Reduce Asthma Exacerbations Research Articles

Asthma exacerbations during the pandemic: Time to rethink clinical markers.

BackgroundReductions in asthma exacerbations during the COVID-19 pandemic may have an impact on clinical trial enrollment and outcomes.ObjectiveTo review clinical studies and reports evaluating asthma exacerbations before and during the COVID-19 pandemic.MethodsWe reviewed clinical studies conducted with biologics over the past decade that evaluated asthma exacerbations as the primary endpoint. We also reviewed recent clinical reports evaluating asthma exacerbations during the COVID-19 pandemic.ResultsWe showed that studies which required at least two exacerbations in the prior year resulted in a higher number of exacerbations on study in the placebo arm, and conversely those studies where exacerbations were not required for entering the study failed to meet the primary endpoint. This result confirmed that history of prior exacerbations is a good maker to predict future exacerbations. In addition, a review of the literature confirmed a reduction of asthma exacerbations during the COVID-19 pandemic. Data presented are descriptive; no formal statistics were employed.ConclusionHistorical exacerbations may no longer be the best predictor for exacerbations in a clinical trial/clinical practice due to the COVID-19 pandemic. Other clinical markers associated with exacerbations such as blood eosinophils and exhaled nitric oxide should be considered for enrolment in clinical studies assessing asthma exacerbations.

Epithelial cell alarmin cytokines: Frontline mediators of the asthma inflammatory response.

The exposure of the airway epithelium to external stimuli such as allergens, microbes, and air pollution triggers the release of the alarmin cytokines IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). IL-25, IL-33 and TSLP interact with their ligands, IL-17RA, IL1RL1 and TSLPR respectively, expressed by hematopoietic and non-hematopoietic cells including dendritic cells, ILC2 cells, endothelial cells, and fibroblasts. Alarmins play key roles in driving type 2-high, and to a lesser extent type 2-low responses, in asthma. In addition, studies in which each of these three alarmins were targeted in allergen-challenged mice showed decreased chronicity of type-2 driven disease. Consequently, ascertaining the mechanism of activity of these upstream mediators has implications for understanding the outcome of targeted therapies designed to counteract their activity and alleviate downstream type 2-high and low effector responses. Furthermore, identifying the factors which shift the balance between the elicitation of type 2-high, eosinophilic asthma and type-2 low, neutrophilic-positive/negative asthma by alarmins is essential. In support of these efforts, observations from the NAVIGATOR trial imply that targeting TSLP in patients with tezepelumab results in reduced asthma exacerbations, improved lung function and control of the disease. In this review, we will discuss the mechanisms surrounding the secretion of IL-25, IL-33, and TSLP from the airway epithelium and how this influences the allergic airway cascade. We also review in detail how alarmin-receptor/co-receptor interactions modulate downstream allergic inflammation. Current strategies which target alarmins, their efficacy and inflammatory phenotype will be discussed.

ASTHMA EXACERBATION DUE TO ORAL CONTRACEPTIVE PILLS

ASTHMA EXACERBATION DUE TO ORAL CONTRACEPTIVE PILLS

LONG-TERM REAL-WORLD EFFECTIVENESS OF BENRALIZUMAB IN PATIENTS WITH SEVERE EOSINOPHILIC ASTHMA: RESULTS FROM THE ZEPHYR 2 STUDY

LONG-TERM REAL-WORLD EFFECTIVENESS OF BENRALIZUMAB IN PATIENTS WITH SEVERE EOSINOPHILIC ASTHMA: RESULTS FROM THE ZEPHYR 2 STUDY

Vitamin D Supplementation and Allergic Diseases during Childhood: A Systematic Review and Meta-Analysis.

We performed a systematic review and meta-analysis to investigate the effects of vitamin D (VitD) supplementation on children with allergic diseases. MEDLINE, Embase, Web of Science, the Cochrane library, and three Chinese databases were searched up to 15 August 2022. Randomized controlled trials (RCTs) comparing a VitD supplementation versus a placebo for children with allergic diseases were included. Thirty-two RCTs with 2347 participants were included. VitD supplementation did not reduce the risk of asthma exacerbations in children compared with placebo overall (risk ratio (RR) = 0.84, 95% confidence interval (CI): 0.65 to 1.08, p = 0.18), but reduced the risk of asthma exacerbation in children with baseline serum 25(OH)D of <10 ng/mL compared with placebo (RR = 0.48, 95% CI: 0.28 to 0.83, p = 0.009). VitD supplementation significantly reduced Scoring Atopic Dermatitis or the Eczema Area and Severity Index scores in children with atopic dermatitis compared with placebo (standard mean difference = −0.5, 95% CI: −0.87 to −0.12, p = 0.009). VitD supplementation also reduced the symptom-medication score in children with allergic rhinitis compared with placebo (mean (standard deviation): 43.7 (3.3) vs. 57.8 (4.4), p = 0.001). In conclusion, VitD supplementation did not reduce asthma exacerbation risk in children overall but may reduce asthma exacerbation risk in children with serum 25(OH)D concentration < 10 ng/mL. VitD supplementation reduces the severity of atopic dermatitis and symptoms of allergic rhinitis in children.

Effectiveness of Low-Dose Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis (EGPA): A Real-Life Experience

Introduction: Data showing effectiveness of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA) are limited. Methods: This is a single-center retrospective chart review of patients with EGPA treated with mepolizumab. Clinical, laboratory, functional parameters and asthma, rhinitis control, and quality of life scores (Asthma Control Test [ACT], Asthma Quality of Life Questionnaire [AQLQ], Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ], and SinoNasal Outcome Test [SNOT]-22) were evaluated at the baseline, 6th month, and 12th month. Complete response was defined as the absence of asthma and/or ear, nasal symptoms and exacerbations with a prednisone of ≤7.5 mg/day, partial response if it was achieved with a prednisone of >7.5 mg/day. Results: Overall, 25 patients (18 F/7 M) with a median age of 47 years (23–76) were enrolled. Mepolizumab 100 mg/month was administered (dose increased to 300 mg/month in 3 patients). Mepolizumab significantly decreased daily dose of oral corticosteroid (OCS) from 11.04 mg to 3.65 mg together with a significant improvement in ACT, AQLQ, RQLQ, and SNOT-22 scores and a significant reduction in asthma exacerbations and blood eosinophil count at the 6th and 12th month (all p values <0.05). The mean forced expiratory volume in 1 s increased (at baseline: 1.88 L to 2.46 L at the 12th month [p = 0.037]). Seventy-six percent of patients responded completely at the 6th month and 81.25% at the 12th month. The complete responders at the 6th and 12th month were older than partial responders and nonresponders (p = 0.030 and p = 0.057, respectively). Patients with complete response at the 6th month were on lower doses of OCS than partial responders and nonresponders (p = 0.029). Conclusions: Low-dose mepolizumab was effective in EGPA patients by improving sinonasal and asthma outcomes, while reducing the need for OCS.

Racial and ethnic disparities in biologic prescriptions for asthma in the United States

In the United States, morbidity and mortality from asthma are declining, but racial and ethnic differences in asthma burden remain unresolved.1 Compared with White patients, individuals of underrepresented backgrounds have a higher prevalence of moderate-to-severe persistent asthma, difficult-to-treat asthma, and emergency room utilization for asthma care.2,3 Asthma biologics that target type 2 airway inflammation lessen disease burden, reduce asthma exacerbation risk, and improve quality-of-life metrics.

Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial

Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone. This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588. Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab. Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations. US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline.

The Therapeutic Potential for Targeting Group 2 Innate Lymphoid Cells in Asthma

T helper type 2 cells (Th2 cells) and group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma, including airway eosinophilic inflammation. ILC2s are activated by epithelial-derived cytokines [interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP)] from airway epithelial cells, leading to the release of high amounts of type 2 cytokines, such as IL-5 and IL-13. ILC2s induce airway inflammation in an antigen-independent manner, and ILC2s are considered to be involved in the pathogenesis of asthma exacerbation. Furthermore, ILC2 activation might also confer steroid resistance. Many recent studies in humans and mice are increasingly demonstrating that the function of ILC2s is regulated not just by epithelial-derived cytokines but by a variety of cytokines and mediators derived from innate immune cells. Furthermore, the biologics targeting these cytokines and/or their receptors have been shown to reduce asthma exacerbations and improve lung function and quality of life in asthmatics. This article reviews the current treatment landscape for type 2 airway inflammation in asthma and discusses the therapeutic potential for targeting ILC2s.

Anti-IL-5 therapies for asthma.

Anti-IL-5 therapies for asthma.

Omalizumab is associated with improved asthma outcomes in children and adolescents with serum immunoglobulin E above dosing guidelines

Asthma is an increasingly common chronic disease in children, accounting for more hospitalizations than many other chronic health conditions.1 Omalizumab is used to treat severe allergic asthma in children 6 years and older and improves asthma control and reduces asthma exacerbations and health care utilization as early as 16 weeks into treatment.2,3 Omalizumab dosing guidelines are dependent on serum immunoglobulin E (IgE) level and body weight and were designed to produce serum free IgE levels of 25 ng/mL or lower, which was associated with improved outcomes in clinical trials.

Efficacy, safety, and tolerability of lebrikizumab in adolescent patients with uncontrolled asthma (ACOUSTICS).

BackgroundLebrikizumab is a monoclonal antibody that modulates activity of interleukin‐13. The Phase 3 ACOUSTICS study assessed lebrikizumab efficacy and safety in adolescents with uncontrolled asthma despite standard‐of‐care treatment.MethodsAdolescents (aged 12–17 years) with uncontrolled asthma, prebronchodilator forced expiratory volume in 1 s 40%–90% predicted, and stable background therapy were randomised 1:1:1 to receive lebrikizumab 125 or 37.5 mg or placebo subcutaneously once every 4 weeks. Primary efficacy endpoint was asthma exacerbation rate over 52 weeks.ResultsBetween August 2013 and July 2016, 579 patients were screened and 346 were randomised; 224 (65%) completed the study with 52 weeks of treatment. Lebrikizumab 125 mg (n = 116) reduced the exacerbation rate at 52 weeks versus placebo (n = 117; adjusted rate ratio [RR] 0.49 [95% CI 0.28–0.83]; 51% rate reduction). Lebrikizumab 37.5 mg (n = 113) was less effective at reducing exacerbations (RR 0.60 [95% CI 0.35–1.03]; 40% rate reduction). In patients with blood eosinophil counts ≥300 cells/μl, both lebrikizumab doses reduced exacerbations (125 mg: RR 0.44 [95% CI 0.21–0.89]; 37.5 mg: 0.42 [95% CI 0.19–0.93]). Treatment‐emergent adverse events, serious adverse events, and adverse events leading to study discontinuation occurred in 155 (68%), 7 (3%), and 5 (2%) of 229 patients who received lebrikizumab (both 125 and 37.5 mg doses) and in 72 (62%), 4 (3%), and 1 (1%) of 117 who received placebo, respectively. No deaths occurred.ConclusionLebrikizumab 125 mg reduced asthma exacerbation rates in adolescents with uncontrolled asthma. However, the study was prematurely terminated (sponsor's decision) potentially limiting interpretation of results.Clinical trial registrationNCT01875003 (www.ClinicalTrials.gov).

Impact of COVID-19 pandemic on asthma exacerbations: Retrospective cohort study of over 500,000 patients in a national English primary care database.

SummaryBackgroundSeveral countries reported a substantial reduction in asthma exacerbations associated with COVID-19 pandemic-related restrictions. However, it is not known if these early reported declines were short-term and if these have rebounded to pre-pandemic levels following easing of lockdown restrictions.MethodsWe undertook a retrospective, cohort study of all asthma patients in a national primary care database of almost 10 million patients, Optimum Patient Care Database (OPCRD), identified from January 1, 2010, to December 31, 2015, using a previously validated algorithm. We subsequently followed the identified cohort of asthma patients from January 1, 2016, to October 3, 2021, and identified every asthma exacerbation episode with a validated algorithm. To quantify any pandemic-related change in exacerbations, we created a control time-series (mean of 2016-2019) and then compared the change in exacerbation rate in 2020-2021 over quarterly periods when compared with the control period (the pre-pandemic period). We undertook overall and stratified analyses by age group, sex, and English region.FindingsWe identified 100,362 asthma patients (502,669 patient-years) from across England who experienced at least one exacerbation episode (298,390 exacerbation episodes during the entire follow-up). Except for the first quarter of 2020, the exacerbation rates were substantially lower (>25%) during all quarters in 2020-2021 when compared with the rates during 2016-2019 (39.7% (95% Confidence Interval (CI): 34.6, 44.9) in quarter-2, 2020; 46.5% (95%CI: 36.7, 56.4) in quarter-3, 2020; 56.3% (95%CI: 48.7, 63.9) in quarter-4, 2020; 63.2% (95%CI: 53.9, 72.5) in quarter-1, 2021; 57.7% (95%CI: 52.9, 62.4) in quarter-2, 2021; 53.3% (95%CI: 43.8, 62.8) in quarter-3, 2021).InterpretationThere was a substantial and persistent reduction in asthma exacerbations across England over the first 18 months after the first lockdown. This is unlikely to be adequately explained by changes in health-seeking behaviour, pandemic-related healthcare service disruption, or any air-quality improvements.FundingAsthma UK, Health Data Research UK (HDR UK), Medical Research Council (MRC), National Institute for Health Research (NIHR).

Digital interventions to improve adherence to maintenance medication in asthma.

Digital interventions to improve adherence to maintenance medication in asthma.

Improvement in Lung Function with Dupilumab Does Not Predict Its Effects on Reducing Asthma Exacerbation.

Improvement in Lung Function with Dupilumab Does Not Predict Its Effects on Reducing Asthma Exacerbation.

In Black and Latinx patients, as-needed inhaled glucocorticoids reduced asthma exacerbations at 15 mo.

Israel E, Cardet JC, Carroll JK, et al. Reliever-triggered inhaled glucocorticoid in Black and Latinx adults with asthma. N Engl J Med. 2022;386:1505-18. 35213105.

Pediatric Research Challenge, Alignment with the National Research Agenda

Pediatric Research Challenge, Alignment with the National Research Agenda

Applying dissemination and implementation research methods to translate a school-based asthma program

Our school-based asthma program has reduced asthma exacerbations for youth with health disparities in the Denver metropolitan area, due partly to addressing social determinants of health, such as access to health care and medications. Dissemination and implementation (D&I) science approaches accelerate the translation of evidence-based programs into routine practice. D&I methods are being applied more commonly to improve health equity. The purpose of this publication was to give an overview of D&I research methods, using our school-based asthma program as an example. To successfully scale out our program across the state of Colorado, we are applying a D&I framework that guides the adaptation of our existing implementation approach to better meet our stakeholders' local context-the Exploration, Preparation, Implementation, Sustainment framework. In a pragmatic trial design, we will evaluate the outcomes of implementing the program across 5 Colorado regions, with attention to health equity, using a second commonly used D&I framework-Reach, Effectiveness, Adoption, Implementation, and Maintenance. Our central hypothesis is that our program will have broad and equitable reach to eligible students (primary outcome) and will reduce asthma attacks and symptoms. This D&I approach accelerates dissemination of our program and is an applicable process for translating other effective allergy/asthma programs to address asthma and allergy-related disparities.

Omalizumab treatment reduces asthma exacerbations regardless of airway bronchodilator reversibility

In asthma, the type 2 inflammatory response mediated by IgE leads to airway remodeling and subsequent symptom presentation.1 Blocking the action of IgE can decrease airway remodeling, including reducing wall thickness and inflammation.2,3 Airway smooth muscle thickness and vascularity are inversely correlated with postbronchodilator FEV1.4 In patients with allergic asthma, bronchodilator reversibility can indicate pulmonary function and is associated with lung function improvement during omalizumab therapy.

Efficacy and Safety of Fevipiprant in Asthma: A Review and Meta-Analysis.

Fevipiprant is a non-steroidal oral prostaglandin D2 (PGD2) receptor 2 antagonist that reduces bronchial wall inflammation, possibly improving clinical outcomes in the asthmatic population.A systemic review search was conducted on PubMed, Embase, and Central Cochrane Registry. Randomized clinical trials were included with Fevipiprant as an intervention arm compared to placebo. For continuous variables, the standardized mean difference, and for discrete variables, Mantel-Haenszel Risk Ratio (MH Risk ratio) was used for analysis. Confidence interval of 95% and p-value < 0.05 was considered significant. The analysis was done using a random-effects model irrespective of heterogeneity. Heterogeneity was evaluated using the I2 statistic.A total of five articles, including seven trials, were included in the analysis. There was significant increase in post-bronchodilator forced expiratory volume in one second (FEV1) 0.249 (0.157-0.341), p<0.001 and pre-bronchodilator FEV1 0.115 (0.043 to 0.188), p=0.002. A decrease in asthma control questionnaire (ACQ) score of -0.124 (-0.187 to -0.062), p<0.001, was reported. Statistically significant asthma exacerbation reduction was reported in the high eosinophil count population with a daily dose of 450mg 0.77 relative risks (RR) (0.61-0.97). There was a positive deviation toward Fevipiprant 450mg dose for asthma reduction in the overall population, but it was not statistically significant. Fevipiprant produced a slight statistically significant reduction in asthma exacerbations in the high eosinophil count population with favorable deviation in the overall population. It significantly increased pre-and post-bronchodilator FEV1 and improved ACQ scores in treated patients. The benefits, though statistically significant, failed to translate into clinical importance.