endotypes of asthma and the biologics that have been developed to treat them.

Lung function, airway and peripheral basophils and eosinophils are associated with molecular pharmacogenomic endotypes of steroid response in severe asthma.

INTRODUCTION: Asthma is a complex disease with heterogeneous expression/severity. There is growing interest in defining asthma endotypes consistently associated with different responses to therapy, focusing on type 2 inflammation (Th2) as a key pathological mechanism. Current asthma endotypes are defined primarily by clinical/laboratory criteria. Each endotype is likely characterised by distinct molecular mechanisms that identify optimal therapies. METHODS: We applied unsupervised (without a priori clinical criteria) principal component analysis on sputum airway cells RNA-sequencing transcriptomic data from 19 asthmatics from the Severe Asthma Research Program at baseline and 6-8 weeks follow-up after a 40 mg dose of intramuscular corticosteroids. We investigated principal components PC1, PC3 for association with 55 clinical variables. RESULTS: PC3 was associated with baseline Th2 clinical features including blood (rank-sum p=0.0082) and airway (rank-sum p=0.0024) eosinophilia, FEV1 change (Kendall tau-b R=-0.333 (-0.592 to -0.012)) and follow-up FEV1 albuterol response (Kendall tau-b R=0.392 (0.079 to 0.634)). PC1 with blood basophlia (rank-sum p=0.0191). The top 5% genes contributing to PC1, PC3 were enriched for distinct immune system/inflammation ontologies suggesting distinct subject-specific clusters of transcriptomic response to corticosteroids. PC3 association with FEV1 change was reproduced in silico in a comparable independent 14-subject (baseline, 8 weeks after daily inhaled corticosteroids (ICS)) airway epithelial cells microRNAome dataset. CONCLUSIONS: Transcriptomic PCs from this unsupervised methodology define molecular pharmacogenomic endotypes that may yield novel biology underlying different subject-specific responses to corticosteroid therapy in asthma, and optimal personalised asthma care. Top contributing genes to these PCs may suggest new therapeutic targets.

Mapping geographic variability of severe uncontrolled asthma in the United States: Management implications.

BACKGROUND: The US population-level data on asthma morbidity and mortality are available primarily through state-level surveys. We hypothesize that considerable county-level heterogeneity may be obscured by state-level data, thus impeding focused initiatives to improve asthma outcomes. OBJECTIVE: To assess heterogeneity in the prevalence of uncontrolled, severe, and severe uncontrolled asthma by evaluating state- and county-level morbidity reflected in large administrative claims data sets and identify relationships between pharmacotherapy-based morbidity and the Centers for Disease Control and Prevention's asthma mortality data. METHODS: Asthma prevalence and morbidity were identified using medical and pharmacy claims from the IQVIA Longitudinal Access and Adjudication Data database (July 2015-June 2018). Heat maps ranked the prevalence of severe uncontrolled asthma by deciles in all 50 states and the District of Columbia, plus 2935 counties. Mortality in states (2016) and 3147 counties (1999-2018) was similarly mapped and ranked and contrasted with claims-based morbidity. RESULTS: Among 4,506,527 individuals with asthma, 640,936 (14.2%) received age-specific therapy for severe asthma. Of those with severe asthma, 144,232 (22.5%) filled 2 or more annual courses of systemic steroids and were designated as having severe uncontrolled asthma. Most states with high mortality had relatively few patients with severe uncontrolled asthma. A marked correlation between mortality and morbidity and trends by urban vs rural and metropolitan status were found at the county level. CONCLUSION: Intrastate heterogeneity in the morbidity and mortality of severe uncontrolled asthma at the county level is not evident in state-level analyses. Increased local awareness of systemic corticosteroid use as an indicator of uncontrolled asthma should prompt regional educational and public health efforts to improve outcomes.

Evaluating enrollment and outcome criteria in trials of biologics for chronic rhinosinusitis with nasal polyps.

OBJECTIVE: Treatment for chronic rhinosinusitis with nasal polyps (CRSwNP) generally involves intranasal corticosteroids (INCS) and saline irrigation, followed by short courses of systemic corticosteroids (SCS) or surgery with postoperative medical therapy for patients who do not respond to INCS. However, both SCS use and surgery are associated with a range of adverse effects or complications, have a high recurrence rate, and are unsuitable for some patients. Biologics targeting the underlying pathophysiology are promising treatment alternatives for these patients. Dupilumab, omalizumab, and mepolizumab are approved for use in patients with severe, uncontrolled CRSwNP. However, the lack of a consistent definition of severe CRSwNP makes the decision to initiate biologic treatment particularly complex. Furthermore, the position of each biologic in the overall management of CRSwNP remains to be clarified. DATA SOURCES: Publications reporting results of phase III trials of dupilumab, omalizumab, mepolizumab, and benralizumab in the treatment of CRSwNP. STUDY SELECTIONS: Randomized, controlled phase III trials of biologics approved for CRSwNP. RESULTS: These trials all used different enrollment criteria. We discuss the complexities of assessing CRSwNP disease severity and highlight how these impact comparisons of the populations and outcomes of the phase III biologic trials. CONCLUSION: To position biologic agents appropriately within the existing CRSwNP treatment paradigm, future trials will need to include comparable patient populations and standardized outcome measures. Such trials will help to ensure that biologic treatment is targeted appropriately to support optimal clinical outcomes.

Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: A randomized clinical trial.

BACKGROUND: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. OBJECTIVES: This study evaluated astegolimab efficacy and safety in patients with severe asthma. METHODS: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured ∼30 patients who were eosinophil-high (≥300 cells/µL) and ∼95 patients who were eosinophil-low (<300 cells/µL) per arm. RESULTS: Overall, adjusted AER reductions relative to placebo were 43% (P = .005), 22% (P = .18), and 37% (P = .01) for 490-mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P = .002), 14% (P = .48), and 35% (P = .05) for 490-mg, 210-mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab- and placebo-treated groups. CONCLUSIONS: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.

SPLUNC1: a novel marker of cystic fibrosis exacerbations.

BACKGROUND: Acute pulmonary exacerbations (AE) are episodes of clinical worsening in cystic fibrosis (CF), often precipitated by infection. Timely detection is critical to minimise morbidity and lung function declines associated with acute inflammation during AE. Based on our previous observations that airway protein short palate lung nasal epithelium clone 1 (SPLUNC1) is regulated by inflammatory signals, we investigated the use of SPLUNC1 fluctuations to diagnose and predict AE in CF. METHODS: We enrolled CF participants from two independent cohorts to measure AE markers of inflammation in sputum and recorded clinical outcomes for a 1-year follow-up period. RESULTS: SPLUNC1 levels were high in healthy controls (n=9, 10.7 µg·mL-1), and significantly decreased in CF participants without AE (n=30, 5.7 µg·mL-1; p=0.016). SPLUNC1 levels were 71.9% lower during AE (n=14, 1.6 µg·mL-1; p=0.0034) regardless of age, sex, CF-causing mutation or microbiology findings. Cytokines interleukin-1ß and tumour necrosis factor-α were also increased in AE, whereas lung function did not decrease consistently. Stable CF participants with lower SPLUNC1 levels were much more likely to have an AE at 60 days (hazard ratio (HR)±se 11.49±0.83; p=0.0033). Low-SPLUNC1 stable participants remained at higher AE risk even 1 year after sputum collection (HR±se 3.21±0.47; p=0.0125). SPLUNC1 was downregulated by inflammatory cytokines and proteases increased in sputum during AE. CONCLUSION: In acute CF care, low SPLUNC1 levels could support a decision to increase airway clearance or to initiate pharmacological interventions. In asymptomatic, stable patients, low SPLUNC1 levels could inform changes in clinical management to improve long-term disease control and clinical outcomes in CF.

Mepolizumab improves clinical outcomes in patients with severe asthma and comorbid conditions.

BACKGROUND: Comorbidities can complicate the management of severe asthma; therefore, the presence of comorbid conditions or traits often need to be considered when considering treatment options for patients with severe asthma. The aim of this analysis is to investigate the efficacy of mepolizumab in patients with severe eosinophilic asthma and comorbidities. METHODS: This was a post hoc analysis (GSK ID:209140) of data from the Phase IIb/III studies DREAM, MENSA, SIRIUS, and MUSCA. Patients aged ≥ 12 years with severe eosinophilic asthma were randomized to: mepolizumab 750, 250, or 75 mg intravenously or placebo (DREAM); mepolizumab 75 mg intravenously or 100 mg subcutaneously or placebo (MENSA); or mepolizumab 100 mg subcutaneously or placebo (SIRIUS and MUSCA) every 4 weeks for 24 weeks in SIRIUS and MUSCA, 32 weeks in MENSA or 52 weeks in DREAM. In this analysis the primary endpoint was the annual rate of clinically significant exacerbations; secondary endpoints were Asthma Control Questionnaire-5 score, St George's Respiratory Questionnaire total score, and pre-bronchodilator forced expiratory volume in 1 s at study end. Subgroups were based on comorbidities at baseline. RESULTS: Overall, 1878 patients received placebo (n = 689) or mepolizumab (n = 1189). Across all comorbidity subgroups mepolizumab reduced the rate of clinically significant exacerbations by 44-68% versus placebo, improved Asthma Control Questionnaire-5 score by 0.27-0.59 points, and improved St George's Respiratory Questionnaire total score by 5.0-11.6 points. Pre-bronchodilator forced expiratory volume in 1 s was improved by 27.1-286.9 mL in all but one comorbidity subgroup, the diabetes mellitus subgroup. CONCLUSIONS: Mepolizumab reduces exacerbations, and improves asthma control, health-related quality of life, and lung function in patients with severe eosinophilic asthma despite comorbid conditions, including upper respiratory conditions, psychopathologies, cardiovascular conditions, gastroesophageal reflux disease, diabetes mellitus, and obesity. TRIAL REGISTRATION: https://clinicaltrials.gov/ DREAM, MEA112997/NCT01000506; MENSA, MEA115588/NCT01691521; SIRIUS, MEA115575/NCT01842607; MUSCA, 200862/NCT02281318.

Single-cell characterization of a model of poly I:C-stimulated peripheral blood mononuclear cells in severe asthma.

BACKGROUND: Asthma has been associated with impaired interferon response. Multiple cell types have been implicated in such response impairment and may be responsible for asthma immunopathology. However, existing models to study the immune response in asthma are limited by bulk profiling of cells. Our objective was to Characterize a model of peripheral blood mononuclear cells (PBMCs) of patients with severe asthma (SA) and its response to the TLR3 agonist Poly I:C using two single-cell methods. METHODS: Two complementary single-cell methods, DropSeq for single-cell RNA sequencing (scRNA-Seq) and mass cytometry (CyTOF), were used to profile PBMCs of SA patients and healthy controls (HC). Poly I:C-stimulated and unstimulated cells were analyzed in this study. RESULTS: PBMCs (n = 9414) from five SA (n = 6099) and three HC (n = 3315) were profiled using scRNA-Seq. Six main cell subsets, namely CD4 + T cells, CD8 + T cells, natural killer (NK) cells, B cells, dendritic cells (DCs), and monocytes, were identified. CD4 + T cells were the main cell type in SA and demonstrated a pro-inflammatory profile characterized by increased JAK1 expression. Following Poly I:C stimulation, PBMCs from SA had a robust induction of interferon pathways compared with HC. CyTOF profiling of Poly I:C stimulated and unstimulated PBMCs (n = 160,000) from the same individuals (SA = 5; HC = 3) demonstrated higher CD8 + and CD8 + effector T cells in SA at baseline, followed by a decrease of CD8 + effector T cells after poly I:C stimulation. CONCLUSIONS: Single-cell profiling of an in vitro model using PBMCs in patients with SA identified activation of pro-inflammatory pathways at baseline and strong response to Poly I:C, as well as quantitative changes in CD8 + effector cells. Thus, transcriptomic and cell quantitative changes are associated with immune cell heterogeneity in this model to evaluate interferon responses in severe asthma.

A Network of Sputum MicroRNAs Is Associated with Neutrophilic Airway Inflammation in Asthma.

Rationale: MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA-mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published.Objectives: Identify microRNA and mRNA networks in the sputum of patients with asthma.Methods: We conducted a genome-wide analysis of microRNA and mRNA in the sputum from patients with asthma and correlated expression with clinical phenotypes. Weighted gene correlation network analysis was implemented to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway.Measurements and Main Results: Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. Multiple microRNAs in the nely module correlated with two mRNA modules enriched for TLR (Toll-like receptor) and T-helper cell type 17 (Th17) signaling and endoplasmic reticulum stress. hsa-miR-223-3p was a key regulator of the TLR and Th17 pathways in the sputum of subjects with asthma.Conclusions: This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.

Single-Cell Transcriptional Archetypes of Airway Inflammation in Cystic Fibrosis.

Rationale: Cystic fibrosis (CF) is a life-shortening, multisystem hereditary disease caused by abnormal chloride transport. CF lung disease is driven by innate immune dysfunction and exaggerated inflammatory responses that contribute to tissue injury. To define the transcriptional profile of this airway immune dysfunction, we performed the first single-cell transcriptome characterization of CF sputum.Objectives: To define the transcriptional profile of sputum cells and its implication in the pathogenesis of immune function and the development of CF lung disease.Methods: We performed single-cell RNA sequencing of sputum cells from nine subjects with CF and five healthy control subjects. We applied novel computational approaches to define expression-based cell function and maturity profiles, herein called transcriptional archetypes.Measurements and Main Results: The airway immune cell repertoire shifted from alveolar macrophages in healthy control subjects to a predominance of recruited monocytes and neutrophils in CF. Recruited lung mononuclear phagocytes were abundant in CF and were separated into the following three archetypes: activated monocytes, monocyte-derived macrophages, and heat shock-activated monocytes. Neutrophils were the most prevalent in CF, with a dominant immature proinflammatory archetype. Although CF monocytes exhibited proinflammatory features, both monocytes and neutrophils showed transcriptional evidence of abnormal phagocytic and cell-survival programs.Conclusions: Our findings offer an opportunity to understand subject-specific immune dysfunction and its contribution to divergent clinical courses in CF. As we progress toward personalized applications of therapeutic and genomic developments, we hope this inflammation-profiling approach will enable further discoveries that change the natural history of CF lung disease.