Clinical features and later prognosis of replicable early-life wheeze clusters from two birth cohorts 12 years apart.

BACKGROUND: Clustering techniques can define the heterogeneity of asthma and wheezing. Defining early-life wheezing clusters and associated asthma risk could potentially inform patient management strategies. Clustering models that yield replicable cluster groups will have greater validity and clinical utility. This study sought to identify early-life wheezing clusters that are translatable into clinical practice and assess their stability over time in two whole-population birth cohorts established a decade apart from the same geographical location. METHODS: Nonparametric K-means cluster analysis was performed separately on two birth cohorts from the Isle of Wight, UK; the Isle of Wight Birth Cohort (IOWBC) and Food Allergy and Intolerance Research Cohort (FAIR), using clinically defining variables in wheezing subjects in the first 3-4 years. Associations of resulting clusters with potential early-life risk factors and 10-year asthma outcomes were further assessed. RESULTS: Five clusters were identified in both cohorts: (1) infantile-onset-transient-non-atopic-wheeze, (2) infantile-onset-persistent-non-atopic-wheeze, (3) infantile-onset-atopic-wheeze, (4) early-childhood-onset-non-atopic-wheeze, and (5) early-childhood-onset-atopic-wheeze. Two atopic wheezing clusters (3 and 5) were associated with greatest early-life wheeze frequency, highest wheeze persistence, and asthma prevalence at 10 years. Cluster 1 was commonest but had lowest early-life wheeze frequency and asthma prevalence at 10 years. Cluster 2, characterized by limited atopy but recurrent infantile respiratory infections and ongoing early-life wheezing, had high 10-year asthma prevalence only in IOWBC. CONCLUSIONS: Early-life wheeze comprises several disease clusters (two more severe and three mild-moderate) with differing relationships to later childhood asthma, which can be replicated over time supporting their potential validity and clinical utility.

Is Once Versus Twice Daily Dosing Better for Adherence in Asthma and Chronic Obstructive Pulmonary Disease?

BACKGROUND: Patients with asthma and chronic obstructive pulmonary disease (COPD) may be prescribed once- or twice-daily dosing of controller inhalers. OBJECTIVE: To assess differences in controller adherence by dosing schedule and age. METHODS: Electronic medication monitors (EMMs) captured the date and time of inhaler actuations over 90 days in patients using the Propeller Health platform. Prescribed inhaler schedule was self-reported. Once- versus twice-daily schedule comparisons were assessed retrospectively using regressions adjusting for age. RESULTS: A total of 6294 patients with asthma and 1791 patients with COPD were included. On average, once-daily users had significantly higher median (interquartile range [IQR]) daily adherence than twice-daily users (asthma: 63.3 [IQR: 31.1, 86.7]% vs 50.3 [IQR: 21.1, 78.3]%, P < .001; COPD: 83.3 [IQR: 57.2, 95.6]% vs 64.7 [IQR: 32.8, 88.9]%, P < .001). This pattern persisted in all age groups, with the exception of 4- to 17-year-olds in asthma. The lowest adherence was in the young adult population (18- to 29-year-olds). The percentage of patients who achieved ≥80% adherence was significantly higher among once- versus twice-daily users in asthma (34.3% vs 23.6%, P < .001) and COPD (54.8% vs 38.6%, P < .001). The adjusted odds of once- versus twice-daily users achieving ≥80% adherence was 1.36 (95% confidence interval: 1.19-1.56, P < .001) in asthma and 1.73 (95% confidence interval: 1.38-2.17, P < .001) in COPD. Most once-daily patients with COPD took their medication in the morning versus at night; there was no difference in morning versus afternoon/evening administration in all other asthma and COPD groups. CONCLUSION: Patients with asthma and COPD who were prescribed once-daily versus twice-daily medications were more likely to adhere to their inhalers. Patients with COPD had higher adherence than those with asthma, possibly reflecting, in part, the older cohort age. The effect of greater adherence on exacerbations is a topic for future analysis.

Factors to Consider in Prescribing Asthma Biologic Therapies to Children.

The increasing availability of biologics, both by expanding age indications and by development of new therapies, provides additional options to treat children and adolescents with severe asthma. However, the evidence for these biologics in these populations is limited compared with that for adult studies. As such, before initiation of therapy, possible alternative therapies that can also provide asthma control, confirmation of the diagnosis of asthma, management of comorbidities, and assessment of adherence should be explored. The choice of a biologic should be a shared decision-making process between providers and families, balancing biologic efficacy, goals of care, administration, and ability to treat multiple conditions. Response to treatment should be periodically evaluated not only to ensure an ineffective treatment is not continued but also to consider when to potentially discontinue therapy should it be beneficial. The utilization of biologics in children and adolescents with severe asthma also leads to unanswered questions on their role in disease remission and long-term outcomes.

Difficult-to-Treat Asthma Management in School-Age Children.

The World Health Organization divides severe asthma into three categories: untreated severe asthma; difficult-to-treat severe asthma; and severe, therapy-resistant asthma. The apparent frequency of severe asthma in the general population of asthmatic children is probably around 5%. Upon referral of these children, it is important to evaluate the diagnosis of asthma carefully before modifying management and applying a long-term monitoring plan. Identification of pathophysiologic phenotypes using objective biomarkers is essential in our routine assessments of severe asthma. Although conventional pharmacologic approaches should be attempted first, there is growing recognition that children with difficult-to-treat asthma may have unique clinical phenotypes that may necessitate alternative treatment approaches including asthma biologics. These new medications, especially those with effects on multiple pathologic features of asthma, raise the hope that new treatment strategies could induce remission. Besides introducing new medications, the opportunity for closer monitoring is feasible with advances in digital health. Therefore, we have the opportunity to improve response to medications, individualize treatment, and monitor response along with potential steps to prevent severe asthma.

Assessing asthma control: comparison of electronic-recorded short-acting beta-agonist rescue use and self-reported use utilizing the asthma control test.

Background: Question 4 (Q4) of the Asthma Control Test (ACT) asks patients to report their SABA use over the prior 4 weeks, a criterion for evaluating the impairment domain of asthma control. Biases in recall may lead to a misclassification of asthma control and has implications for asthma control determination and management strategies.Objective: To correlate objective electronic-recorded short-acting beta-agonist (SABA) use with self-reported use via Q4 of the ACT.Methods: Patients ≥18 years of age with a self-reported diagnosis of asthma were enrolled in a digital health electronic medication monitoring (EMM) platform, which recorded the date and time of SABA actuations and prompted the completion of the ACT. The correlations between ACT Q4 responses and EMM-recorded SABA use were evaluated using Spearman's rank correlation coefficients.Results: 1,062 patients (mean age: 35.4 years, mean ACT: 16.3) were included in analyses. Higher Q4 scores, indicating lower SABA use, were moderately and negatively correlated with EMM-recorded SABA use (ρ = -0.59 [95% CI: -0.63, -0.54]). Thirty-five percent of patients underreported SABA use when comparing Q4 to EMM-recorded SABA use.Conclusions: While ACT Q4 and EMM-recorded use were moderately correlated, underreported SABA use on the ACT highlights the need for objective measures of SABA use in asthma control assessments. The use of EMM-recorded SABA data has the potential for clinicians to more accurately determine asthma control, guide changes to controller therapy, and estimate imminent exacerbation risk.

Electronic medication monitors help determine adherence subgroups in asthma.

Non-adherence to treatment regimens in asthma is well described, however less is known about temporal patterns of medication use. We monitored 20 weeks of controller medication use and analyzed these patterns in patients ≥4 years of age with self-reported asthma enrolled in a digital health program. At baseline, approximately 20%, 28%, 25% and 27% of patients had optimal, moderate, sub-optimal and poor adherence, respectively. Medication adherence decreased in all groups in this study. The largest absolute decreases in adherence (-32%) were observed for moderately adherent patients. Certain adherence patterns which demonstrated greater declines, that, once identified, could be intervened upon.

It's Time to Start Phenotyping Our Patients with Asthma.

Advances in the management of pediatric asthma, including biologics, offer practitioners the ability to tailor therapies to individual patients. However, asthma treatment guidelines have not kept up with current studies. This review explores the current literature incorporating the use of phenotyping in pediatric patients with asthma to provide precision therapy. Biomarkers can be used to more accurately predict the development of asthma, identify features that may be associated with difficult-to-control or severe asthma, and forecast response to therapies. Biomarkers and other phenotypic data can also be helpful in patients with uncontrolled, severe asthma in the selection of a biologic therapy.

Cost-effectiveness and comparative effectiveness of biologic therapy for asthma: To biologic or not to biologic?

OBJECTIVE: To evaluate relevant studies and documents that address the cost-effectiveness and comparative effectiveness of biologics current approved by the US Food and Drug Administration for the treatment of asthma. DATA SOURCES: Publications currently available on biologics, the Global Initiative for Asthma pocket book on difficult-to-treat asthma in adolescents and adults, and the recent Institute for Clinical and Economic Review on biologic therapies for the treatment of asthma. STUDY SELECTIONS: Priority was placed on studies that speak to the cost-effectiveness and comparative effectiveness of biologic therapies published from 2016 to 2019. RESULTS: Current pricing for all biologics exceeds measures of cost-effectiveness. To meet available measures indicating cost-effectiveness, prices would have to be reduced by a minimum of approximately 60%. The effect of biologics on exacerbations is similar but should be interpreted in the context of comparable patient phenotypes. The effect on quality of life is deemed modest based on the available study designs. CONCLUSION: To maximize cost-effectiveness of the biologics, emphasis should be placed on identifying predictors of response, focusing on those patients receiving oral corticosteroid therapy, and assessing the effect of treatment for decisions that relate to continuation. Multidisciplinary stakeholder efforts are needed to ensure responsible application of biologic therapy.

Controlling the Risk Domain in Pediatric Asthma through Personalized Care.

Strategies to control the risk domain of NHLBI EPR-3 (National Heart, Lung, and Blood Institute Expert Panel Report-3) asthma guidelines, which includes exacerbations requiring systemic corticosteroids, reduction in lung growth, and progressive loss of lung function, and treatment-related adverse effects, are evolving in children and adolescents. Increasing evidence demonstrates that children and adolescents with asthma are at risk of a reduction in lung growth, leading to lower lung function and potentially chronic obstructive pulmonary disease as adults. Readily available clinical biomarkers for atopy, including aeroallergen testing, total serum IgE, blood eosinophilia, and spirometry, are being utilized to phenotype difficult-to-treat pediatric patients, to assess risk for seasonal exacerbations, and to predict response to controller therapies. The Composite Asthma Severity Index is a novel, freely available scoring system to define asthma control, incorporating NHLBI EPR-3 risk and impairment domains. As new asthma controller therapies, such as tiotropium, are introduced for pediatric use, the safety of established controller therapies including inhaled corticosteroid and long-acting beta-agonist are being reexamined. Macrolide antibiotics may be an oral corticosteroid sparing alternative for the treatment of severe respiratory tract infection in preschool-aged children. Seasonally directed courses of omalizumab may provide an alternative approach to prevent fall asthma exacerbations in children. Combining these pharmaceuticals and biomarker-directed therapies provide potential new options and personalized approaches to gain asthma control in pediatric patients failing current management.

Approaching Current and New Drug Therapies for Pediatric Asthma.

As new therapies for pediatric asthma are approved by the Food and Drug Administration, clinicians should be aware of their benefits and limitations. Accompanying these therapies are potential obstacles, including the delivery of inhaled therapies and age-specific issues regarding implementation and adherence. New insights are being added to well-established controller medications, including inhaled corticosteroids and long-acting ß-agonists, while new medications previously approved in adults, including tiotropium and biologics, are now being evaluated for use in children. These drugs can be useful additive therapies to treat patients who are currently not responding to guidelines-based therapy.

Advances in asthma in 2016: Designing individualized approaches to management.

In this year's Advances in Asthma review, we discuss viral infections in asthmatic patients and potential therapeutic agents, the microbiome, novel genetic associations with asthma, air quality and climate effects on asthma, exposures during development and long-term sequelae of childhood asthma, patient-centered outcomes research, and precision medicine. In addition, we discuss application of biomarkers to precision medicine and new information on asthma medications. New evidence indicates that rhinovirus-triggered asthma exacerbations become more severe as the degree of sensitization to dust mite and mouse increase. The 2 biggest drivers of asthma severity are an allergy pathway starting with allergic sensitization and an environmental tobacco smoke pathway. In addition, allergic sensitization and blood eosinophils can be used to select medications for management of early asthma in young children. These current findings, among others covered in this review, represent significant steps toward addressing rapidly advancing areas of knowledge that have implications for asthma management.

Incorporating technology to advance asthma controller adherence.

PURPOSE OF REVIEW: Technological innovations, including text messaging, smart phone applications, and electronic monitoring devices, aimed at improving asthma controller adherence are being rapidly introduced both into clinical care and directly marketed to patients. This review analyzes recent clinical trials implementing these interventions, with a focus on their benefits and shortcomings. RECENT FINDINGS: Poor medication adherence continues to exert significant morbidity on patients with asthma. Objective, real-time measures to monitor adherence can overcome the limitations of prior methods, including self-report and prescription refills. Technological advances, especially those incorporating reminder systems, have demonstrated improved controller adherence. The increased adherence in these trials has not translated into consistent clinical improvement, including reducing hospitalizations, emergency department visits, and asthma exacerbations, possibly secondary to study design and poor inhalation technique. SUMMARY: Novel monitoring and reminder technology can augment patient medication adherence and provide clues to management before escalating therapy. Further studies are needed to investigate the overarching clinical impact of this technology, especially as it grows into routine clinical practice.

Advances in asthma 2015: Across the lifespan.

In 2015, progress in understanding asthma ranged from insights to asthma inception, exacerbations, and severity to advancements that will improve disease management throughout the lifespan. 2015's insights to asthma inception included how the intestinal microbiome affects asthma expression with the identification of specific gastrointestinal bacterial taxa in early infancy associated with less asthma risk, possibly by promoting regulatory immune development at a critical early age. The relevance of epigenetic mechanisms in regulating asthma-related gene expression was strengthened. Predicting and preventing exacerbations throughout life might help to reduce progressive lung function decrease and disease severity in adulthood. Although allergy has long been linked to asthma exacerbations, a mechanism through which IgE impairs rhinovirus immunity and underlies asthma exacerbations was demonstrated and improved by anti-IgE therapy (omalizumab). Other key molecular pathways underlying asthma exacerbations, such as cadherin-related family member 3 (CDHR3) and orosomucoid like 3 (ORMDL3), were elucidated. New anti-IL-5 therapeutics, mepolizumab and reslizumab, were US Food and Drug Administration approved for the treatment of patients with severe eosinophilic asthma. In a clinical trial the novel therapeutic inhaled GATA3 mRNA-specific DNAzyme attenuated early- and late-phase allergic responses to inhaled allergen. These current findings are significant steps toward addressing unmet needs in asthma prevention, severity modification, disparities, and lifespan outcomes.