Is the assessment of asthma treatment efficacy sufficiently comprehensive?

The goal of asthma guideline therapy is to achieve disease control, by minimizing impairment and decreasing the risk of exacerbations and adverse effects of the disease and its treatment. The primary objective of most clinical trials of biologics for severe asthma is a reduction in exacerbation rate. Recently, studies with patients at the lower guideline steps have also selected exacerbation reduction as a primary objective. These trials in patients with milder disease frequently demonstrate statistically significantly fewer exacerbations, but their power calculations reflect larger sample size and smaller effect size. Exacerbations have a precise consensus definition, although a minimal clinically important difference has not been established. Reduction of exacerbations in severe asthma is commonly 10-fold greater than in mild disease. Further, reduction in exacerbations is not always associated with reduced impairment. If superior control is the objective, both domains should demonstrate consistent and parallel improvement. The disconnect may reflect the need for alternative tools for measurement of impairment or, possibly, different therapeutic mechanisms of action. Determining response to biologics or discussion of disease remission requires assessing symptoms that may occur daily rather than focusing on exacerbations that occur once or twice a year for patients at the highest steps of care according to the guidelines.

Applying the dissemination and implementation sciences to allergy and immunology: A Work Group Report from the AAAAI Quality, Adherence, and Outcomes Committee.

Translating evidence-based practice (EBP) into real-world clinical settings often takes a considerable amount of time and resources. In allergy and immunology, the dissemination and implementation (D&I) sciences facilitate the study of how variations in knowledge, resources, patient populations, and staffing models lead to differences in the clinical care of asthma, allergic disease, and primary immunodeficiency. Despite the need for validated approaches to study how to best apply EBP in the real world, the D&I sciences are underutilized. To address this gap, an American Academy of Allergy, Asthma & Immunology (AAAAI) work group was convened to provide an overview for the role of the D&I sciences in clinical care and future research within the field. For the D&I sciences to be leveraged effectively, teams should be multidisciplinary and inclusive of community and clinical partners, and multimethods approaches to data collection and analyses should be used. Used appropriately, the D&I sciences provide important tools to promote EBP and health equity as well as optimization of clinical practice in allergy and immunology.

Variability in forced expiratory volume in 1 s in children with symptomatically well-controlled asthma.

AIMS: Spirometry is used by many clinicians to monitor asthma in children but relatively little is understood about its variability over time. The aim of this study was to determine the variability of forced expiratory volume in 1 s (FEV1) in children with symptomatically well-controlled asthma by applying three different methods of expressing change in FEV1 over 3-month intervals. METHODS: Data from five longitudinal studies of children with asthma which measured FEV1 at 3-month intervals over 6 or 12 months were used. We analysed paired FEV1 measurements when asthma symptoms were controlled. The variability of FEV1% predicted (FEV1%), FEV1 z-score (FEV1z) and conditional z score for change (Zc) in FEV1 was expressed as limits of agreement. RESULTS: A total of 881 children had 3338 FEV1 measurements on occasions when asthma was controlled; 5184 pairs of FEV1 measurements made at 3-month intervals were available. Each unit change in FEV1 z score was equivalent to a Zc 1.45 and an absolute change in FEV1% of 11.6%. The limits of agreement for change in FEV1% were -20 and +21, absolute change in FEV1 z were -1.7 and +1.7 and Zc were -2.6 and +2.1. Regression to the mean and increased variability in younger children were present for change in FEV1% and FEV1z comparisons, but not Zc. CONCLUSION: Given the wide limits of agreement of paired FEV1 measurements in symptomatically well-controlled children, asthma treatment should primarily be guided by symptoms and not by a change in spirometry.

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.

Assessment of dupilumab in children with moderate-to-severe type 2 asthma with or without evidence of allergic asthma.

BACKGROUND: Cytokines, such as interleukins (IL)-4/5/13, play a key role in multiple type 2 inflammatory diseases, including allergic asthma. Dupilumab, a human monoclonal antibody, blocks the shared receptor component for IL-4/IL-13, inhibiting signaling. In this post hoc analysis of VOYAGE (NCT02948959), dupilumab efficacy was evaluated in patients aged 6-11 years with type 2 asthma with or without evidence of allergic asthma (baseline serum total IgE ≥30 IU/mL and ≥1 perennial aeroallergen-specific IgE ≥0.35kU/L). METHODS: Annualized severe exacerbation rates (AER) and changes in pre-bronchodilator (Pre-BD) forced expiratory volume in one second (FEV1 ), percent-predicted pre-BD FEV1 (ppFEV1 ), and Asthma Control Score (ACQ)-7 were assessed during the treatment period. RESULTS: 350 children (261 with and 89 without evidence of allergic asthma) were included. Dupilumab versus placebo significantly reduced AER in patients with (0.24 vs. 0.62, relative risk reduction [RRR]: 62% [95% CI, 39-76], P < .0001) and without (0.39 vs. 0.80, RRR: 51% [95% CI, 0-76], P < .05) evidence of allergic asthma. Significant improvements in ppFEV1 , pre-bronchodilator FEV1 , and ACQ-7 scores were observed in dupilumab versus placebo throughout the treatment period in patients with evidence of allergic asthma. In patients without evidence of allergic asthma, numerical improvements in pre-bronchodilator FEV1 and asthma control were observed by Week 52. CONCLUSION: Dupilumab versus placebo reduced asthma exacerbations in children with type 2 asthma irrespective of evidence of allergic asthma; similar trends were observed in changes in lung function. Significant improvement in asthma control was observed in patients with evidence of allergic asthma, but not in those without.

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.

The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions.

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

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

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

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

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

Electronic medication monitoring versus self-reported use of inhaled corticosteroids and short-acting beta2-agonists in uncontrolled asthma.

OBJECTIVE: Current standard of care, patient self-report and clinician estimation, overestimates true inhaled corticosteroids (ICS) adherence. We compare self-reported inhaled ICS and short-acting beta 2-agonists (SABA) use with objective data from electronic medication monitors (EMMs). METHODS: Adults with uncontrolled asthma and prescribed ICS and SABA were enrolled. At visit one, participants' ICS and SABA inhalers were fitted with EMMs to track real-time medication usage over 14 days. Participants were asked to complete paper diaries to self-report medication usage over the same period. Participant self-report of ICS adherence and SABA use versus objective ICS adherence and SABA use was compared using Wilcoxon signed-rank tests. RESULTS: One hundred participants (80% female, mean age 48.5 years, 60% completed college, 80% privately insured) had complete data. Participant self-report (median (IQR): 0.8 (0.0, 2.0)) was greater than objectively measured (median (IQR): 0.43 (0.1, 2.1)) SABA use, but the difference was not statistically significant (P = 0.64). Participant self-report (median (IQR): 97 (67, 100)) was significantly greater than objectively measured (median (IQR): 75 (54, 93)) ICS adherence (P = 0.002). CONCLUSIONS: Significant discrepancies between self-report and objective ICS usage were observed. EMM can provide clinicians with accurate data on ICS medication taking behavior, thus reducing medication regimen complexity, side effects, and costs.

Factors Associated with Persistence of Severe Asthma from Late Adolescence to Early Adulthood.

RATIONALE: Asthma severity in children generally starts mild but may progress and stay severe for unknown reasons. OBJECTIVES: Identify factors in childhood that predict persistence of severe asthma in late adolescence and early adulthood. METHODS: The Childhood Asthma Management Program is the largest and longest asthma trial in 1041 children aged 5-12 years with mild to moderate asthma. We evaluated 682 participants from the program with analyzable data in late adolescence (age 17-19) and early adulthood (age 21-23). MEASUREMENTS: Severe asthma was defined using criteria from the American Thoracic Society and the National Asthma Education and Prevention Program to best capture severe asthma. Logistic regression with stepwise elimination was used to analyze clinical features, biomarkers, and lung function predictive of persistence of severe asthma. MAIN RESULTS: In late adolescence and early adulthood 12% and 19% of the patents had severe asthma, respectively; only 6% were severe at both time periods. For every 5% decrease in post bronchodilator FEV1/FVC in childhood, the odds of persistence of severe asthma increased 2.36-fold (95% CI: 1.70-3.28; p <0.0001), for participants with maternal smoking during pregnancy odds of persistence of severe asthma increased 3.17-fold (95% CI: 1.18-8.53, p=0.02). Reduced growth lung function trajectory was significantly associated with persistence of severe asthma compared to normal growth. CONCLUSIONS: Lung function and maternal smoking during pregnancy were significant predictors of severe asthma from late adolescence to early adulthood. Interventions to preserve lung function early may prevent disease progression.

PrecISE: Precision Medicine in Severe Asthma: An adaptive platform trial with biomarker ascertainment.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. A large proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

Does lung function change in the months after an asthma exacerbation in children?

BACKGROUND: There are limited data describing lung function changes in children after an asthma exacerbation. Our hypothesis was that lung function does not fully recover in children in the months following an asthma exacerbation. METHODS: We used a data set of children with asthma where lung function (including FEV1 , FEV1 /FVC ratio and FEF25-75 ) was measured at 3-month intervals over a year. Mixed-level models compared spirometry measured on two occasions 3 months apart before a single exacerbation (assessments 1 and 2) with measurements made on two occasions after the exacerbation (assessments 3 and 4), with adjustment for covariates. Changes in spirometry over a year were also analysed across those with exacerbations in no, one or more than one 3-month periods. RESULTS: For the 113 children who had a single exacerbation, spirometry measured at assessments 1 or 2 did not differ from measurements at assessments 3 or 4 when the whole population was considered. When stratified into tertiles by change in %FEV1 between assessments 2 and 3, those with the greater reduction were more likely to be treated with long-acting beta-agonist, but in this category, %FEV1 at assessment 4 had returned to the value at assessment 1. %FEV1 did not change over a 12-month period within and between the three exacerbation categories (n = 809). CONCLUSION: One or more asthma exacerbation was not associated with a fall in lung function for the whole population. In a subset of individuals, lung function does fall after an exacerbation but returns to pre-exacerbation values after a period of months.

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.

Update on the NAEPPCC Asthma Guidelines: The wait is over, or is it?

As an asthma specialist, one is often asked to discuss the asthma guidelines. The challenge that one faces is deciding which guidelines to use as a resource for discussion or presentation. It often comes down to the following questions: What is the question? What message does one want to deliver? Where is the most current information? and Who is the target audience? This commentary will help answer those questions as it guides the reader through the new update of the National Heart, Lung and Blood Institute/National Asthma Education and Prevention Program guidelines and then outlines differences between 2 widely used strategies for the management of asthma: the Global Initiative for Asthma and the National Heart, Lung and Blood Institute/National Asthma Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma.

An expert consensus framework for asthma remission as a treatment goal.

With novel therapies in development, there is an opportunity to consider asthma remission as a treatment goal. In this Rostrum, we present a generalized framework for clinical and complete remission in asthma, on and off treatment, developed on the basis of medical literature and expert consensus. A modified Delphi survey approach was used to ascertain expert consensus on core components of asthma remission as a treatment target. Phase 1 identified other chronic inflammatory diseases with remission definitions. Phase 2 evaluated components of those definitions as well as published definitions of spontaneous asthma remission. Phase 3 evaluated a remission framework created using consensus findings. Clinical remission comprised 12 or more months with (1) absence of significant symptoms by validated instrument, (2) lung function optimization/stabilization, (3) patient/provider agreement regarding remission, and (4) no use of systemic corticosteroids. Complete remission was defined as clinical remission plus objective resolution of asthma-related inflammation and, if appropriate, negative bronchial hyperresponsiveness. Remission off treatment required no asthma treatment for 12 or more months. The proposed framework is a first step toward developing asthma remission as a treatment target and should be refined through future research, patient input, and clinical study.

Development and initial validation of the Asthma Severity Scoring System (ASSESS).

BACKGROUND: Tools for quantification of asthma severity are limited. OBJECTIVE: We sought to develop a continuous measure of asthma severity, the Asthma Severity Scoring System (ASSESS), for adolescents and adults, incorporating domains of asthma control, lung function, medications, and exacerbations. METHODS: Baseline and 36-month longitudinal data from participants in phase 3 of the Severe Asthma Research Program (NCT01606826) were used. Scale properties, responsiveness, and a minimally important difference were determined. External replication was performed in participants enrolled in the Severe Asthma Research Program phase 1/2. The utility of ASSESS for detecting treatment response was explored in participants undergoing corticosteroid responsiveness testing with intramuscular triamcinolone and participants receiving biologics. RESULTS: ASSESS scores ranged from 0 to 20 (8.78 ± 3.9; greater scores reflect worse severity) and differed among 5 phenotypic groups. Measurement properties were acceptable. ASSESS was responsive to changes in quality of life with a minimally important difference of 2, with good specificity for outcomes of asthma improvement and worsening but poor sensitivity. Replication analyses yielded similar results, with a 2-point decrease (improvement) associated with improvements in quality of life. Participants with a 2-point or greater decrease (improvement) in ASSESS scores also had greater improvement in lung function and asthma control after triamcinolone, but these differences were limited to phenotypic clusters 3, 4, and 5. Participants treated with biologics also had a 2-point or greater decrease (improvement) in ASSESS scores overall. CONCLUSIONS: The ASSESS tool is an objective measure that might be useful in epidemiologic and clinical research studies for quantification of treatment response in individual patients and phenotypic groups. However, validation studies are warranted.

Does treatment guided by exhaled nitric oxide fraction improve outcomes in subgroups of children with asthma?

INTRODUCTION: Exhaled nitric oxide fraction (F ENO), a biomarker of eosinophilic airway inflammation, may be useful to guide asthma treatment. F ENO-guided treatment may be more effective in certain subgroups for improving asthma outcomes compared to standard treatment. METHODS: An individual patient data analysis was performed using data from seven randomised clinical trials (RCTs) which used F ENO to guide asthma treatment. The incidence of an asthma exacerbation and loss of control, and the time to first exacerbation and loss of control were described between five subgroups of RCT participants. RESULTS: Data were available in 1112 RCT participants. Among those not treated with leukotriene receptor antagonists (LTRA), but not among those who were treated with LTRA, F ENO-guided treatment was associated with reduced exacerbation risk (OR 0.68, 95% CI 0.49-0.94), longer time to first exacerbation (hazard ratio (HR) 0.76, 95% CI 0.57-0.99) and borderline reduced risk for loss of control (OR 0.70, 95% CI 0.49-1.00). Nonobese children, compared to obese children, were less likely to lose asthma control when treatment was guided by F ENO (OR 0.69, 95% CI 0.48-0.99) and time to loss of control was longer (HR 0.77, 95% CI 0.61-0.99). CONCLUSIONS: Asthma treatment guided by F ENO may be more effective in achieving better asthma outcomes for patients who are not treated with LTRA and who are not obese, compared to standard practice.

Using fractional exhaled nitric oxide to guide step-down treatment decisions in patients with asthma: a systematic review and individual patient data meta-analysis.

BACKGROUND: High exhaled nitric oxide fraction (F ENO) levels are associated with greater risk of asthma exacerbation. However, it is not clear how F ENO can be used to guide safe reductions in inhaled corticosteroid (ICS) doses in asthma patients. This study assesses the ability of F ENO to guide ICS reductions. METHODS: Systematic searching of electronic databases identified prospective observational studies and randomised controlled trials which recruited participants with mild-to-moderate asthma aged ≥12 years and measured F ENO before reducing ICS. We performed multilevel mixed-effects logistic regression in relation to acute exacerbations and estimated each participant's exacerbation risk using our logistic regression model. RESULTS: We included data from seven out of eight eligible studies, representing 384 participants. ICS doses were halved in four studies and withdrawn in three studies. A baseline F ENO measurement of ≥50 ppb was associated with increased risk of exacerbations (crude OR 3.14, 95% CI 1.41-7.00, p=0.005; adjusted OR 3.08, 95% CI 1.36-6.98, p=0.007) and corresponded to an estimated exacerbation risk cut-off of 15%. Reducing ICS when estimated exacerbation risk was <15% versus <10% would result in fewer patients remaining on the same ICS dose (40 (10.4%) out of 384 versus 141 (36.7%) out of 384), but similar proportions of patients avoiding exacerbations (222 (91.4%) out of 243, 95% CI 87.1-94.6% versus 311 (90.4%) out of 344, 95% CI 86.8-93.3%). CONCLUSION: In patients with mild-to-moderate asthma, gradual ICS reduction when F ENO is <50 ppb may help decrease ICS use without increasing exacerbations. Future research should aim to validate these findings in larger populations.

Addressing the risk domain in the long-term management of pediatric asthma.

There is growing concern regarding the long-term outcomes of early and poorly controlled childhood asthma, either of which can potentially lead to the development of severe asthma in adults and irrecoverable loss of lung function leading to chronic obstructive pulmonary disease. These outcomes of inadequately controlled asthma should prompt a change in practice to better and/or earlier identify children at risk of adverse respiratory outcomes of asthma, to monitor disease progression, and to design intervention strategies that could either prevent or reverse asthma progression in children. The careful follow-up of spirometry over time-in the form of lung function trajectories, the application of biomarkers to assist in the diagnosis of early asthma and medication selection for these patients, as well as methods to identify patients at risk of asthma attacks-can be used to develop individualized management strategies for children with asthma. It is now time for asthma specialists to communicate this information to patients, parents, and primary care physicians and to incorporate them into routine clinical assessments of children with asthma. In time, these concepts of risk management and prevention can be refined to provide a more comprehensive approach to asthma care so as to prevent adverse respiratory outcomes from poorly controlled childhood asthma.