Risk Of Asthma Exacerbations Research Articles

The effect and relative importance of sleep disorders for all-cause mortality in middle-aged and older asthmatics

BackgroundPrevious studies observed that sleep disorders potentially increased the risk of asthma and asthmatic exacerbation. We aimed to examine whether excessive daytime sleepiness (EDS), probable insomnia, objective short sleep duration (OSSD), and obstructive sleep apnea (OSA) affect all-cause mortality (ACM) in individuals with or without asthma.MethodsWe extracted relevant data from the Sleep Heart Health Study established in 1995–1998 with an 11.4-year follow-up. Multivariate Cox regression analysis with a proportional hazards model was used to estimate the associations between ACM and four sleep disorders among asthmatic patients and individuals without asthma. Dose-response analysis and machine learning (random survival forest and CoxBoost) further evaluated the impact of sleep disorders on ACM in asthmatic patients.ResultsA total of 4538 individuals with 990 deaths were included in our study, including 357 asthmatic patients with 64 deaths. Three multivariate Cox regression analyses suggested that OSSD (adjusted HR = 2.67, 95% CI: 1.23–5.77) but not probable insomnia, EDS or OSA significantly increased the risk of ACM in asthmatic patients. Three dose-response analyses also indicated that the extension of objective sleep duration was associated with a reduction in ACM in asthmatic patients compared to very OSSD patients. Severe EDS potentially augmented the risk of ACM compared with asthmatics without EDS (adjusted HR = 3.08, 95% CI: 1.11–8.56). Machine learning demonstrated that OSSD of four sleep disorders had the largest relative importance for ACM in asthmatics, followed by EDS, OSA and probable insomnia.ConclusionsThis study observed that OSSD and severe EDS were positively associated with an increase in ACM in asthmatic patients. Periodic screening and effective intervention of sleep disorders are necessary for the management of asthma.

REAL-WORLD EFFECTIVENESS OF DUPILUMAB IN ASTHMA: FINDINGS FROM THE US ADVANTAGE STUDY

<h3>Introduction</h3> Real-world evidence on patients with moderate-to-severe asthma treated with dupilumab is limited. Patients included in clinical trials may differ from the ones seen on a clinical office setting. The objective of our study was to characterize real-world effectiveness of dupilumab in US, as an add-on treatment in patients with moderate to severe asthma. <h3>Methods</h3> We retrospectively included patients (≥12 years of age) diagnosed with asthma, initiating dupilumab (index) between November 2018 to September 2020, with 12 months pre- and post-index information. The study employed a pre-post self-control design (TriNetX Dataworks, USA). Asthma exacerbation rates before vs. after dupilumab initiation were analyzed using Generalized Estimating Equations models with Poisson probabilistic link to estimate incidence rate ratios (IRRs). Sensitivity analyses on asthma exacerbations adjusted for COVID-19 confounding effects were performed using natural cubic splines to allow for time-varying effect estimates during pre- and post-pandemic time periods. <h3>Results</h3> A total of 2400 patients initiating dupilumab met all study criteria and 75.3% were biologic naïve. Dupilumab reduced risk of asthma exacerbations by 38% (IRR: 0.62 [95% confidence interval: 0.58-0.65], P=<.0001). Significant reductions in asthma exacerbations were observed in patients with at least 1 or 2, pre-index, asthma exacerbations, by eosinophil count categories, and when adjusted for impact of COVID-19 (Table-1) <h3>Conclusion</h3> The US ADVANTAGE study demonstrated real-world effectiveness of dupilumab in reducing asthma exacerbation among patients 12 years and older in US clinical practice. These findings are generally consistent with data from previous pivotal clinical trials with dupilumab.

Short-acting β2 -agonist use and asthma exacerbations in Swedish children: A SABINA Junior study.

In adults and adolescents with asthma, use of ≥3 short-acting β2 -agonist (SABA) canisters/year is associated with increased exacerbation risk. Whether this association is present in younger children remains unknown. In this SABA use IN Asthma (SABINA) Junior study, we assessed the association of SABA collection with exacerbation risk in the general Swedish pediatric asthma population. This population-based cohort study utilized linked data from the Swedish national healthcare registries involving patients with asthma (<18 years) treated in secondary care between 2006-2015. Exacerbation risk, by baseline SABA collection (0-2 vs. ≥3 canisters, further examined as ordinal/continuous variable) and stratified on comorbid atopic disease (allergic rhinitis, dermatitis and eczema, and food/other allergies), was assessed for 1-year follow-up using negative binomial regression. Of 219,561 patients assessed, 45.4%, 31.7%, and 26.5% of patients aged 0-5, 6-11, and 12-17 years, respectively, collected ≥3 SABA canisters during the baseline year (high use). Collection of ≥3 SABA canisters (vs. 0-2) was associated with increased exacerbation risk during follow-up (incidence rate ratios [95% confidence interval]: 1.35 [1.29-1.42], 1.22 [1.15-1.29], and 1.26 [1.19-1.34] for 0-5-, 6-11-, and 12-17-year-olds, respectively); the association persisted with SABA as a continuous variable and was stronger among patients without atopic diseases (32%-44% increased risk versus. 14%-21% for those with atopic disease across groups). High SABA use was associated with increased asthma exacerbation risk in children, particularly in those without comorbid atopic diseases, emphasizing the need for asthma medication reviews and reformative initiatives by caregivers and healthcare providers on SABA use.

Optimal follow-up period after switching to another inhaled corticosteroid/long-acting β2 agonist in patients with asthma: A retrospective study using Japanese administrative claims data.

Switching inhalation devices is a reasonable option if problems with control, adherence, or inhalation technique occur in patients with asthma treated with inhaled corticosteroid (ICS)/long-acting β2 agonist (LABA). However, evidence to determine the extent to which the carefully monitored period persists after switching is insufficient. In this study, we aimed to investigate the duration of the carefully monitored period after switching to another ICS/LABA. This retrospective study used claims data from Japanese health insurance associations from May 2014 to April 2019. A total of 1,951 patients who switched to another ICS/LABA during the study period were selected for analysis. The relative risk of the first exacerbation after switching was calculated for each four-week interval after the switch compared with that before the switch in a self-controlled case series design. We further assessed patient background associated with exacerbations during the follow-up period. In the primary analysis, the risk of asthma exacerbation compared to the control period was derived from a conditional logistic regression model, which showed a significant decrease immediately after the switch (1 to 4 weeks, Odds ratio [OR] 0.37, 95% confidence interval [CI] 0.26–0.54). Subsequently, the risk increased again and was not significantly different from the control period until week 32 (OR 0.55, 95% CI 0.29–1.04). In a sensitivity analysis among patients with a history of exacerbations, up to week 20 was the period of no continuous risk reduction (OR 0.84, 95% CI 0.41–1.70). In the secondary analysis, chronic rhinosinusitis, sleep disorders, and a history of asthma exacerbation were significantly associated with asthma exacerbation. The incidence of exacerbation remained high for approximately 4 to 7 months after patients with asthma switched to another ICS/LABA. Therefore, these patients should be carefully monitored for at least 4 to 7 months and should be re-assessed at an earlier point in time, if necessary.

Association Between Medication Adherence and Risk of COPD in Adult Asthma Patients: A Retrospective Cohort Study in Canada.

Poor adherence to prescribed asthma medications and risk of severe asthma exacerbations have been well established. However, the effects of changes in asthma medication compliance levels and subsequent risk of COPD is unknown and yet to be investigated. This study investigated the independent effect of medication adherence (MA) and asthma severity levels on the risk of COPD. We used four linked administrative health databases from the Population data BC to identify asthma patients aged 18 years and older between January 1, 1998 and December 31, 1999 without diagnosis of COPD. The primary event was time-to-COPD diagnosis during the follow-up period (January 1, 2000 to December 31, 2018). The proportion of days covered (PDC) - was used as a surrogate measure for medication adherence (MA) assessed at optimal-level (≥ 0.80), Intermediate-level (0.50-0.79), and low-level (< 0.5) of adherence. A propensity adjusted analysis with Marginal Structural Cox (MSC) model was employed to estimate the adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for the effect of medication adherence and asthma severity over time. At cohort entry, the sample included 68,211 asthma patients with an overall mean age of 48.2 years. The 18-year incidence of COPD in asthma patients was 9.8 per 1000-persons year. In an inverse weighted propensity adjusted analysis of the MSC model, higher MA levels were significantly associated with decreased risk of COPD as follows: optimal-level (aHR: 0.19, 95% CI: 0.17-0.24); Intermediate-level (aHR: 0.20, 95% CI: 0.18, 0.23) compared to the low-level adherence group. A significant increase in COPD risk was observed in severe asthma patients with low medication adherence (aHR: 1.72, 95% CI: 1.52-1.93), independent of other patient factors. Optimal (≥ 0.80) and intermediate adherence (0.5 to 0.79) levels were associated with reduced risk of COPD incidence over time. Interventions aimed at improving adherence to prescribed medications in adult asthma patients should be intensified to reduce their risk of COPD.

Long-term effects of vitamin D on exacerbation rate, health care utilization and lung function in children with asthma.

Asthma exacerbations lead to unplanned health care utilization and reduced lung function in children. Sufficient vitamin D level has been found to have a short-term protective effect against asthma exacerbation in children. However, it is unclear whether this effect remains in the long term. We evaluated the long-term effects of vitamin D levels on the occurrence of asthma exacerbations, emergency department visits or hospitalizations, and lung function among children with asthma, and further investigated the temporal trends of the effects. In this retrospective cohort study, children with asthma who were admitted to the Children's Hospital of Chongqing Medical University from 2017 to 2021 were enrolled. Negative binomial, Poisson, or logistic regression model was used for the multivariable analysis, adjusting for age, sex, body mass index z-score, and severity of asthma exacerbation. Of the 370 children with asthma, 87.8% had vitamin D level less than or equal to 30 ng/mL. After adjustment for confounding factors, higher baseline vitamin D levels in asthma children were significantly associated with reduced occurrence of asthma exacerbations during the first [odds ratio 0.842, 95% confidence interval (CI): 0.805-0.881; P<0.001], second (odds ratio 0.848, 95% CI: 0.793-0.907; P<0.001) and third years (odds ratio 0.865, 95% CI: 0.811-0.922; P<0.001) of follow-up. Higher vitamin D levels in asthmatic children were also strongly associated with a reduced number of emergency department visits or hospitalizations during the first (odds ratio 0.880, 95% CI: 0.842-0.920; P<0.001), second (odds ratio 0.885, 95% CI: 0.832-0.941; P<0.001), and third years (odds ratio 0.922, 95% CI: 0.851-0.998; P=0.044) of follow-up. In addition, the vitamin D levels in asthmatic children were found to be negatively associated with the odds of large airway dysfunction (odds ratio 0.865, 95% CI: 0.771-0.970; P=0.013) and small airway dysfunction (odds ratio 0.922, 95% CI: 0.855-0.996; P=0.038) during the first year of follow-up. Sufficient vitamin D level is associated with lower risk of asthma exacerbations and health care utilization over a 3-year period, and improved lung function over 1 year. The protective effects of vitamin D on asthmatic children decreased over time.

250 Tracking Asthma Medication Use in Children After an Emergency Department Visit With a Smart Inhaler and Connected Mobile Application

Asthma is the most common chronic childhood illness and the third leading cause of hospitalization among pediatric patients in the US. It is responsible for more than 1.8 million emergency department (ED) visits per year and represents significant health care burden and costs. The primary objective of this study is to determine the feasibility of employing a “smart” inhaler connected to a mobile application to track asthma inhaler use after an ED visit. Future goals are to determine if regular daily use of a steroid inhaler results in less rescue medication use, and to connect this usage with real time environmental data to build a risk profile to alert patients of conditions that increase risk of asthma exacerbation.

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.

Urinary total conjugated 3-bromotyrosine, asthma severity, and exacerbation risk.

Asthma is an inflammatory disease of the airways characterized by eosinophil recruitment, eosinophil peroxidase release, and protein oxidation through bromination, which following tissue remodeling results in excretion of 3-bromotyrosine. Predicting exacerbations and reducing their frequency is critical for the treatment of severe asthma. In this study, we aimed to investigate whether urinary total conjugated bromotyrosine can discriminate asthma severity and predict asthma exacerbations. We collected urine from participants with severe (n = 253) and nonsevere (n = 178) asthma, and the number of adjudicated exacerbations in 1-yr longitudinal follow-up was determined among subjects enrolled in the Severe Asthma Research Program, a large-scale National Institutes of Health (NIH)-funded consortium. Urine glucuronidated bromotyrosine and total conjugated forms were quantified by hydrolysis with either glucuronidase or methanesulfonic acid, respectively, followed by liquid chromatography-tandem mass spectrometry analyses of free 3-bromotyrosine. Blood and sputum eosinophils were also counted. The majority of 3-bromotyrosine in urine was found to exist in conjugated forms, with glucuronidated bromotyrosine representing approximately a third, and free bromotyrosine less than 1% of total conjugated bromotyrosine. Total conjugated bromotyrosine was poorly correlated with blood (r2 = 0.038) or sputum eosinophils (r2 = 0.0069). Compared with participants with nonsevere asthma, participants with severe asthma had significantly higher urinary total conjugated bromotyrosine levels. Urinary total conjugated bromotyrosine was independently associated with asthma severity, correlated with the number of asthma exacerbations, and served as a predictor of asthma exacerbation risk over 1-yr of follow-up.

Dupilumab efficacy and safety in Latin American patients with uncontrolled, moderate-to-severe asthma: phase 3 LIBERTY ASTHMA QUEST study

Objective While advances in asthma care have been made in Latin America, there is still a large unmet need in patients with uncontrolled asthma. This post hoc analysis of the QUEST study assessed safety and efficacy of dupilumab in the subgroup of patients enrolled in Latin American countries with a type 2 inflammatory asthma phenotype (blood eosinophils ≥ 150cells/µL or FeNO ≥25ppb). Methods LIBERTY ASTHMA QUEST (NCT02414854) was a phase 3, multinational, randomized, double-blind, placebo-controlled study in patients with uncontrolled, moderate-to-severe asthma. Eligible patients ≥ 12 years of age were randomized in a 2:2:1:1 ratio to receive 52 weeks of add-on subcutaneous dupilumab 200 or 300 mg every 2 weeks or matched-volume placebos. Pre-specified co-primary efficacy endpoints were the annualized rate of severe exacerbations during the treatment period and the change from baseline in pre-bronchodilator FEV1 at treatment week 12. Asthma control, changes in asthma biomarker levels, and dupilumab safety were also evaluated. Results 530 (27.9% of the overall QUEST population; dupilumab: 353, placebo: 177) Latin-American patients were recruited; 420 (79.2%) had a type 2 inflammatory asthma phenotype. Dupilumab vs placebo reduced the annualized rate of severe exacerbations by 52.7% (P < 0.001) and increased pre-bronchodilator FEV1 at week 12 by 0.15 L (P < 0.001), in the type 2 population. Safety was consistent with the known dupilumab safety profile. Conclusions Consistent with the results in the overall population, dupilumab reduced the risk of severe asthma exacerbations and improved lung function in Latin American patients with uncontrolled, moderate-to-severe asthma and a type 2 phenotype.

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.

Determinants of asthma control and exacerbations in moderate to severe asthma

Determinants of asthma control and exacerbations in moderate to severe asthma

Reduced bronchodilator reversibility correlates with non-type 2 high asthma and future exacerbations: A prospective cohort study

BackgroundGiven that airway obstruction in asthma is not always fully reversible, reduced bronchodilator reversibility (BDR) may be a special asthma phenotype. ObjectiveTo explore the characteristics of BDRhigh/low phenotypes (defined using two BDR criteria) and their associations with asthma exacerbations (AEs). MethodsAfter baseline assessments, all patients were classified into BDRhigh or BDRlow phenotypes. This study consisted of 2 parts. Part I was a 12-month prospective observational cohort study designed to identify the clinical characteristics and associations with future AEs in BDRhigh/low phenotypes (n = 456). Part II, designed as a post hoc analysis of the data obtained in Part I, was conducted to assess the association between BDRhigh/low phenotypes and treatment responsiveness (n = 360). ResultsSubjects with BDRlow phenotypes had better baseline asthma symptom control and was negatively associated with eosinophilic asthma and type 2 (T2) high asthma. During the 12-month follow-up, those with BDRlow phenotypes had a higher risk of severe AEs (SAEs) (guideline-based criterion: RRadj = 2.24, 95% CI = [1.25, 3.68]; Ward's criterion: RRadj = 2.46, 95% CI = [1.40, 4.00]) and moderate-to-severe AEs (MSAEs) (guideline-based criterion: RRadj = 1.83, 95% CI = [1.22, 2.56]; Ward's criterion: RRadj = 1.94, 95% CI = [1.32, 2.68]) in the following year according to logistic regression models. Similar findings were obtained with negative binominal regression models. BDRlow phenotype was a risk factor for an insensitive response to anti-asthma treatment (guideline-based criterion: ORadj = 1.96, 95% CI = [1.05, 3.65]; Ward's criterion: ORadj = 2.01, 95% CI = [1.12, 3.58]). ConclusionWe identified that BDRlow phenotype was associated with non-T2 high asthma and future AEs. These findings have clinically relevant implications for asthma management.

Risk factors for asthma exacerbations during pregnancy: a systematic review and meta-analysis.

Conflicting literature exists regarding the risk factors for exacerbations among pregnant women with asthma. This systematic review and meta-analysis aimed to determine risk factors for asthma exacerbations during pregnancy. Electronic databases were searched for the following terms: (asthma or wheeze) and (pregnan* or perinat* or obstet*) and (exacerb* or flare up or morbidit* or attack*).All studies published between 2000 and 24 August 2021 were considered for inclusion if they reported at least one potential risk factor of asthma exacerbations in pregnant women with asthma. Of the 3337 references considered, 35 publications involving 429 583 pregnant women with asthma were included. Meta-analyses were conducted to determine mean difference in risk factor between exacerbation groups, or the relative risks of exacerbation with certain risk factors. Good study quality was found through the Newcastle-Ottawa Scale (median score 8, interquartile range 7-9). Increased maternal age (mean difference 0.62, 95% CI 0.11-1.13), obesity (relative risk 1.25, 95% CI 1.15-1.37), smoking (relative risk 1.35, 95% CI 1.04-1.75), black ethnicity (relative risk 1.62, 95% CI 1.52-1.73), multiparity (relative risk 1.31, 95% CI 1.01-1.68), depression/anxiety (relative risk 1.42, 95% CI 1.27-1.59), moderate-severe asthma (relative risk 3.44, 95% CI 2.03-5.83, versus mild) and severe asthma (relative risk 2.70, 95% CI 1.85-3.95, versus mild-moderate) were associated with an increased risk of asthma exacerbations during pregnancy. Future interventions aimed at reducing exacerbations in pregnancy could address the modifiable factors, such as smoking and depression/anxiety, and introduce more regular monitoring for those with nonmodifiable risk factors such as obesity and more severe asthma.

SABA use as an indicator for asthma exacerbation risk: an observational cohort study (SABINA Canada).

BackgroundPatients with asthma use short-acting β-agonists (SABA) to relieve symptoms but SABA alone does not treat underlying inflammation. Thus, over-reliance on SABA may result in poor asthma control and negative health outcomes.ObjectiveTo describe use of SABA and characterise the relationship with severe exacerbations in the Canadian provinces of Nova Scotia (NS) and Alberta (AB).MethodsIn this longitudinal Canadian SABA In Asthma (SABINA) study, patients with an asthma diagnosis were identified between 2016 and 2020 within two provincial administrative datasets (Health Data Nova Scotia and Alberta Health Services). All patients were followed for ≥24 months, with the first 12 months used to measure baseline asthma severity. Medication use and the relationship of SABA overuse (three or more canisters per year) with severe asthma exacerbations were characterised descriptively and via regression analysis.ResultsA total of 115 478 patients were identified (NS: n=8034; AB: n=107 444). SABA overuse was substantial across both provinces (NS: 39.4%; AB: 28.0%) and across all baseline disease severity categories. Patients in NS with SABA overuse had a mean±sd annual rate of 0.46±1.11 exacerbations, compared to 0.30±1.36 for those using fewer than three canisters of SABA. Patients in AB had mean±sd exacerbation rates of 0.31±0.86 and 0.17±0.62, respectively. The adjusted risk of severe exacerbation was associated with SABA overuse (NS: incidence ratio rate 1.36, 95% CI 1.18–1.56; AB: incidence ratio rate 1.32, 95% CI 1.27–1.38).ConclusionThis study supports recent updates to Canadian Thoracic Society and Global Initiative for Asthma guidelines for asthma care. SABA overuse is associated with increased risk of severe exacerbations and can be used to identify patients at a higher risk for severe exacerbations.

Albuterol–Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma

BackgroundAs asthma symptoms worsen, patients typically rely on short-acting β2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation.MethodsWe conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol–budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide (with each dose consisting of two actuations of 90 μg and 80 μg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 μg of albuterol and 80 μg of budesonide (with each dose consisting of two actuations of 90 μg and 40 μg, respectively [the lower-dose combination group]), or 180 μg of albuterol (with each dose consisting of two actuations of 90 μg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population.ResultsA total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P=0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P=0.052). The incidence of adverse events was similar in the three trial groups.ConclusionsThe risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 μg of albuterol and 160 μg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.)

Efficacy and Safety of Masitinib in Corticosteroid-Dependent Severe Asthma: A Randomized Placebo-Controlled Trial

BackgroundMasitinib is an oral tyrosine kinase inhibitor that selectively targets mast cell activity and platelet-derived growth factor receptor (PDGFR) signaling, both of which are implicated in various mechanisms of asthma pathogenesis.ObjectiveAssessment of masitinib as an add-on to standard maintenance therapy as compared with placebo in the treatment of oral corticosteroid-dependent severe asthma.MethodsWe conducted a randomized (2:1), placebo-controlled study of masitinib (6 mg/kg/d) in adults with severe asthma uncontrolled by high dose inhaled corticosteroids and long-acting beta-adrenoreceptor agonists plus oral corticosteroids (OCS) (≥7.5 mg/d). No minimum baseline blood eosinophil count was specified. Following a protocol amendment, the primary endpoint was reduction of annualized severe asthma exacerbation rate adjusted for the overall time on treatment (SAER). Subgroup analysis according to yearly cumulative OCS intake was also performed, a higher OCS dose indicating more severe asthma that is harder to control.ResultsFollowing an average exposure of approximately 13 months, masitinib (n = 240) reduced the SAER by 35% relative to placebo (n = 115) (rate ratio (RR) 0.65 (95% CI [0.47–0.90]; P = 0.010)). For patients with eosinophil ≥150 cell/µL, masitinib (n = 181) reduced SAER by 38% relative to placebo (n = 87); RR 0.62 (95% CI [0.42–0.91]; P = 0.016). Benefit of masitinib was shown to increase in the most severely affected patients (OCS intake of >1000 mg/year), with a significant (P < 0.01) reduction in SAER of 50%–70%. Safety was consistent with the known masitinib profile.ConclusionOrally administered masitinib reduces the risk of asthma exacerbations in severe asthma patients, with an acceptable safety profile. Masitinib may potentially provide a new treatment option for oral corticosteroid-dependent severe asthma.

Association between sub-daily exposure to ambient air pollution and risk of asthma exacerbations in Australian children

Short-term exposure to ambient air pollution is associated with risk of asthma attacks. We investigated the association between ultra-short-term exposure to air pollution and risk of childhood asthma exacerbations. Hourly data on emergency department visits (EDVs) for asthma in children during 2013–2015 in Brisbane, Australia, were obtained. We undertook time-stratified case-crossover analyses to examine the hourly association between exposure to air pollutants (particles with diameter ≤10 μm (PM10), particles with diameter ≤2.5 μm (PM2.5), ozone (O3), and nitrogen dioxide (NO2)) and risk of EDVs for asthma after controlling for temperature, relative humidity, public holidays and circulating levels of influenza and respiratory syncytial virus. Risk of EDVs for asthma increased within a few hours after exposure to O3 (odds ratio [OR]: 1.170, 95% confidence interval (CI): 1.003–1.365) or NO2 (OR: 1.359, 95%CI: 1.049–1.760). The association between O3 exposure and risk of EDVs for asthma was stronger in boys (OR: 1.244, 95%CI: 1.025–1.511) than that in girls (OR: 1.055, 95%CI: 0.818–1.361). The association between NO2 exposure and risk of EDVs for asthma was stronger in school-age children [OR ranged from 1.376 (95%CI: 1.044–1.813) to 3.607 (95%CI: 1.552–8.385) across different lags] than that in preschool-age children, whereas the association between PM10 exposure and risk of EDVs for asthma was greater in preschool-age children [OR ranged from 1.873 (95%CI: 1.022–3.433) to 1.878 (95%CI: 1.028–3.431)] than that in school-age children. We observed an association of risk of EDVs for asthma with daytime air pollution exposure, but not with night-time air pollution exposure. This study suggests that risk of childhood asthma exacerbations increases within a few hours of air pollution exposure.

Temporal Dynamics of the Nasopharyngeal Microbiome and its Relationship with Childhood Asthma Exacerbation.

ABSTRACTDespite distinct nasopharyngeal microbiome (NPM) profiles between asthmatics and healthy subjects, little is known about the NPM dynamics and its relation to childhood asthma exacerbation (AE). We investigated NPM changes by longitudinally collecting 135 flocked nasopharyngeal swabs (FNPSs) from 33 school-age asthmatic children at six time points (2 to 4-week intervals) from September to December 2017 in Hong Kong. Subjects were categorized into AE and stable asthma (AS) groups according to whether they experienced any exacerbation during follow-up. One-off FNPSs from nine nonasthmatic children were included as controls. Microbiota profiles were analyzed using 16S rRNA gene sequencing. All 144 NPMs were classified into six microbiome profile groups (MPGs), each dominated by Moraxella, Corynebacterium 1, Dolosigranulum, Staphylococcus, Streptococcus, or Anoxybacillus. The microbial diversity and compositions of NPM in exacerbation samples were different from both baseline samples and those from healthy controls. Moraxella and Dolosigranulum-dominated NPM exhibited high temporal stability revealed by MPG transition analysis. NPM diversity decreased whereas microbial composition remained similar over time. The relative abundances of Moraxella increased while Corynebacterium 1, Anoxybacillus, and Pseudomonas decreased longitudinally. However, these temporal patterns did not differ between AE and AS groups, suggesting that short-term dynamic patterns were not sufficient to predict AE occurrence. Asthmatic NPM underwent Moraxella expansion during AE and presented a high microbiome resilience (recovery potential) after AE resolution. Microbial pathways involved in methane, ketone bodies, and vitamin B3 metabolisms were enhanced during AE and primarily contributed by Moraxella.IMPORTANCE Evidence on the dynamic changes of NPM in asthmatic patients remains limited. Here, we present that asthmatic NPMs deviating from a healthy status still showed resilience after disturbance. Our data imply from a longitudinal perspective that Moraxella increase is closely related to AE occurrence. The finding of functional dysbiosis (imbalance) during AE offers a plausible explanation for the known association between nasopharyngeal Moraxella expansion and increased AE risk. This work serves as a basis for future long-term prospective studies leveraging multiomics approaches to elucidate the temporal association between NPM and pediatric AE.

Identifying asthma patients at high risk of exacerbation in a routine visit: A machine learning model

BackgroundTools capable of predicting the risk of asthma exacerbations can facilitate asthma management in clinical practice. However, existing tools require additional data from patients beyond electronic medical records. ObjectiveTo predict asthma exacerbation in an upcoming year using electronically accessible data conditional on past adherence to asthma medications. MethodsThis retrospective cohort study included patients with ≥1 hospitalization or ≥2 medical claims for asthma within 2 consecutive years between 2002 and 2015 in Quebec administrative databases. Cohort entry (CE) was defined as the date of the first asthma-related ambulatory visit on or after meeting the operational definition of asthma. Adherence to each controller medication and use of each rescue medication was measured in the year prior to CE. Elastic-net regularized logistic regression was applied. ResultsAmong 98,823 patients, the mean age was 55.9 years and 36.2% were men. The area under the curve for prediction was 0.708. In the model, the use of long-acting anticholinergic or long-acting β2-agonists in the year prior to CE increased the odds of exacerbation by 24% and 21%, respectively. Among patients who received rescue medication, low and high adherence to controller medications increased the odds by 2%–5% compared with patients with medium adherence. Patients with a predicted risk of ≥0.20 were more likely to develop future exacerbation. ConclusionThis risk prediction indicated that asthma-related medication use increased the risk of asthma exacerbation. A potential U-shaped relationship between adherence to controller medications and the risk of exacerbation was identified among users of rescue medications.