Severe asthma in children is characterized by sustained symptoms despite treatment with high doses of inhaled corticosteroids or oral corticosteroids. Children with severe asthma may fall into 2 categories, difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities, or poor adherence due to adverse psychological or environmental factors. In contrast, treatment resistant is defined as difficult asthma despite management of these factors. It is increasingly recognized that severe asthma is a highly heterogeneous disorder associated with a number of clinical and inflammatory phenotypes that have been described in children with severe asthma. Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with long-acting β-agonists and other add-on therapies, such as antileukotrienes and methylxanthines. It is important to identify and address the influences that make asthma difficult to control, including reviewing the diagnosis and removing causal or aggravating factors. Better definition of the phenotypes and better targeting of therapy based upon individual patient phenotypes is likely to improve asthma treatment in the future.

Background: Although exhaled breath condensate (EBC) pH has been identified as an "emerging" biomarker of interest for asthma clinical trials, the clinical determinants of EBC pH remain poorly understood. Other studies have associated acid reflux-induced respiratory symptoms, for example, cough, with transient acidification of EBC. Objective: We sought to determine the clinical and physiologic correlates of EBC acidification in a highly characterized sample of children with poorly controlled asthma. We hypothesized that (1) children with asymptomatic gastroesophageal reflux determined by 24-hour esophageal pH monitoring would have a lower EBC pH than children without gastroesophageal reflux, (2) treatment with lansoprazole would alter EBC pH in those children, and (3) EBC acidification would be associated with increased asthma symptoms, poorer asthma control and quality of life, and increased formation of breath nitrogen oxides (NOx). Methods: A total of 110 children, age range 6 to 17 years, with poor asthma control and esophageal pH data enrolled in the Study of Acid Reflux in Children with Asthma (. NCT00442013) were included. Children submitted EBC samples for pH and NOx measurement at randomization and at study weeks 8, 16, and 24. Results: Serial EBC pH measurements failed to distinguish asymptomatic gastroesophageal reflux and was not associated with breath NOx formation. EBC pH also did not discriminate asthma characteristics such as medication and health care utilization, pulmonary function, and asthma control and quality of life both at baseline and across the study period. Conclusion: Despite the relative ease of EBC collection, EBC pH as a biomarker does not provide useful information of children with asthma who were enrolled in asthma clinical trials.

Background Childhood asthma clusters, or subclasses, have been developed by computational methods without evaluation of clinical utility. Objective To replicate and determine whether childhood asthma clusters previously identified computationally in the Severe Asthma Research Program (SARP) are associated with treatment responses in Childhood Asthma Research and Education (CARE) Network clinical trials. Methods A cluster assignment model was determined by using SARP participant data. A total of 611 participants 6 to 18 years old from 3 CARE trials were assigned to SARP pediatric clusters. Primary and secondary outcomes were analyzed by cluster in each trial. Results CARE participants were assigned to SARP clusters with high accuracy. Baseline characteristics were similar between SARP and CARE children of the same cluster. Treatment response in CARE trials was generally similar across clusters. However, with the caveat of a smaller sample size, children in the early-onset/severe-lung function cluster had best response with fluticasone/salmeterol (64% vs 23% 2.5× fluticasone and 13% fluticasone/montelukast in the Best ADd-on Therapy Giving Effective Responses trial; P =.011) and children in the early-onset/comorbidity cluster had the least clinical efficacy to treatments (eg, -0.076% change in FEV 1 in the Characterizing Response to Leukotriene Receptor Antagonist and Inhaled Corticosteroid trial). Conclusions In this study, we replicated SARP pediatric asthma clusters by using a separate, large clinical trials network. Early-onset/severe-lung function and early-onset/comorbidity clusters were associated with differential and limited response to therapy, respectively. Further prospective study of therapeutic response by cluster could provide new insights into childhood asthma treatment.

Background: Minority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk. Objective: We evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations. Methods: One thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n = 760). Results: Twenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV1 percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P = .30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P = .13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P = .74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P = .03]). Conclusion: Black subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect.

Abstract Asthma is a chronic inflammatory disorder of the airways associated with airway hyper-responsiveness and airflow limitation in response to specific triggers. Whereas inflammation is important for tissue regeneration and wound healing, the profound and sustained inflammatory response associated with asthma may result in airway remodeling that involves smooth muscle hypertrophy, epithelial goblet-cell hyperplasia, and permanent deposition of airway extracellular matrix proteins. Although the specific mechanisms responsible for asthma are still being unraveled, free radicals such as reactive oxygen species and reactive nitrogen species are important mediators of airway tissue damage that are increased in subjects with asthma. There is also a growing body of literature implicating disturbances in oxidation/reduction (redox) reactions and impaired antioxidant defenses as a risk factor for asthma development and asthma severity. Ultimately, these redox-related perturbations result in a vicious cycle of airway inflammation and injury that is not always amenable to current asthma therapy, particularly in cases of severe asthma. This review will discuss disruptions of redox signaling and control in asthma with a focus on the thiol, glutathione, and reduced (thiol) form (GSH). First, GSH synthesis, GSH distribution, and GSH function and homeostasis are discussed. We then review the literature related to GSH redox balance in health and asthma, with an emphasis on human studies. Finally, therapeutic opportunities to restore the GSH redox balance in subjects with asthma are discussed. Antioxid. Redox Signal. 17, 375–408.

In this cross-sectional evaluation of 77 severe and 71 non-severe asthmatics ages 6–17, boys, unlike girls with severe asthma, exhibited adult-like patterns of air-trapping and post-bronchodilator airflow limitation, apparently coincident with the onset of the severe asthma phenotype.

Background/aims: When conducting clinical trials comparing over-the-counter (OTC) medications, the wide availability of these treatments are a potential challenge to maintaining study integrity. We seek to describe adherence to a study protocol involving widely available OTC medications. Methods: To prospectively evaluate associations between acetaminophen use and asthma in 300 children aged 1–5 years, we conducted a double blind, randomized, controlled trial where parents administered blinded forms of either acetaminophen or ibuprofen as needed to their children over a 48 week period. Written and verbal instructions encouraged the exclusive use of the blinded study medication and discouraged OTC use. Adherence was determined by evaluating the frequency of use of per-protocol blinded study medication compared to off-protocol use of OTC medications. Results: 4195 doses of acetaminophen or ibuprofen were received by children during the study which included 3664 doses (87.3%) of blinded study medication adhering to the protocol and 531 doses (12.7%) of OTC products deviating from the protocol with better adherence among those randomized to ibuprofen as compared to acetaminophen (89.5% vs. 85.5% of doses, p < 0.01). Individually, 227 participants (75.7%) remained fully adherent by not receiving any OTC medications. Pre-study preference for either acetaminophen or ibuprofen by the participants' families was not associated with differential rates of adherence to the blinded medication. Conclusion: This parallel study demonstrated greater than 85% of acetaminophen or ibuprofen doses were blinded study medications adhering to the protocol while less than 15% were OTC deviations from the protocol. This successfully implemented study design provides a template to comparatively evaluate these and other OTC medications.

Background: Approximately 8-23% of premature infants develop pulmonary hypertension (PH), and this diagnosis confers a higher possibility of mortality. As a result, professional societies recommend PH screening in premature infants. However, the risk factors for and the outcomes of PH may differ depending on the timing of its diagnosis, and little evidence is available to determine at-risk infants in the referral neonatal population. The objective of this study was to define clinical and echocardiographic characteristics of infants with pulmonary hypertension during the neonatal hospital course and at or near-term. Methods: Infants who had the following billing codes: < 32 weeks, birth weight < 1500 g, neonatal unit, and echocardiograph had records abstracted from a data warehouse at Children's Healthcare o f Atlanta. The outcome was defined as late PH on the final echocardiogram for all patients, and, separately, for patients with multiple studies. Descriptive statistics, univariable, and multivariable models were evaluated, and odds ratios and 95% confidence intervals are expressed below as (OR, CI). Results: 556 infants were included in the overall study, 59 had PH on their final echocardiogram (11%). In multivariable analyses, atrial septal defect (2.9, 1.4-6.1), and intrauterine growth restriction (2.7, 1.2-6.3) increased the odds of late PH, whereas caffeine therapy decreased PH (0.4, 0.2-0.8). When the analyses were restricted to 32 infants who had multiple echocardiograms during their hospitalization, the association between atrial septal defect (5.9, 2.0-16.5) and growth restriction (3.7, 1.3-10.7) and late PH was strengthened, but the effect of caffeine therapy was no longer significant. In this smaller subgroup, infants with late PH had their final echocardiogram at a median of 116 days of life, and 42-74% of them had right ventricular pathology. Conclusions: Early clinical variables are associated with PH persistence in a referral neonatal population. Identification of early clinical factors may help guide the ascertainment of infant risk for late PH, and may aid in targeting sub-groups that are most likely to benefit from PH screening.

Background: Our objective was to determine those characteristics associated with reversibility of airflow obstruction and response to maximal bronchodilation in children with severe asthma through the Severe Asthma Research Program (SARP). Methods: We performed a cross-sectional analysis evaluating children ages 6–17 years with non-severe (NSA) and severe asthma (SA). Participants underwent spirometry before and after 180 μg of albuterol to determine reversibility (≥12% increase in FEV1). Participants were then given escalating doses up to 720 μg of albuterol to determine their maximum reversibility. Results: We evaluated 230 children (n=129 SA, n=101 NSA) from 5 centers across the U.S. in the SARP I and II cohorts. SA (OR 2.08, 95%CI 1.05 to 4.13), second-hand smoke exposure (OR 2.81, 95%CI 1.23 to 6.43), and FeNO (OR 1.97, 95%CI 1.35 to 2.87) were associated with increased odds of airway reversibility after maximal bronchodilation, while higher pre-bronchodilator FEV1% predicted (OR 0.91, 95%CI 0.88 to 0.94) was associated with decreased odds. In an analysis using the SARP III cohort (n=186), blood neutrophils, IgE and FEV1% predicted were significantly associated with bronchodilator reversibility. In addition, children with bronchodilator response have greater healthcare utilization. Bronchodilator reversibility was associated with reduced lung function at enrollment and one-year follow-up though less decline in lung function over one year compared to those without reversibility. Conclusions: Lung function, that is FEV1 % predicted, is a predictor of bronchodilator response in children with asthma. Additionally, smoke exposure, higher FeNO or IgE level, and low peripheral blood neutrophils are associated with greater likelihood of bronchodilator reversibility. Bronchodilator response can identify a phenotype of pediatric asthma associated with low lung function and poor asthma control.