Asthma Clinical Trials Research Articles

Targeting the IL-5 pathway in eosinophilic asthma: A comparison of anti-IL-5 versus anti-IL-5 receptor agents.

Eosinophilic asthma is characterized by frequent exacerbations, poor symptom control and accelerated lung function decline. It is now recognized that the immune response underlying eosinophilic asthma involves a complex network of interconnected pathways from both the adaptive and innate immune systems. Within this response, interleukin-5 (IL-5) plays a central role in eosinophil differentiation, activation and survival and has emerged as a key target for therapies treating severe asthma. The monoclonal antibodies mepolizumab and reslizumab target the ligand IL-5, preventing its interaction with eosinophils; in contrast, benralizumab binds to the IL-5 receptor (IL-5R), preventing IL-5 from binding and leading to substantially greater eosinophil reduction by enhanced antibody-dependent cell-mediated cytotoxicity. Although no direct head-to-head clinical trials of asthma have been published to formally evaluate the clinical significance of these different therapeutic approaches, the potential benefits of partial versus complete eosinophil depletion continue to remain an important area of study and debate. Here, we review the existing real-world and clinical study data of anti-IL-5/anti-IL-5R therapies in severe eosinophilic asthma.

Enrollment of underserved racial and ethnic populations in pediatric asthma clinical trials

BackgroundLimited data exist on enrollment trends of historically underserved racial and ethnic children in clinical trials. ObjectiveWe sought to evaluate documentation and representation of race and ethnicity in pediatric asthma clinical trials in the US. MethodsThis is a cross-sectional study of US-based interventional trials studying pediatric asthma completed between 2008 and 2022 and registered on ClinicalTrials.gov. Enrollment disparities were assessed using the enrollment prevalence difference (EPD) measure – the median difference between the proportion of participants enrolled and asthma prevalence in the US population by race and ethnicity. ResultsOf the 67 trials reviewed, 53 (79.2%) and 36 (53.7%) reported on race and ethnicity in ClinicalTrials.gov, respectively. Most participants were White (39.1%), Black (37.1%), and non-Hispanic (66.1%). Black, Hispanic, Multiracial, and White children were enrolled in expected proportions based on their contribution to asthma burden. However, American Indian or Alaska Native (AI/AN) (EPD: -1, 95% CI: -1, -1) and Asian children (EPD: -3, 95% CI: -3, -3) were underrepresented, relative to disease burden in these respective groups. Fewer Black children were enrolled in drug or device trials (β=-0.80; 95% CI -1.60, -0.01) than in other trials. Fewer Hispanic children were enrolled in early phase than late phase trials (β=-2.42; 95% CI -3.66, -1.19). ConclusionsEnrollment in pediatric asthma trials conducted in the US was commensurate with the demographics of children affected by asthma for most racial and ethnic groups, but AI/AN and Asian children were underrepresented. Concerted efforts are needed to promote inclusion of these underserved groups in future trials.

Long-term Safety and Efficacy of Dupilumab in Patients With Uncontrolled, Moderate-to-Severe Asthma Recruited From Korean Centers: A Subgroup Analysis of the Phase 3 LIBERTY ASTHMA TRAVERSE Trial.

Long-term data are limited on the safety and efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma from Korea. The current subgroup analysis was designed to evaluate the long-term safety and efficacy of dupilumab in patients enrolled from Korean centers in the parent studies (phase 2b and QUEST) and who participated in the TRAVERSE open-label extension (OLE) study. TRAVERSE was a global, multicenter, OLE study that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks for up to 96 weeks in patients (n = 2,282) with uncontrolled, moderate-to-severe asthma who completed prior dupilumab asthma clinical trials. The primary outcome was the incidence of any treatment-emergent adverse events (TEAEs); the secondary outcomes included annualized severe exacerbation rate, pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), and 5-item Asthma Control Questionnaire (ACQ-5) score. Safety outcomes were consistent with the parent studies and the overall TRAVERSE population; out of 74 patients, 70 experienced ≥ 1 TEAE, and 6 (8.1%) discontinued because of adverse events. During the treatment period, the unadjusted annualized severe exacerbation rate was low (0.470). Improvement in pre-BD FEV1 was seen as early as Week 2 with a mean change from the parent study baseline (PSBL), standard deviation (SD) of 0.42 L (0.47), which was sustained until Week 96. Mean change from PSBL (SD) in ACQ-5 score was -1.32 (0.76) at Week 48. This subgroup analysis of TRAVERSE showed the long-term safety and efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma enrolled from Korean centers. ClinicalTrials.gov Identifier: NCT02134028.

Prevalence, Diagnostic Utility and Associated Characteristics of Bronchodilator Responsiveness.

Rationale: The prevalence and diagnostic utility of bronchodilator responsiveness (BDR) in a real-life setting is unclear. Objective: To explore this uncertainty in patients aged ⩾12 years with physician-assigned diagnoses of asthma, asthma and chronic obstructive pulmonary disease (COPD), or COPD in NOVELTY, a prospective cohort study in primary and secondary care in 18 countries. Methods: The proportion of patients with a positive BDR test in each diagnostic category was calculated using 2005 (ΔFEV1 or ΔFVC ⩾12% and ⩾200 ml) and 2021 (ΔFEV1 or ΔFVC >10% predicted) European Respiratory Society/American Thoracic Society criteria. Measurements and Main Results: We studied 3,519 patients with a physician-assigned diagnosis of asthma, 833 with a diagnosis of asthma + COPD, and 2,436 with a diagnosis of COPD. The prevalence of BDR was 19.7% (asthma), 29.6% (asthma + COPD), and 24.7% (COPD) using 2005 criteria and 18.1%, 23.3%, and 18.0%, respectively, using 2021 criteria. Using 2021 criteria in patients diagnosed with asthma, BDR was associated with higher fractional exhaled nitric oxide; lower lung function; higher symptom burden; more frequent hospital admissions; and greater use of triple therapy, oral corticosteroids, or biologics. In patients diagnosed with COPD, BDR (2021) was associated with lower lung function and higher symptom burden. Conclusions: BDR prevalence in patients with chronic airway diseases receiving treatment ranges from 18% to 30%, being modestly lower with the 2021 than with the 2005 European Respiratory Society/American Thoracic Society criteria, and it is associated with lower lung function and greater symptom burden. These observations question the validity of BDR as a key diagnostic tool for asthma managed in clinical practice or as a standard inclusion criterion for clinical trials of asthma and instead suggest that BDR be considered a treatable trait for chronic airway disease.

Whole Genome Sequencing Identifies Novel Common and Low-Frequency Variants Associated With Age-Related Macular Degeneration.

To identify associations of common, low-frequency, and rare variants with advanced age-related macular degeneration (AMD) using whole genome sequencing (WGS). WGS data were obtained for 2123 advanced AMD patients (participants of clinical trials for advanced AMD) and 2704 controls (participants of clinical trials for asthma [N = 2518] and Alzheimer's disease [N = 186]), and joint genotype calling was performed, followed by quality control of the dataset. Single variant association analyses were performed for all identified common, low-frequency, and rare variants. Gene-based tests were executed for rare and low-frequency variants using SKAT-O and three groups of variants based on putative impact information: (1) all variants, (2) modifier impact variants, and (3) high- and moderate-impact variants. To ascertain independence of the identified associations from previously reported AMD and asthma loci, conditional analyses were performed. Previously identified AMD variants at the CFH, ARMS2/HTRA1, APOE, and C3 loci were associated with AMD at a genome-wide significance level. We identified new single variant associations for common variants near the PARK7 gene and in the long non-coding RNA AC103876.1, and for a rare variant near the TENM3 gene. In addition, gene-based association analyses identified a burden of modifier variants in eight intergenic and gene-spanning regions and of high- and moderate-impact variants in the C3, CFHR5, SLC16A8, and CFI genes. We describe the largest WGS study in AMD to date. We confirmed previously identified associations and identified several novel associations that are worth exploring in further follow-up studies.

Impact of COVID-19 measures on exacerbation rates and healthcare visits in US asthma patients.

Objective: To compare exacerbation rates and healthcare resource utilization (HCRU) in real-world patients in the United States who had moderate-to-severe asthma on medium- or high-dose inhaled corticosteroid/long-acting β₂-agonist therapy at different stages before and after the pandemic. Methods: This noninterventional, retrospective study described demographics, exacerbations, HCRU, and medication use in patients from a US-wide healthcare claims database in 4 consecutive years anchored around March 15, 2020 (start date of the first emergency health measures against coronavirus disease 2019 [COVID-19], or the first lockdown, in the United States, termed "restriction onset" hereafter). Four cohorts of patients potentially eligible for moderate-to-severe asthma clinical trials at the beginning (index) of each of four 1-year periods (March 15, 2018, 2019, 2020, 2021, respectively) were built. Exacerbations, healthcare visits, and asthma medication use were counted in the 1-year period after the index for each cohort. Results: The prevalence of patients with one or more exacerbation per year decreased by 10.00% in the first year after the restriction onset compared with the year before and attenuated over time to 6.37% in the second year. The proportion of inpatient, emergency department, and physician's office visits remained stable over the time periods evaluated for all patients and those patients who experienced one or more exacerbations. Asthma treatment of patients who experienced one or more exacerbations also remained stable over the 4 years. Conclusion: The effect of COVID-19 public health measures on asthma exacerbation rates might have affected clinical trials being run during this period and should be considered in their analysis. Asthma clinical trials run under pandemic hygiene restrictions should consider lower exacerbation frequency in their study design, while treatment and healthcare visits seem unchanged.

Assessing asthma symptoms in children: qualitative research supporting the development of the Pediatric Asthma Diary—Child (PAD-C) and Pediatric Asthma Diary—Observer (PAD-O)

BackgroundPediatric asthma has been identified by regulators, clinicians, clinical trial sponsors, and caregivers as an area in need of novel fit-for-purpose clinical outcome assessments (COAs) developed in accordance with the U.S. Food and Drug Administration’s (FDA’s) regulatory guidance for evaluating clinical benefit in treatment trials. To address this gap, the Patient-Reported Outcome (PRO) Consortium’s Pediatric Asthma Working Group has continued development of 2 COAs to assess asthma signs and symptoms in pediatric asthma clinical trials to support efficacy endpoints: a PRO measure, the Pediatric Asthma Diary—Child (PAD-C) for children 8–11 years old (y.o.) and an observer-reported outcome measure, the Pediatric Asthma Diary-Observer (PAD—O) for caregivers of children 4–11 y.o. This qualitative research aimed to generate evidence regarding the content validity of the PAD-C and PAD-O.MethodsSemi-structured combined concept elicitation and cognitive interviews were conducted with a diverse sample of U.S. participants (15 children 8–11 y.o. and 30 caregivers of children 4–11 y.o.). All children had clinician-diagnosed mild to severe asthma. Interviews explored the experience of pediatric asthma and assessed the understanding and relevance of both measures. Interviews were conducted across 3 iterative rounds to allow for modifications.ResultsConcept elicitation findings demonstrated that the core sign/symptom and impact concepts assessed in the PAD-C (cough, hard to breathe, out of breath, wheezing, chest tightness, and nighttime awakenings/symptoms) and PAD-O (cough, difficulty breathing, short of breath, wheezing, and nighttime awakenings/signs) correspond to those most frequently reported by participants; concept saturation was achieved. All PAD-C and PAD-O instructions and core items were well understood and considered relevant by most participants. Feedback from participants, the Pediatric Asthma Working Group, advisory panel, and FDA supported modifications to the measures, including addition of 1 new item to both measures and removal of 1 caregiver item.ConclusionsFindings provide strong support for the content validity of both measures. The cross-sectional measurement properties of both measures and their user experience and feasibility in electronic format will be assessed in a future quantitative pilot study with qualitative exit interviews, intended to support the reliability, construct validity, final content, and, ultimately, FDA qualification of the measures.

Comprehension by Caregivers and Adolescents of Clinical Trial Information Delivered via Multimedia Video Versus Conventional Practice: Nonrandomized Controlled Trial.

Research participants often misunderstand the required elements of informed consent information, whether provided in written or oral format. Informed consent instruments with embedded evidence-based learning theory principles administered in multimedia electronic formats may improve comprehension and retention. This study aims to determine whether study information comprehension and retention using an interactive multimedia video consent process was noninferior to comprehension and retention after an in-person face-to-face interaction with a conventional written consent document for caregivers and adolescents enrolled in a clinical trial. Participants were caregivers and children aged 12 to 17 years who were enrolled in a clinical trial of asthma treatment. Consent information was presented as a multimedia web-based video consent interaction or as a conventional written consent document with in-person interaction between the prospective participants and the study staff. The trial used a parallel nonrandomized noninferiority design that compared the 2 consent methods. Caregivers and adolescents completed a 17-item open-ended comprehension questionnaire (score range 17-51) at enrollment and at the end of the study 20 weeks later. Comprehension and retention were compared between the consent formats. Noninferiority was established if the 95% CI upper bound of the difference in scores (conventional format minus web-based) was less than the noninferiority margin of 2.4; superiority was established if the upper bound of the CI was <0. In total, 54 caregiver and adolescent dyads completed the interactive multimedia web-based video consent, and 25 dyads completed the conventional consent. Overall, 33% (26/79) of all adolescents were Black, 57% (45/79) were male, and 61% (48/79) had a household income of <US $60,000 per year. For caregivers, the interactive multimedia web-based format was noninferior to the conventional format at enrollment (difference between the conventional and web-based formats: mean -0.30, 95% CI -2.52 to 1.92) and was superior at the end of the study 20 weeks later (mean -2.20, 95% CI -3.9 to -0.5). There was a loss of comprehension over 20 weeks (mean -1.65, 95% CI -3.1 to -0.19) with the conventional format but not with the multimedia web-based format (mean 0.14, 95% CI -0.84 to 1.12). For adolescents, the noninferiority of the multimedia web-based format was not established. Caregivers who are considering enrolling their adolescent in an asthma clinical trial have similar comprehension of study information when delivered through an interactive multimedia web-based platform, which incorporates evidence-based learning theory principles, compared with having a conventional in-person, face-to-face discussion. The retention of study information over time was better with the multimedia format for caregivers. ClinicalTrials.gov NCT02061280; https://clinicaltrials.gov/ct2/show/NCT02061280 and NCT01437995; https://clinicaltrials.gov/ct2/show/NCT01437995.

Treating asthma in the time of COVID

The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19-related therapies.

A parametric model to jointly characterize rate, duration, and severity of exacerbations in episodic diseases

BackgroundThe natural history of many chronic diseases is characterized by periods of increased disease activity, commonly referred to as flare-ups or exacerbations. Accurate characterization of the burden of these exacerbations is an important research objective.MethodsThe purpose of this work was to develop a statistical framework for nuanced characterization of the three main features of exacerbations: their rate, duration, and severity, with interrelationships among these features being a particular focus. We jointly specified a zero-inflated accelerated failure time regression model for the rate, an accelerated failure time regression model for the duration, and a logistic regression model for the severity of exacerbations. Random effects were incorporated into each component to capture heterogeneity beyond the variability attributable to observed characteristics, and to describe the interrelationships among these components.ResultsWe used pooled data from two clinical trials in asthma as an exemplary application to illustrate the utility of the joint modeling approach. The model fit clearly indicated the presence of heterogeneity in all three components. A novel finding was that the new therapy reduced not just the rate but also the duration of exacerbations, but did not have a significant impact on their severity. After controlling for covariates, exacerbations among more frequent exacerbators tended to be shorter and less likely to be severe.ConclusionsWe conclude that a joint modeling framework, programmable in available software, can provide novel insights about how the rate, duration, and severity of episodic events interrelate, and enables consistent inference on the effect of treatments on different disease outcomes.Trial registration Ethics approval was obtained from the University of British Columbia Human Ethics Board (H17-00938).

Artificial intelligence based software facilitates spirometry quality control in asthma and COPD clinical trials.

Acquiring high-quality spirometry data in clinical trials is important, particularly when using forced expiratory volume in 1 s or forced vital capacity as primary end-points. In addition to quantitative criteria, the American Thoracic Society (ATS)/European Respiratory Society (ERS) standards include subjective evaluation which introduces inter-rater variability and potential mistakes. We explored the value of artificial intelligence (AI)-based software (ArtiQ.QC) to assess spirometry quality and compared it to traditional over-reading control. A random sample of 2000 sessions (8258 curves) was selected from Chiesi COPD and asthma trials (n=1000 per disease). Acceptability using the 2005 ATS/ERS standards was determined by over-reader review and by ArtiQ.QC. Additionally, three respiratory physicians jointly reviewed a subset of curves (n=150). The majority of curves (n=7267, 88%) were of good quality. The AI agreed with over-readers in 91% of cases, with 97% sensitivity and 93% positive predictive value. Performance was significantly better in the asthma group. In the revised subset, n=50 curves were repeated to assess intra-rater reliability (κ=0.83, 0.86 and 0.80 for each of the three reviewers). All reviewers agreed on 63% of 100 unique tests (κ=0.5). When reviewers set the consensus (gold standard), individual agreement with it was 88%, 94% and 70%. The agreement between AI and "gold-standard" was 73%; over-reader agreement was 46%. AI-based software can be used to measure spirometry data quality with comparable accuracy as experts. The assessment is a subjective exercise, with intra- and inter-rater variability even when the criteria are defined very precisely and objectively. By providing consistent results and immediate feedback to the sites, AI may benefit clinical trial conduct and variability reduction.

Diagnosis and treatment of adult asthma patients in Serbia: a 2022 experts group position statement

ABSTRACT Introduction Asthma is the most common non-communicable chronic lung condition across all ages. Epidemiological data indicate that many asthma patients in Serbia remain undiagnosed and untreated. The implementation of recent global advances in asthma management is limited due to the lack of a systematic approach, drug availability and regulatory affairs. In addition, the global coronavirus disease pandemic has posed a significant challenge, particularly in resource-limited settings. Areas covered In this paper, we propose an algorithm for treating adult asthma patients in Serbia. We performed PubMed database search on published asthma clinical trials and guidelines from 1 January 2015 to 10 March 2020. The consensus process incorporated a modified Delphi method that included two rounds of e-mail questionnaires and three rounds of national asthma expert meetings. We focus on 1) objective diagnosis of asthma, 2) the implementation of up-to-date therapeutic options, and 3) the identification and referral of severe asthma patients to newly established severe asthma centers. Expert opinion Regional specificities and variations in healthcare systems require the adaptation of evidence-based knowledge. Practical, clinically oriented algorithms designed to overcome local barriers in healthcare delivery may facilitate timely and adequate asthma diagnosis and the local implementation of current advances in asthma management.

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework.

Sub-stratification of type-2 high airway disease for therapeutic decision-making: A 'bomb' (blood eosinophils) meets 'magnet' (FeNO) framework.

Is Inhaler Technique Adequately Assessed and Reported in Clinical Trials of Asthma and Chronic Obstructive Pulmonary Disease Therapy? A Systematic Review and Suggested Best Practice Checklist

Inhaled medications are central to treating asthma and chronic obstructive pulmonary disease (COPD), yet critical inhaler technique errors are made by up to 90% of patients. In the clinical research setting, recruitment of subjects with poor inhaler technique may give a false impression of both the benefits and the necessity of add-on treatments such as biologic therapies. To assess the frequency with which inhaler technique is assessed and reliably optimized before and during patient enrollment into randomized controlled trials (RCTs) addressing the efficacy of topical therapy, and the escalation of therapy for asthma and COPD. Systematic searches were conducted of PubMed and Embase for RCTs published in the past 10 years involving patients with a diagnosis of asthma or COPD undergoing escalation of baseline inhaled therapy (stepping up, changing, adding, switching, increasing, etc) or the introduction of biologic agents. Searches highlighted 1,014 studies, 118 of which were eligible after the removal of duplicates as well as screening and full text review. Of these, only 14 (11.9%) included accessible information in the methods section or referred to such information in online supplements or protocols concerning assessment of participants' inhaler technique. We therefore developed the proposed Best Practice Inhaler Technique Assessment and Reporting Checklist. Our study identifies a concerning lack of checking and correcting inhaler technique, or at least reporting that this was undertaken, before enrollment in asthma and COPD RCTs, which may affect the conclusions drawn. Mandating the use of a standardized checklist in RCT protocols and ensuring all published RCTs report checking and correcting inhaler technique before enrollment are important next steps.

The Racial and Ethnic Makeup of the Asthma Clinical Trials informing the 2020 NHLBI asthma guidelines update

Black/African American and Hispanic people in the United States are disproportionately impacted by asthma with increased prevalence, morbidity, and mortality. However, these groups are often under-represented in asthma clinical and translational research studies which is a barrier to achieving health equity. We describe the racial/ethnic makeup of participants in clinical trials which informed the recent 2020 National Heart, Lung, and Blood Institute (NHLBI) asthma management guidelines focused update.

A stochastic mixed effects model to assess treatment effects and fluctuations in home‐measured peak expiratory flow and the association with exacerbation risk in asthma

Home‐based measures of lung function, inflammation, symptoms, and medication use are frequently collected in respiratory clinical trials. However, new statistical approaches are needed to make better use of the information contained in these data‐rich variables. In this work, we use data from two phase III asthma clinical trials demonstrating the benefit of benralizumab treatment to develop a novel longitudinal mixed effects model of peak expiratory flow (PEF), a lung function measure easily captured at home using a hand‐held device. The model is based on an extension of the mixed effects modeling framework to incorporate stochastic differential equations and allows for quantification of several statistical properties of a patient's PEF data: the longitudinal trend, long‐term fluctuations, and day‐to‐day variability. These properties are compared between treatment groups and related to a patient's exacerbation risk using a repeated time‐to‐event model. The mixed effects model adequately described the observed data from the two clinical trials, and model parameters were accurately estimated. Benralizumab treatment was shown to improve a patient's average PEF level and reduce long‐term fluctuations. Both of these effects were shown to be associated with a lower exacerbation risk. The day‐to‐day variability was neither significantly affected by treatment nor associated with exacerbation risk. Our work shows the potential of a stochastic model‐based analysis of home‐based lung function measures to support better estimation and understanding of treatment effects and disease stability. The proposed analysis can serve as a complement to descriptive statistics of home‐based measures in the reporting of respiratory clinical trials.

Heterogeneity of Mild to Moderate Persistent Asthma in Children: Confirmation by Latent Class Analysis and Association With 1-Year Outcomes

To identify latent classes of childhood asthma and determine if latent class assignments predict subsequent lung function abnormalities and exacerbation rate at 12 months of follow-up.2593 children aged 5 to 18 years enrolled in NHLBI clinical trials on mild-to-moderate asthma and who had documented adherence to article or electronic diaries.Latent class analyses were performed on the subjects on the basis of data that had been obtained as part of the clinical trials, which included questionnaires, asthma documentation and characterization by spirometry, asthma control questionnaires, total immunoglobulin E, blood eosinophils, and allergy tests. Primary outcomes included pulmonary function and the exacerbation rate over 1 year of follow-up.Five latent classes were identified. Class 1 was as follows: multiple allergic sensitizations with partially reversible airflow limitation. Class 2 was as follows: multiple sensitization with reversible airflow limitation; Class 3 was as follows: lesser sensitization with reversible airflow limitation. Class 4 was as follows: multiple sensitization with normal lung function. Class 5 was as follows: lesser sensitization with normal lung function. Lesser sensitization means mostly nonsensitivity or monosensitivity. Latent class 2 was the largest group (35.7%), followed by class 4 (27.6%), class 5 (15.0%), class 3 (12.1%), and class 1 (9.4%). Children in class 1 had lower pulmonary function at the end of the first year, with lesser treatment response. Children in class 2 revealed improvement in lung function with treatment, and seemed to respond to any controller therapy, whereas those in class 4 and 5 had a greater response to inhaled corticosteroids. Exacerbations occurred in 52.5% of class 1, 43.0% of class 4, 41.6% of class 2, 36.8% of class 3, and 34.1% of class 5; class 1 had significantly increased exacerbations, compared with that of the other classes. Inhaled corticosteroids treatment significantly reduced exacerbations in classes 1, 2, and 4 but not in classes 3 and 5. Lung function deficits persisted despite treatment of class 1.Exacerbation rates were highest in children with multiple sensitization and partially reversible airflow limitation. Sensitization and lung function measures in children may be useful for predicting future risk in clinical settings.Because these children were all enrolled in asthma clinical trials, the results may not be generalizable to the overall pediatric asthma population, but the results do reveal that children with asthma may benefit from comanagement with an allergist to better predict those at the most risk and need for more than conventional medications.

Changes in asthma and general health after Hurricane Harvey: A natural experiment utilizing an asthma clinical trial, Harris County, TX

BACKGROUND AND AIM: On August 25, 2017, roughly two-thirds through a clinical trial (HIITBAC1) targeting low-income African-American adults with poorly controlled asthma, Hurricane Harvey made landfall along the Gulf coast. Of the 263 HIITBAC1 enrollees, we re-enrolled 75 of 107 who had exited HIITBAC1 during the 12 months before Harvey to assess their health and resilience before and after the disaster. Here we report on the change observed in several key measures. METHODS: Data collected before and after Harvey were largely the same, and included clinical measures, Asthma Control Test (ACT), Asthma Quality of Life Questionnaire (MiniAQLQ), PROMIS global health, PROMIS emotional support, an exposure history, healthcare utilization, and (in most pre- and all post-Harvey enrollees) an in-home assessment of environmental hazards. In addition, we obtained blood samples; information about their Harvey experience, including trauma scores; and exhaled nitric oxide and airborne mold samples from the post-Harvey enrollees. A linear mixed model was used to assess pre- versus post-Harvey changes in health outcomes and the association with flooding damage, and quantile regression to assess eNO association with spore count. Analyses controlled for potential confounders. RESULTS:The average age was 55 years (83% female) and 57% of participants had a household income $15,000. Compared to pre-Harvey, post-Harvey scores on key health outcomes (i.e., ACT, MiniAQLQ, global physical health, global mental health) decreased significantly. Post Harvey, global physical health was significantly lower for those who flooded, compared with those who did not, whereas global mental health was lower for those reporting Harvey-related home damage. Neither flooding nor Harvey-related home damage were associated with ACT and MiniAQLQ after adjusting for pre-disaster characteristics. Post Harvey, no statistically significant association between eNO and spore counts was found. CONCLUSIONS:Our initial analyses suggest that Hurricane Harvey adversely affected health in this vulnerable population. KEYWORDS: Asthma, Environmental disparities, Environmental epidemiology, Exposure assessment, Natural disaster

Use of Health Related Quality of Life in Clinical Trials for Severe Asthma: A Systematic Review.

BackgroundAsthma Health Related Quality of Life (HRQoL) is an outcome important to patients with severe asthma and can provide clinicians with additional insight into the benefits of treatment. The aim of this systematic review is to examine the use and reporting of HRQoL questionnaires within randomised controlled trials (RCTs) of biologics, fevipiprant and bronchial thermoplasty.MethodsWe followed the guidelines on the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement. Of the 2380 retrieved articles, 52 studies were identified for inclusion.ResultsSixty-three percent included an asthma HRQoL questionnaire. It was a secondary outcome in the majority of cases (73%). The proportion of studies including an asthma HRQoL questionnaire did not change significantly over a 20-year period. While the Asthma Quality of Life Questionnaire (AQLQ) was used in 45% of studies, 55% used a variety of 4 questionnaires. Most (70%) of the studies that included a HRQoL questionnaire did not report its subscale scores. Approximately half (52%) of studies that used HRQoL reported this in the abstract of the paper. A higher proportion of studies used an asthma control questionnaire compared to a HRQoL questionnaire (71% vs 63%).ConclusionIn order to increase the use of asthma HRQoL questionnaires in RCTs of severe asthma treatments, the drivers and barriers to their use must first be understood. At present, the patients’ perspective is underrepresented in RCTs of biologics, fevipiprant and bronchial thermoplasty for severe asthma.

Type-2 airway inflammation in mild asthma patients with high blood eosinophils and high fractional exhaled nitric oxide.

Type‐2 (T2) inflammation is a characteristic feature of asthma. Biological therapies have been developed to target T2‐inflammation in asthma. IL‐13 is a key component of T2‐inflammation in asthma, driving mucus hypersecretion, IgE‐induction, and smooth muscle contraction. Early phase clinical trials for treatments that target T2‐inflammation require biomarkers to assess pharmacological effects. The aim of this study was to examine levels of IL‐13 inducible biomarkers in the airway epithelium of patients with mild asthma compared to healthy controls. Ten patients with mild asthma with high blood eosinophil and high fractional exhaled nitric oxide (FeNO) were recruited, and six healthy subjects. Blood eosinophil and FeNO reproducibility was assessed prior to bronchoscopy. Epithelial brushings were collected and assessed for IL‐13 inducible gene expression. Blood eosinophil and FeNO levels remained consistent in both patients with asthma and healthy subjects. Of the 11 genes assessed, expression levels of 15LOX1, POSTN, CLCA1, SERPINB2, CCL26, and NOS2 were significantly higher in patients with asthma compared to healthy controls. These six genes, present in patients with mild asthma with T2 inflammation, have the potential to be used in translational early phase asthma clinical trials of novel therapies as bronchial epithelial biomarkers.