Regenerative Metaplastic Clones in COPD Lung Drive Inflammation and Fibrosis.

Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema that represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers.

Benralizumab versus Mepolizumab for Eosinophilic Granulomatosis with Polyangiitis.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by eosinophilic inflammation. Benralizumab, a monoclonal antibody against the interleukin-5α receptor expressed on eosinophils, may be an option for treating EGPA. METHODS: We conducted a multicenter, double-blind, phase 3, randomized, active-controlled noninferiority trial to evaluate the efficacy and safety of benralizumab as compared with mepolizumab. Adults with relapsing or refractory EGPA who were receiving standard care were randomly assigned in a 1:1 ratio to receive benralizumab (30 mg) or mepolizumab (300 mg) subcutaneously every 4 weeks for 52 weeks. The primary end point was remission at weeks 36 and 48 (prespecified noninferiority margin, -25 percentage points). Secondary end points included the accrued duration of remission, time to first relapse, oral glucocorticoid use, eosinophil count, and safety. RESULTS: A total of 140 patients underwent randomization (70 assigned to each group). The adjusted percentage of patients with remission at weeks 36 and 48 was 59% in the benralizumab group and 56% in the mepolizumab group (difference, 3 percentage points; 95% confidence interval [CI], -13 to 18; P = 0.73 for superiority), showing noninferiority but not superiority of benralizumab to mepolizumab. The accrued duration of remission and the time to first relapse were similar in the two groups. Complete withdrawal of oral glucocorticoids during weeks 48 through 52 was achieved in 41% of the patients who received benralizumab and 26% of those who received mepolizumab. The mean (±SD) blood eosinophil count at baseline was 306.0±225.0 per microliter in the benralizumab group and 384.9±563.6 per microliter in the mepolizumab group, decreasing to 32.4±40.8 and 71.8±54.4 per microliter, respectively, at week 52. Adverse events were reported in 90% of the patients in the benralizumab group and 96% of those in the mepolizumab group; serious adverse events were reported in 6% and 13%, respectively. CONCLUSIONS: Benralizumab was noninferior to mepolizumab for the induction of remission in patients with relapsing or refractory EGPA. (Funded by AstraZeneca; MANDARA ClinicalTrials.gov number, NCT04157348.).

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.).

Association Between T2-related Comorbidities and Effectiveness of Biologics in Severe Asthma.

Rationale: Previous studies investigating the impact of comorbidities on the effectiveness of biologic agents have been relatively small and of short duration and have not compared classes of biologic agents. Objectives: To determine the association between type 2-related comorbidities and biologic agent effectiveness in adults with severe asthma (SA). Methods: This cohort study used International Severe Asthma Registry data from 21 countries (2017-2022) to quantify changes in four outcomes before and after biologic therapy-annual asthma exacerbation rate, FEV1% predicted, asthma control, and long-term oral corticosteroid daily dose-in patients with or without allergic rhinitis, chronic rhinosinusitis (CRS) with or without nasal polyps (NPs), NPs, or eczema/atopic dermatitis. Measurements and Main Results: Of 1,765 patients, 1,257, 421, and 87 initiated anti-IL-5/5 receptor, anti-IgE, and anti-IL-4/13 therapies, respectively. In general, pre- versus post-biologic therapy improvements were noted in all four asthma outcomes assessed, irrespective of comorbidity status. However, patients with comorbid CRS with or without NPs experienced 23% fewer exacerbations per year (95% CI, 10-35%; P < 0.001) and had 59% higher odds of better post-biologic therapy asthma control (95% CI, 26-102%; P < 0.001) than those without CRS with or without NPs. Similar estimates were noted for those with comorbid NPs: 22% fewer exacerbations and 56% higher odds of better post-biologic therapy control. Patients with SA and CRS with or without NPs had an additional FEV1% predicted improvement of 3.2% (95% CI, 1.0-5.3; P = 0.004), a trend that was also noted in those with comorbid NPs. The presence of allergic rhinitis or atopic dermatitis was not associated with post-biologic therapy effect for any outcome assessed. Conclusions: These findings highlight the importance of systematic comorbidity evaluation. The presence of CRS with or without NPs or NPs alone may be considered a predictor of the effectiveness of biologic agents in patients with SA.

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.).

Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma.

BACKGROUND: Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear. METHODS: In a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety. RESULTS: A total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups. CONCLUSIONS: Interleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03387852.).

Biomarkers and clinical outcomes after tezepelumab cessation: Extended follow-up from the 2-year DESTINATION study.

BACKGROUND: Long-term tezepelumab treatment in the DESTINATION study (NCT03706079) resulted in reduced asthma exacerbations, reduced biomarker levels, and improved lung function and symptom control in patients with severe, uncontrolled asthma. OBJECTIVE: To explore the time course of changes in biomarkers and clinical manifestations after treatment cessation after 2 years of tezepelumab treatment. METHODS: DESTINATION was a 2-year, phase 3, multicenter, randomized, placebo-controlled, double-blind study of tezepelumab treatment in patients (12-80 years old) with severe asthma. Patients received their last treatment doses at week 100 and could enroll in an extended follow-up period from weeks 104 to 140. Change over time in key biomarkers and clinical outcomes were assessed in tezepelumab vs placebo recipients for 40 weeks after stopping treatment. RESULTS: Of 569 patients enrolled in the extended follow-up period, 426 were included in the analysis (289 received tezepelumab and 137 placebo). In the 40-week period after the last tezepelumab dose, blood eosinophil counts, fractional exhaled nitric oxide levels, and Asthma Control Questionnaire-6 scores gradually increased from weeks 4 to 10, with a gradual reduction in pre-bronchodilator forced expiratory volume in 1 second such that blood eosinophil counts, fractional exhaled nitric oxide levels, and clinical outcomes returned to placebo levels; however, none of these outcomes returned to baseline levels. Total IgE levels increased later from week 28 and remained well below placebo and baseline levels during the 40-week period after the last tezepelumab dose. CONCLUSION: This analysis reveals the benefits of continued tezepelumab treatment in the management of patients with severe, uncontrolled asthma, compared with stopping treatment after 2 years. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03706079.

Impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in patients with severe asthma.

BACKGROUND: There is little agreement on clinically useful criteria for identifying real-world responders to biologic treatments for asthma. OBJECTIVE: To investigate the impact of pre-biologic impairment on meeting domain-specific biologic responder definitions in adults with severe asthma. METHODS: This was a longitudinal, cohort study across 22 countries participating in the International Severe Asthma Registry (https://isaregistries.org/) between May 2017 and January 2023. Change in 4 asthma domains (exacerbation rate, asthma control, long-term oral corticosteroid [LTOCS] dose, and lung function) was assessed from biologic initiation to 1 year post-treatment (minimum 24 weeks). Pre- to post-biologic changes for responders and nonresponders were described along a categorical gradient for each domain derived from pre-biologic distributions (exacerbation rate: 0 to 6+/y; asthma control: well controlled to uncontrolled; LTOCS: 0 to >30 mg/d; percent-predicted forced expiratory volume in 1 second [ppFEV1]: <50% to ≥80%). RESULTS: Percentage of biologic responders (ie, those with a category improvement pre- to post-biologic) varied by domain and increased with greater pre-biologic impairment, increasing from 70.2% to 90.0% for exacerbation rate, 46.3% to 52.3% for asthma control, 31.1% to 58.5% for LTOCS daily dose, and 35.8% to 50.6% for ppFEV1. The proportion of patients having improvement post-biologic tended to be greater for anti-IL-5/5R compared with for anti-IgE for exacerbation, asthma control, and ppFEV1 domains, irrespective of pre-biologic impairment. CONCLUSION: Our results provide realistic outcome-specific post-biologic expectations for both physicians and patients, will be foundational to inform future work on a multidimensional approach to define and assess biologic responders and response, and may enhance appropriate patient selection for biologic therapies. TRIAL REGISTRATION: The ISAR database has ethical approval from the Anonymous Data Ethics Protocols and Transparency (ADEPT) committee (ADEPT0218) and is registered with the European Union Electronic Register of Post-Authorization studies (ENCEPP/DSPP/23720). The study was designed, implemented, and reported in compliance with the European Network Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) Code of Conduct (EUPAS38288) and with all applicable local and international laws and regulation, and registered with ENCEPP (https://www.encepp.eu/encepp/viewResource.htm?id=38289). Governance was provided by ADEPT (registration number: ADEPT1220).

The impact of insomnia and depression on asthma control.

BACKGROUND: Poor sleep quality is often reported by individuals with asthma, particularly by those who have poor asthma control overall. However, there is little understanding of how underlying sleep disorders such as insomnia may impact asthma control. Furthermore, given the frequent overlap of depression and insomnia, the incremental impact of mood disorders and insomnia on asthma control remains unclear. METHODS: We conducted a retrospective analysis of patients at a large asthma center to further elucidate connections between these disease processes. Asthma patients with and without a diagnosis of insomnia were matched by age, sex, Charlson comorbidity index, and biologic therapy. We evaluated the presence of concurrent obstructive sleep disorder, mood disorders, exacerbation frequency, and asthma control test (ACT) scores. RESULTS: From a cohort of 659 patients with an asthma diagnosis, 89 subjects with insomnia (13.5%) were matched 1:1 to patients without insomnia. Compared to those without insomnia, patients with insomnia were more likely to have a concurrent diagnosis of obstructive sleep apnea (57.3% vs. 18%, p < 0.001) and to have a diagnosis of depression or anxiety (68.5% vs. 11.4%, p < 0.001). Among insomnia patients, there was an average of 0.93 asthma exacerbations per year, compared to 0.59 exacerbations per year for those without insomnia (p = 0.039). CONCLUSION: Our data reveal a considerable interaction between insomnia, depression, and obstructive sleep apnea in individuals with asthma. The increased exacerbation rate suggests that underlying sleep and mood disorders negatively affect asthma control.

Unmet needs and evidence gaps in hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis.

Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are rare systemic inflammatory disorders with overlapping symptoms, elevated eosinophil counts, and heterogenous clinical presentations. Although progress has been made in recent years, there are substantial gaps in our understanding of the pathologic mechanisms involved in these diseases, as well as numerous unmet needs relating to both diagnosis and patient management. For example, in most cases of HES, the underlying cause of hypereosinophilia is unknown, while in EGPA, although a polygenic genetic susceptibility has been found, understanding of the pathogenic mechanisms remains largely elusive. Delineating differences between certain disease variants may be challenging, and there are no reliable predictive markers of disease course. In addition, the current diagnostic criteria for HES and classification criteria for EGPA are not easy to implement in a nonspecialist setting, and specialist referral pathways need to be signposted more clearly. Furthermore, disease-specific activity scores need to be developed to aid the assessment of treatment effects, and improved biomarkers are needed to aid with treatment stratification. In this review, we outline the limitations of our current understanding of HES and EGPA and highlight areas for future work, which ultimately should help improve patient management and outcomes.

Ocular manifestations of ANCA-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. METHODS: This study retrospectively analysed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. RESULTS: Data from 1441 patients were analysed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n = 224) than during follow-up (n = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n = 168) and visual impairment (n = 195). CONCLUSION: Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy.

Urine eosinophil-derived neurotoxin: A potential marker of activity in select eosinophilic disorders.

BACKGROUND: Biomarkers of eosinophilic disease activity, especially in the context of novel therapies that reduce blood eosinophil counts, are an unmet need. Absolute eosinophil count (AEC) does not accurately reflect tissue eosinophilia or eosinophil activation. Therefore, the aims of this study were to compare the reliability of plasma and urine eosinophil major basic protein 1, eosinophil cationic protein, eosinophil-derived neurotoxin (EDN), and eosinophil peroxidase measurement and to evaluate the usefulness of eosinophil granule protein (EGP) measurement for the assessment of disease activity in patients with eosinophil-associated diseases treated with mepolizumab, benralizumab, or dexpramipexole. METHODS: Eosinophil granule protein concentrations were measured in serum, plasma, and urine from healthy volunteers and patients with hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA), and eosinophilic asthma using a multiplex assay. RESULTS: Urine EGP concentrations remained stable, whereas serum and plasma EGP concentrations increased significantly with delayed processing. Plasma (p) EDN, but not urine (u) EDN, concentration correlated with AEC and negatively correlated with prednisone dose. Both pEDN and uEDN decreased significantly following treatment of HES patients with benralizumab and EGPA patients with mepolizumab. uEDN appeared to increase with clinical relapse in both patient groups. CONCLUSIONS: Measurement of EGP in urine is noninvasive and unaffected by cellular lysis. Although plasma and urine EDN concentrations showed a similar pattern following benralizumab and mepolizumab treatment, the lack of correlation between AEC or prednisone dose and uEDN concentrations suggests that measurement of uEDN may provide a potential biomarker of disease activity in patients with HES and EGPA.

Eosinophilic respiratory disorders and the impact of biologics.

PURPOSE OF REVIEW: Eosinophils are involved in combating parasitic, bacterial, viral infections as well as certain malignancies. However, they are also implicated in an array of upper and lower respiratory disease states. Through a deeper understanding of disease pathogenesis, targeted biologic therapies have revolutionized glucocorticoid sparing treatment of eosinophilic respiratory diseases. This review will focus on the impact of novel biologics on the management of asthma, eosinophilic granulomatosis with polyangiitis, allergic bronchopulmonary aspergillosis (ABPA), hypereosinophilic syndrome (HES) and chronic rhinosinusitis with nasal polyposis (CRSwNP). RECENT FINDINGS: Key immunologic pathways affecting Type 2 inflammation through immunoglobulin E (IgE), interleukin (IL-4), IL-5, IL-13, and upstream alarmins such as thymic stromal lymphopoietin (TSLP), have led to novel drug developments. We explore the mechanism of action for Omalizumab, Mepolizumab, Benralizumab, Reslizumab, Dupilumab, and Tezepelumab, their respective Food and Drug Administration (FDA) indications, and biomarkers affecting treatment decisions. We also highlight investigational therapeutics that are likely to impact the future management of eosinophilic respiratory diseases. SUMMARY: Insight into the biology of eosinophilic respiratory diseases has been critical for understanding disease pathogenesis and has contributed to the development of effective eosinophil-targeted biologic interventions.

Preference for and impact of telehealth vs in-person asthma visits among Black and Latinx adults.

BACKGROUND: Black and Latinx adults experience disproportionate asthma-related morbidity and limited specialty care access. The severe acute respiratory syndrome coronavirus 2 pandemic expanded telehealth use. OBJECTIVE: To evaluate visit type (telehealth [TH] vs in-person [IP]) preferences and the impact of visit type on asthma outcomes among Black and Latinx adults with moderate-to-severe asthma. METHODS: For this PREPARE trial ancillary study, visit type preference was surveyed by e-mail or telephone post-trial. Emergency medical record data on visit types and asthma outcomes were available for a subset (March 2020 to April 2021). Characteristics associated with visit type preferences, and relationships between visit type and asthma outcomes (control [Asthma Control Test] and asthma-related quality of life [Asthma Symptom Utility Index]), were tested using multivariable regression. RESULTS: A total of 866 participants consented to be surveyed, with 847 respondents. Among the participants with asthma care experience with both visit types, 42.0% preferred TH for regular checkups, which associated with employment (odds ratio [OR] = 1.61; 95% confidence interval [CI], 1.09-2.39; P = .02), lower asthma medication adherence (OR = 1.06; 95% CI, 1.01-1.11; P = .03), and having more historical emergency department and urgent care asthma visits (OR = 1.10 for each additional visit; 95% CI, 1.02-1.18; P = .02), after adjustment. Emergency medical record data were available for 98 participants (62 TH, 36 IP). Those with TH visits were more likely Latinx, from the Southwest, employed, using inhaled corticosteroid-only controller therapy, with lower body mass index, and lower self-reported asthma medication adherence vs those with IP visits only. Both groups had comparable Asthma Control Test (18.4 vs 18.9, P = .52) and Asthma Symptom Utility Index (0.79 vs 0.84, P = .16) scores after adjustment. CONCLUSION: TH may be similarly efficacious as and often preferred over IP among Black and Latinx adults with moderate-to-severe asthma, especially for regular checkups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02995733.

Open-inhaler versus single-inhaler triple therapy (long-acting muscarinic antagonist, inhaled corticosteroid, and long-acting ß2-agonist) in asthma patients: a narrative review.

OBJECTIVE: To review the evidence for the use of open-inhaler (inhaled corticosteroid [ICS] plus long-acting ß2-agonist [LABA] with separate add-on long-acting muscarinic antagonist [LAMA]) versus single-inhaler triple therapy (ICS/LABA/LAMA combination) and the merits of add-on LAMA to ICS/LABA in patients with uncontrolled asthma. DATA SOURCES: Original research articles were identified from PubMed using the search term "triple therapy asthma." Information was also retrieved from the ClinicalTrials.gov website. STUDY SELECTIONS: Articles detailing the use of add-on LAMA to ICS plus LABA (open-inhaler triple therapy), and closed triple therapy compared with ICS plus LABA dual therapy, addressing patient symptoms, exacerbations, and health-related quality of life. RESULTS: Open-inhaler triple therapy was associated with a significantly reduced incidence of hospitalizations and emergency department visits and a decrease in ICS dose, oral corticosteroids use, and antibiotics use. Exacerbations and acute respiratory events were also reduced. Single-inhaler triple therapy showed a greater improvement in lung function, asthma control, and health status and was noninferior to open-inhaler triple therapy for Asthma Quality of Life Questionnaire scores. Single-inhaler triple therapy may also lead to improved therapy adherence. CONCLUSION: Add-on LAMA to ICS plus LABA (open- or single-inhaler triple therapy) improves the response in patients who remain symptomatic and provides a reasonable alternative to ICS dose escalation in treatment-refractory patients.

Caribbean Latinx with moderate-severe asthma bear greater asthma morbidity than other Latinx.

BACKGROUND: Hispanic/Latinx (HL) ethnicity encompasses racially and culturally diverse subgroups. Studies suggest that Puerto Ricans (PR) may bear greater asthma-related morbidity than Mexicans, but these were conducted in children or had limited clinical characterization. OBJECTIVES: This study sought to determine whether disparities in asthma morbidity exist among HL adult subgroups. METHODS: Adults with moderate-severe asthma were recruited from US clinics, including from Puerto Rico, for the Person Empowered Asthma Relief (PREPARE) trial. Considering the shared heritage between PR and other Caribbean HL (Cubans and Dominicans [C&D]), the investigators compared baseline self-reported clinical characteristics between Caribbean HL (CHL) (PR and C&D: n = 457) and other HLs (OHL) (Mexicans, Spaniards, Central/South Americans; n = 141), and between CHL subgroups (C&D [n = 56] and PR [n = 401]). This study compared asthma morbidity measures (self-reported exacerbations requiring systemic corticosteroids, emergency department/urgent care (ED/UC) visits, hospitalizations, health care utilization) through negative binomial regression. RESULTS: CHL compared to OHL were similar in age, body mass index, poverty status, blood eosinophils, and fractional exhaled nitric oxide but were prescribed more asthma controller therapies. Relative to OHL, CHL had significantly increased odds of asthma exacerbations (odds ratio [OR]: 1.84; 95% CI: 1.4-2.4), ED/UC visits (OR: 1.88; 95% CI: 1.4-2.5), hospitalization (OR: 1.98; 95% CI: 1.06-3.7), and health care utilization (OR: 1.91; 95% CI: 1.44-2.53). Of the CHL subgroups, PR had significantly increased odds of asthma exacerbations, ED/UC visits, hospitalizations, and health care utilization compared to OHL, whereas C&D only had increased odds of exacerbations compared to OHL. PR compared to C&D had greater odds of ED/UC and health care utilization. CONCLUSIONS: CHL adults, compared with OHL, adults reported nearly twice the asthma morbidity; these differences are primarily driven by PR. Novel interventions are needed to reduce morbidity in this highly impacted population.

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

BACKGROUND: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients. METHODS: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry. RESULTS: When quintupling the dose of fluticasone (to 250 µg twice a day) was compared with adding salmeterol (50 µg twice a day) and doubling the fluticasone (to 100 µg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age. CONCLUSIONS: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.).

Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.

BACKGROUND: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).

From DREAM to REALITI-A and beyond: Mepolizumab for the treatment of eosinophil-driven diseases.

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.