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Asthma is difficult to diagnose in the child with sickle cell disease because symptoms and pulmonary function abnormalities are similar to the spectrum of pulmonary manifestations in sickle cell disease. There are no published reports of controlled trials of asthma medications in children with sickle cell disease. Thus, treatment decisions should be guided by the Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf). However, issues specific to children with sickle cell disease should be considered. Initial strategies should focus on control of environmental triggers, as effectiveness on asthma outcomes is proven and the cost for implementation can be low. Use of short- and long-acting β2-agonists may prolong QTc, particularly in this population of children who already have a higher prevalence of prolonged QTc than the general population. Long-acting β2-agonist use has been associated with life-threatening asthma exacerbations with ...

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

Rationale: Asthma in children generally starts as being mild but may progress to being severe and may stay severe for unknown reasons. Objectives: To identify factors in childhood that predict the persistence of severe asthma in late adolescence and early adulthood. Methods: The CAMP (Childhood Asthma Management Program) is, to our knowledge, the largest and longest asthma trial to date; it includes 1,041 children aged 5–12 years with mild to moderate asthma. We evaluated 682 program participants with analyzable data in late adolescence (age, 17–19 yr) and early adulthood (age, 21–23 yr). Measurements and Main Results: To best capture the cases of severe asthma, a status of severe asthma was defined by using criteria from the American Thoracic Society and the National Asthma Education and Prevention Program. Logistic regression with stepwise elimination was used to analyze the clinical features, biomarkers, and lung function that are predictive of the persistence of severe asthma. In late adolescence and early adulthood, 12% and 19% of the participants had severe asthma, respectively; only 6% at both time points had severe cases. For every 5% decrease in the postbronchodilator FEV(1)/FVC ratio in childhood, the odds of the persistence of severe asthma increased by 2.36-fold (95% confidence interval [CI], 1.70–3.28; P

[Figure: see text] The National Institutes of Health’s Environmental Influences on Child Health Outcomes (ECHO) program aims to study high-priority and high-impact pediatric conditions. This broad-based health initiative is unique in the National Institutes of Health research portfolio and involves 2 research components: (1) a large group of established centers with pediatric cohorts combining data to support longitudinal studies (ECHO cohorts) and (2) pediatric trials program for institutions within Institutional Development Awards states, known as the ECHO Institutional Development Awards States Pediatric Clinical Trials Network (ISPCTN). In the current presentation, we provide a broad overview of the ISPCTN and, particularly, its importance in enhancing clinical trials capabilities of pediatrician scientists through the support of research infrastructure, while at the same time implementing clinical trials that inform future health care for children. The ISPCTN research mission is aligned with the health priority conditions emphasized in the ECHO program, with a commitment to bringing state-of-the-science trials to children residing in underserved and rural communities. ISPCTN site infrastructure is critical to successful trial implementation and includes research training for pediatric faculty and coordinators. Network sites exist in settings that have historically had limited National Institutes of Health funding success and lacked pediatric research infrastructure, with the initial funding directed to considerable efforts in professional development, implementation of regulatory procedures, and engagement of communities and families. The Network has made considerable headway with these objectives, opening two large research studies during its initial 18 months as well as producing findings that serve as markers of success that will optimize sustainability.

Background Compared with adults, phenotypic characterization of children with asthma is still limited and it remains difficult to predict which children with asthma are at highest risk for poor outcomes. Objective To identify latent classes in a large population of treatment-adherent children with mild to moderate asthma enrolled in clinical trials and determine whether latent class assignment predicts future lung function abnormalities and exacerbation rate. Methods Latent class analysis was performed on 2593 children with mild to moderate asthma aged 5 18 years, with 19 variables encompassing demographic characteristics, medical history, symptoms, lung function, allergic sensitization, and type 2 inflammation. Outcomes included lung function and the annualized exacerbation rate at 12 months of follow-up. Results Five latent classes were identified with differing demographic features, asthma control, sensitization, type 2 inflammatory markers, and lung function. Exacerbation rates were 1.30 ± 0.12 for class 1 (multiple sensitization with partially reversible airflow limitation), 0.90 ± 0.05 for class 2 (multiple sensitization with reversible airflow limitation), 0.87 ± 0.08 for class 3 (lesser sensitization with reversible airflow limitation), 0.87 ± 0.05 for class 4 (multiple sensitization with normal lung function), and 0.71 ± 0.06 for class 5 (lesser sensitization with normal lung function). Lung function abnormalities persisted in class 1 at 12 months. Conclusions Children with mild to moderate asthma are a heterogeneous group. Allergic sensitization and lung function may be particularly useful in identifying children at the greatest risk for future exacerbation. Additional studies are needed to determine whether latent classes correspond to meaningful phenotypes for the purpose of personalized treatment.

International guidelines provide recommendations for a stepwise approach to the management of asthma in children 0-4 years old, 5-11 years old, and adolescents who are treated as adults. Therapy is aimed at two domains of control: current impairment and future risk. The long-term controller medications, inhaled corticosteroids (ICSs), ICSs in combination with long-acting β2 agonists, leukotriene receptor antagonists, and immunomodulators, exhibit different efficacies for these domains. The risk:benefit ratios of the available medications need to be carefully assessed. This review briefly presents the benefits and the potential risks of available asthma medications in children to assist the practitioner in the optimal use of asthma medications. Specifically, the systemic activity of the ICSs and how to minimize their effects on growth and adrenal activity are reviewed as well as other potential adverse effects. Dosing strategies such as intermittent therapy are also assessed.

Phenotypic variation in asthma, especially early childhood asthma, is increasingly recognized. Although inhaled corticosteroids are recommended as first-line therapy, it has less efficacy in controlling intermittent wheeze due to viral-induced symptoms in early childhood. This article reviews 2 emerging therapies in particular for early childhood wheeze: azithromycin and bacterial lysate therapy. Azithromycin's effects are both antibacterial and anti-inflammatory, and it has been shown in 2 studies in preschoolers to prevent progression to severe respiratory tract infection and decrease duration of wheeze. Bacterial lysates work at multiple stages in the innate and adaptive immune response and have been shown to decrease mean wheeze duration in particular in the preschool age. More research is required although both therapies offer a promising future approach, in particular in the nonatopic preschool wheezer, as we move toward a more personalized approach to childhood asthma.

The National Asthma Education and Prevention Program Guidelines for the Diagnosis and Management of Asthma will update the guidelines on 6 topic areas. This review summarizes the findings for the charge to assess effectiveness of intermittent inhaled corticosteroid therapy with and without long-acting beta-agonist therapy in children 0 to 4 years of age, and children and adults 5 years and older. The complete report can be found on the Agency for Healthcare Research and Quality website.

A growing body of literature has investigated optimizing asthma management by identifying phenotypes and biomarkers to guide the treatment. In particular, management of asthma in preschool children remains challenging due to different phenotype presentation in early life. The focus of this review is to summarize the recent data on personalized medicine in management of preschool children with wheezing.

This is a “proof of concept” study to determine whether inhalation of 13C-urea can be safely used to detect the presence of urease producing bacteria in the airways of patients with cystic fibrosis (CF) by detecting 13CO2 in breath. This was a prospective, 2-part, open label, single-center, single-arm, single-administration, dose-escalation investigational device exemption trial. First, the safety of 20 and 50 mg inhaled 13C-urea was evaluated in 6 healthy adult participants. Then, 3 adult CF participants colonized with Pseudomonas aeruginosa were enrolled for each dose of inhaled 13C-urea. The safety of inhaled 13C-urea was assessed by spirometry and physical examination. 13C-urea was administered using a jet nebulizer, followed by serial spirometry (10 min and 30 min post inhalation) and collection of exhaled breath at 5, 10, and 15 min post inhalation. There was no clinical significant change in any of the spirometry values compared to baseline in healthy participants and CF patients. Mean of 13CO2/12C...

BackgroundAsthma exacerbations occur frequently despite the regular use of asthma-controller therapies, such as inhaled glucocorticoids. Clinicians commonly increase the doses of inhaled glucocorticoids at early signs of loss of asthma control. However, data on the safety and efficacy of this strategy in children are limited.MethodsWe studied 254 children, 5 to 11 years of age, who had mild-to-moderate persistent asthma and had had at least one asthma exacerbation treated with systemic glucocorticoids in the previous year. Children were treated for 48 weeks with maintenance low-dose inhaled glucocorticoids (fluticasone propionate at a dose of 44 μg per inhalation, two inhalations twice daily) and were randomly assigned to either continue the same dose (low-dose group) or use a quintupled dose (high-dose group; fluticasone at a dose of 220 μg per inhalation, two inhalations twice daily) for 7 days at the early signs of loss of asthma control ("yellow zone"). Treatment was provided in a double-blind fashion. The primary outcome was the rate of severe asthma exacerbations treated with systemic glucocorticoids.ResultsThe rate of severe asthma exacerbations treated with systemic glucocorticoids did not differ significantly between groups (0.48 exacerbations per year in the high-dose group and 0.37 exacerbations per year in the low-dose group; relative rate, 1.3; 95% confidence interval, 0.8 to 2.1; P=0.30). The time to the first exacerbation, the rate of treatment failure, symptom scores, and albuterol use during yellow-zone episodes did not differ significantly between groups. The total glucocorticoid exposure was 16% higher in the high-dose group than in the low-dose group. The difference in linear growth between the high-dose group and the low-dose group was -0.23 cm per year (P=0.06).ConclusionsIn children with mild-to-moderate persistent asthma treated with daily inhaled glucocorticoids, quintupling the dose at the early signs of loss of asthma control did not reduce the rate of severe asthma exacerbations or improve other asthma outcomes and may be associated with diminished linear growth. (Funded by the National Heart, Lung, and Blood Institute; STICS ClinicalTrials.gov number, NCT02066129 .).

Summary This letter addresses the controversial issue of the use of oral corticosteroids during wheezing exacerbations in preschool-aged children by demonstrating findings of a prematurely terminated multi-center clinical trial, discussing lessons learned, and suggesting future directions.

Recently, the United States Food and Drug Administration (FDA) elected not to approve a once-daily inhaled corticosteroid/long-acting β2 agonist combination product in 12-17-year-old patients due to lack of sufficient data, despite approval of previous combination products with similar levels of supporting evidence. As the FDA's stance toward adolescent data is changing, the opportunity to learn about their response to asthma medication has now arisen. A review of the relevant issues pertinent to pharmacotherapy of asthma in the 12-17-year-old population is discussed in this review.

Adhesion molecules comprise a large class of proteins that control the trafficking of hematopoietic progenitor cells between the bone marrow compartment and peripheral blood. The normal trafficking of blood-forming cells is dependent upon the controlled regulation of CXCR4, LFA-1 and VLA-4-mediated binding and unbinding events involving stromal elements.1, 2 The mobilization of hematopoietic progenitor cells has been exploited for numerous medical conditions, including the use of erythropoietin for the harvest of autologous red cells transfusions, granulocyte colony stimulating factor (G-CSF) for the release of granulocytes to treat chemotherapy-induced myelosuppression, and plerixafor for the mobilization of CD34 + HPCs cells in autologous stem cell transplantation.3 Autologous and allogeneic stem cell transplantation remains an important therapeutic option for patients who require intensified chemotherapy for a variety of indications. Autologous stem cells were initially directly harvested from the bone marrow compartments of patients prior to receiving cytotoxic therapies. Advances in clinical therapy have allowed hematopoietic progenitor cells (HPCs) to be harvested from the peripheral blood. In human subjects, HPCs comprise a very small faction of peripheral blood mononuclear cells (1 cell/1,000; or 0.1%). Such efforts have become vastly more efficient with the utilization of HPC chemical stimulants, termed mobilizing agents, which enhance the release of CD34+ HPCs from the bone marrow compartment into the peripheral blood for harvest.3-5 However, a number of problems related to the failure to mobilize sufficient numbers of CD34+ HPCs in donors or patients still exist,3, 5 necessitating further efforts to improve stem cell mobilization regimens to be short and maximally efficient. Repurposing (repositioning) of existing drugs can potentially provide one of the approaches to achieve this goal.6 Multiple hematological side effects have been reported to result from treatment with psychoactive phenothiazines. These reported toxicities include leucopenia, granulocytopenia, thrombocytopenia, agranulocytosis, and bone marrow aplasia.7-9 Until recently, the physiological mechanism causing these potentially life-threatening blood dyscrasias was unknown. However, recently we discovered that phenothiazines can almost instantaneously antagonize VLA-4 dependent cell adhesion and, after administration of thioridazine, HPCs could be rapidly mobilized into the peripheral blood in a murine model.10 We proposed that by interfering with VLA-4-mediated cell-cell adhesion involving HPCs in the bone marrow, phenothiazines might mobilize cells from the bone marrow niche. This phenomenon might help to explain the cellular mechanisms behind the frequent observation of dyserthropoeisis in patients who underwent treatment with thioridazine for psychosis.11, 12 Because the time-course for thioridazine-induced stem cell mobilization in human remains unknown, we hypothesized that thioridazine could be employed as a chemical means to mobilize CD34+ progenitor cells for peripheral blood collection. We thus designed an open-label, prospective, non-randomized feasibility clinical trial to assess the mobilizing capacity of thioridazine in healthy individuals.

Evidence is emerging on the use of long-acting muscarinic antagonists (LAMAs) in the management of asthma. Tiotropium bromide (Spiriva® Respimat®) is the only LAMA approved in children and adolescents. As the use of tiotropium becomes more common in clinical practice, it is necessary to review the existing data to identify patients who may benefit from the addition of this medication to their daily asthma regimen. This review discusses recent evidence on the safety and efficacy of tiotropium bromide in the management of asthma in children and adolescents. Current data support that tiotropium bromide has a bronchodilator effect, as evident by improvements in acute lung function compared with placebo; however, data are not yet available to present a stepwise approach or identify phenotypes that would benefit from the addition of tiotropium bromide. Well-designed studies are needed to compare the different step-up options to tiotropium bromide and provide an evidence-based stepwise approach for the management of asthma in children. Furthermore, study design should include identification of phenotypes that might experience a better clinical response to tiotropium bromide compared with other adjunct medications.

Background Overweight/obesity (OW) is linked to worse asthma and poorer inhaled corticosteroid (ICS) response in older children and adults. Objective We sought to describe the relationships between OW and asthma severity and response to ICS in preschool children. Methods This post hoc study of 3 large multicenter trials involving 2- to 5-year-old children compared annualized asthma symptom days and exacerbations among normal weight (NW) (body mass index: 10th-84th percentiles) versus OW (body mass index: ≥85th percentile) participants. Participants had been randomized to daily ICS, intermittent ICS, or daily placebo. Simple and multivariable linear regression was used to compare body mass index groups. Results Within the group not treated with a daily controller, OW children had more asthma symptom days (90.7 vs 53.2, P = .020) and exacerbations (1.4 vs 0.8, P = .009) thanNW children did. Within the ICS-treated groups, OW and NW children had similar asthma symptom days (daily ICS: 47.2 vs 44.0 days, P = .44; short-term ICS: 61.8 vs 52.9 days, P = .46; as-needed ICS: 53.3 vs 47.3 days, P = .53), and similar exacerbations (daily ICS: 0.6 vs 0.8, P = .10; short-term ICS: 1.1 vs 0.8 days, P = .25; as-needed ICS: 1.0 vs 1.1, P = .72). Compared with placebo, daily ICS in OW led to fewer annualized asthma symptom days (90.7 vs 41.2, P = .004) and exacerbations (1.4 vs 0.6, P = .006), while similar protective ICS effects were less apparent among NW. Conclusions In preschool children off controller therapy, OW is associated with greater asthma impairment and exacerbations. However, unlike older asthmatic patients, OW preschool children do not demonstrate reduced responsiveness to ICS therapy.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act. The overall goal of the Best Pharmaceuticals for Children Act Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug-labeling changes. Although significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled for use in children. In general, the younger the child, the less information there is available to guide clinicians. Because asthma often begins in early childhood, it is incumbent on us to continue to address the primary questions raised in this review and carefully evaluate the medications used to manage asthma in children. Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.

Many observational studies have investigated the potential association between vitamin D and asthma. However, it is difficult to find a temporal causal relationship in cross-sectional or observational studies. This review presents recent clinical trials and the evidence of association between vitamin D and asthma in different patient populations and asthma status. Well-designed clinical trials are warranted in order to define the optimal level of vitamin D, as well as dosing and duration of vitamin D supplementation, in pediatric patients.

This review will highlight new information on the use of inhaled corticosteroids (ICSs) for management of asthma with regard to long-term side effects and new treatment approaches. Variability in response to ICSs has been increasingly recognized and contribution of pharmacogenomic, phenotypes and environmental factors have been identified and discussed here. As ICSs remain the cornerstone of persistent asthma management, the CAMP trial provides more data in long-term adverse effect of ICSs. In order to minimize the side effects of ICSs, different asthma management approaches have been proposed in different patient populations. In addition, potential advantages of fine particle ICSs for improving small airway disease have been discussed.

Voluntary consent/assent with adolescents invited to participate in research raises challenging problems. No studies to date have attempted to manipulate autonomy in relation to assent/consent processes. This study evaluated the effects of an autonomy-enhanced individualized assent/consent procedure embedded within a randomized pediatric asthma clinical trial.Families were randomly assigned to remain together or separated during a consent/assent process; the latter we characterize as an autonomy-enhanced assent/consent procedure. We hypothesized that separating adolescents from their parents would improve adolescent assent by increasing knowledge and appreciation of the clinical trial and willingness to participate.Sixty-four adolescent-parent dyads completed procedures. The together versus separate randomization made no difference in adolescent or parent willingness to participate. However, significant differences were found in both parent and adolescent knowledge of the asthma clinical trial based on the assent/consent procedure and adolescent age. The separate assent/consent procedure improved knowledge of study risks and benefits for older adolescents and their parents but not for the younger youth or their parents. Regardless of the assent/consent process, younger adolescents had lower comprehension of information associated with the study medication and research risks and benefits, but not study procedures or their research rights and privileges.The use of an autonomy-enhanced assent/consent procedure for adolescents may improve their and their parent's informed assent/consent without impacting research participation decisions. Traditional assent/consent procedures may result in a "diffusion of responsibility" effect between parents and older adolescents, specifically in attending to key information associated with study risks and benefits.

BackgroundStudies have suggested an association between frequent acetaminophen use and asthma-related complications among children, leading some physicians to recommend that acetaminophen be avoided in children with asthma; however, appropriately designed trials evaluating this association in children are lacking.MethodsIn a multicenter, prospective, randomized, double-blind, parallel-group trial, we enrolled 300 children (age range, 12 to 59 months) with mild persistent asthma and assigned them to receive either acetaminophen or ibuprofen when needed for the alleviation of fever or pain over the course of 48 weeks. The primary outcome was the number of asthma exacerbations that led to treatment with systemic glucocorticoids. Children in both groups received standardized asthma-controller therapies that were used in a simultaneous, factorially linked trial.ResultsParticipants received a median of 5.5 doses (interquartile range, 1.0 to 15.0) of trial medication; there was no significant between-group difference in the median number of doses received (P=0.47). The number of asthma exacerbations did not differ significantly between the two groups, with a mean of 0.81 per participant with acetaminophen and 0.87 per participant with ibuprofen over 46 weeks of follow-up (relative rate of asthma exacerbations in the acetaminophen group vs. the ibuprofen group, 0.94; 95% confidence interval, 0.69 to 1.28; P=0.67). In the acetaminophen group, 49% of participants had at least one asthma exacerbation and 21% had at least two, as compared with 47% and 24%, respectively, in the ibuprofen group. Similarly, no significant differences were detected between acetaminophen and ibuprofen with respect to the percentage of asthma-control days (85.8% and 86.8%, respectively; P=0.50), use of an albuterol rescue inhaler (2.8 and 3.0 inhalations per week, respectively; P=0.69), unscheduled health care utilization for asthma (0.75 and 0.76 episodes per participant, respectively; P=0.94), or adverse events.ConclusionsAmong young children with mild persistent asthma, as-needed use of acetaminophen was not shown to be associated with a higher incidence of asthma exacerbations or worse asthma control than was as-needed use of ibuprofen. (Funded by the National Institutes of Health; AVICA ClinicalTrials.gov number, NCT01606319.).

The National Asthma Education and Prevention Program's Expert Panel Report 3, Guidelines for the Diagnosis and Management of Asthma does not recommend antibiotics for the management of acute episodes of asthma exacerbation. Macrolides seem to have some potential effect beyond or in addition to their antibacterial effect. It has been reported that macrolides may potentially benefit patients with chronic inflammatory airway diseases due to their antibacterial, antiviral, and/or anti-inflammatory effects. This review presents recent data on use of azithromycin in prevention and management of acute exacerbation of respiratory symptoms in infants and young children.

This is a “proof of concept” study to determine whether inhalation of 13C-urea can be safely used to detect the presence of urease producing bacteria in the airways of patients with cystic fibrosis (CF) by detecting 13CO2 in breath. This was a prospective, 2-part, open label, single-center, single-arm, single-administration, dose-escalation investigational device exemption trial. First, the safety of 20 and 50 mg inhaled 13C-urea was evaluated in 6 healthy adult participants. Then, 3 adult CF participants colonized with Pseudomonas aeruginosa were enrolled for each dose of inhaled 13C-urea. The safety of inhaled 13C-urea was assessed by spirometry and physical examination. 13C-urea was administered using a jet nebulizer, followed by serial spirometry (10 min and 30 min post inhalation) and collection of exhaled breath at 5, 10, and 15 min post inhalation. There was no clinical significant change in any of the spirometry values compared to baseline in healthy participants and CF patients. Mean of 13CO2/12CO2 delta over baseline (DOB) values in CF participants at 5, 10, and 15 min post inhalation was as follows: 20 mg dose 4‰ (2.2‰–4.9‰), 1‰ (1.0‰–1.4‰), and 1‰ (0.4‰–1.5‰); 50 mg dose: 10‰ (6.2‰–14.5‰), 3‰ (2.1‰–4.3‰), and 1.5‰ (0.6‰–2.3‰). Inhaled 13C-urea for detection of urease producing bacteria was safe, and preliminary data suggest that 13CO2/12CO2 DOB values may be higher in CF patients with P. aeruginosa at 5–10 min after inhalation of 13C-urea. A future direction is to investigate use of inhaled 13C-urea in young children who have difficulty producing sputum for culturing.

Empiric use of proton pump inhibitors (PPI) for the treatment of poorly controlled asthma has increased substantially in the past decade under the presumption that gastroesophageal reflux is precipitating symptoms. No PPI has a Food and Drug Administration (FDA) approved indication for the treatment of asthma symptoms. Use has been driven by data indicating that up to 80% of children and adults with asthma have reflux by pH probe monitoring and that nearly half of patients lack typical reflux symptoms. Data from controlled studies of adults have shown only a minimal improvement in peak expiratory flow with PPI use in the overall population, with only a slightly larger improvement in patients with diagnosed gastroesophageal reflux disease, and no effect on asthma exacerbation rate in one study. The single largest placebo-controlled study in children with poorly controlled asthma without gastroesophageal reflux symptoms found no improvement in any indices of asthma control, even in children with gastroesoph...

Importance Many preschool children develop recurrent, severe episodes of lower respiratory tract illness (LRTI). Although viral infections are often present, bacteria may also contribute to illness pathogenesis. Strategies that effectively attenuate such episodes are needed. Objective To evaluate if early administration of azithromycin, started prior to the onset of severe LRTI symptoms, in preschool children with recurrent severe LRTIs can prevent the progression of these episodes. Design, Setting, and Participants A randomized, double-blind, placebo-controlled, parallel-group trial conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by December 2014. Participants were 607 children aged 12 through 71 months with histories of recurrent, severe LRTIs and minimal day-to-day impairment. Intervention Participants were randomly assigned to receive azithromycin (12 mg/kg/d for 5 days; n = 307) or matching placebo (n = 300), started early during each predefined RTI (child’s signs or symptoms prior to development of LRTI), based on individualized action plans, over a 12- through 18-month period. Main Outcomes and Measures The primary outcome measure was the number of RTIs not progressing to a severe LRTI, measured at the level of the RTI, that would in clinical practice trigger the prescription of oral corticosteroids. Presence of azithromycin-resistant organisms in oropharyngeal samples, along with adverse events, were among the secondary outcome measures. Results A total of 937 treated RTIs (azithromycin group, 473; placebo group, 464) were experienced by 443 children (azithromycin group, 223; placebo group, 220), including 92 severe LRTIs (azithromycin group, 35; placebo group, 57). Azithromycin significantly reduced the risk of progressing to severe LRTI relative to placebo (hazard ratio, 0.64 [95% CI, 0.41-0.98], P = .04; absolute risk for first RTI: 0.05 for azithromycin, 0.08 for placebo; risk difference, 0.03 [95% CI, 0.00-0.06]). Induction of azithromycin-resistant organisms and adverse events were infrequently observed. Conclusions and Relevance Among young children with histories of recurrent severe LRTIs, the use of azithromycin early during an apparent RTI compared with placebo reduced the likelihood of severe LRTI. More information is needed on the development of antibiotic-resistant pathogens with this strategy. Trial Registration clinicaltrials.gov Identifier:NCT01272635

Inhaled corticosteroids (ICS) are recommended by The National Asthma Education and Prevention Program's Expert Panel Report 3 for all levels of persistent asthma in the pediatric population. The recommended ICS doses are based on assessment of severity and control of asthma. The pharmacodynamics and pharmacokinetics of the current ICSs are reviewed. While comparable efficacy can be achieved with equipotent dosing, some of the newer ICSs, fluticasone propionate, mometasone furoate, and ciclesonide, have pharmacokinetic profiles that produce less risk of systemic effects. However, at high doses systemic activity increases with all ICSs. The clinicians need to weigh the benefits and risks of these different products and dosing schemes in their patients for optimal use.

Study Objectives. To compare pretreatment with albuterol versus montelukast added to the current asthma regimen for protection against exercise-induced bronchospasm in children with mild-to-moderate asthma, and to determine whether cysteinyl leukotriene (Cys-LT) concentrations measured in the exhaled breath condensate correlated with response to montelukast. Design. Prospective, randomized, double-blind, double-dummy, crossover study Setting. Asthma clinic at a university-affiliated medical center. Patients. Eleven children aged 7–17 years with physician-diagnosed mild-to-moderate asthma for at least 6 months and with self-reported exercise-induced bronchospasm (defined as ≤ 15% decrease in forced expiratory volume in 1 sec [FEV1] at screening and baseline visit). Intervention. Patients were randomly assigned to receive 3–7 days of oral montelukast 5–10 mg/day or 2 puffs of an albuterol metered-dose inhaler just before an exercise challenge and then were crossed over to the alternate therapy for the last visit. Measurements and Main Results. Serial spirometry was performed before and at 0, 5, 10, 15, 30, 45, and 60 minutes after the exercise challenge at each visit. Measurement of exhaled breath condensate was performed at the screening visit and study visits 1 and 2. The primary outcome was the maximum change in FEV1 after exercise. Secondary outcomes were the area under the curve for FEV1 (expressed as percentage decrease from baseline) during the first 60 minutes (AUC0–60) after exercise and the proportion of patients in whom exercise-induced bronchospasm was prevented (defined as < 15% decrease in FEV1 after exercise challenge). The mean ± SD maximum decrease in FEV1 was 27.5 ± 7.9% at baseline. Patients receiving montelukast had an 18.3 ± 13.7% decrease in FEV1 compared with 0.7 ± 1.6% in patients receiving albuterol (p=0.002, paired t test). Exercise-induced bronchospasm was prevented in 100% of the patients receiving albuterol compared with 55% receiving montelukast (p

Study Objective. To determine the effect of S-albuterol on the dose response to levalbuterol in patients with moderate bronchoconstriction induced by a methacholine challenge. Design. Prospective, randomized, double-blind, placebo-controlled, crossover study. Setting. University-affiliated clinical trial center. Patients. Twenty-two adults with mild, stable asthma. Intervention. At the screening visit, patients were switched from their β2-agonist to ipratropium bromide for use as an as-needed rescue therapy. At the baseline visit 2–6 days later, the provocative concentration of methacholine to induce a 30% decrease in forced expiratory volume in 1 second (FEV1 PC30) was determined, followed by a nebulized racemic albuterol dose-response study with three doses of albuterol, to familiarize patients with the procedures. At visits 2 and 3, patients were randomly assigned to receive nebulized normal saline placebo or S-albuterol 5 mg before the methacholine challenge and were administered three escalating doses of levalbuterol after the challenge. Measurements and Main Results. Area under the curve for FEV1 over 40 minutes (AUC0–40) after administration of levalbuterol was the primary outcome, with slope of FEV1 as the secondary outcome. In addition, the fraction of exhaled nitric oxide (FeNO) was measured before and after the challenges. In the 17 patients who met criteria for completion, no deleterious effect for S-albuterol was found for FEV1 PC30, AUC0–40 FEV1, or the FEV1 slope0–40. However, S-albuterol reduced the provocative concentration of methacholine to induce a 20% decrease in FEV1 (PC20 0.52 ± 2.06 vs 0.39 ± 1.58 mg/ml, placebo vs S-albuterol, p=0.044) but did not affect FeNO. Conclusion. A single high dose of S-albuterol did not alter the bronchodilator response to levalbuterol. The effect on bronchial responsiveness requires further study.

Few studies have examined how developing obesity in early adulthood affects the course of asthma.We analyzed lung function and asthma impairment and risk among nonobese children with asthma, comparing those who were obese in young adulthood with those who remained nonobese.We carried out the post hoc analysis of 771 subjects with mild to moderate asthma who were not obese (pediatric definition, body mass index [BMI]95th percentile) when enrolled in the Childhood Asthma Management Program at ages 5-12 years. The subjects were then followed to age 20 years or more. For visits at ages 20 years or more, spirometry values as percent predicted and recent asthma symptom scores and prednisone exposure were compared between 579 subjects who were nonobese at all visits and 151 who were obese (adult definition of BMI ≥ 30 kg/m(2)) on at least 1 visit (median number of visits when obese = 4, IQR 2-7).Compared with participants who were nonobese (BMI 23.4 ± 2.6 kg/m(2)), those who became obese (BMI 31.5 ± 3.8 kg/m(2)) had significant decreases in forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) (P.0003) and FEV1 (P = .001), without differences in FVC (P = .15) during visits at ages 20 years or more. For each unit increase of BMI, FEV1 percent predicted decreased by 0.29 (P = .0009). The relationship between BMI and lung function was not confounded by sex or BMI at baseline. Asthma impairment (symptom scores) and risk (prednisone use) did not differ between the 2 groups.Becoming obese in early adulthood was associated with increased airway obstruction, without impact on asthma impairment or risk.

The objective of the study was to measure peak inspiratory flow (PIF) generated through Turbuhaler, Aerolizer, and Diskus inhalers in children 2 to 12 years old. An open-labeled, stratified, random...

Hospitals across the United States develop treatment algorithms for acute bronchospasm, asthma, and chronic obstructive pulmonary disease by following several different pathways. Some institutions use established national guidelines and protocols, some revise national guidelines to apply to their particular environment, and others create specific institution-related treatment algorithms with input from various departments, such as emergency medicine, respiratory therapy, and pharmacy. Although some institutions track outcomes on either a formal or an informal basis, others have not yet implemented outcomes-based programs.

Urinary free cortisol (UFC) concentration is one of the most sensitive indicators of systemic effect of glucocorticoids. The purpose of this study was to determine normal UFC values in healthy chil...

Our aim was to directly compare anti-inflammatory activity, as measured by fraction of exhaled nitric oxide (FeNO), relative efficacy, and safety of a low-dose inhaled corticosteroid and a leukotri...

The purpose of this review is to discuss the effect of daily inhaled corticosteroids (ICSs) on the height of children with asthma. The effect of ICSs on growth and height is dependent on the dose and the therapeutic index of the ICS; however, the effect on final adult height was not clear until recently. New data suggest that if growth suppression occurs with the use of ICSs in children, it is sustained, but not cumulative over the years. The observed reduction in the final adult height is small and does not outweigh the benefits of ICSs, and the growth effect may be minimized by use of newer ICSs and other approaches for management of asthma in children with mild to moderate asthma.

Equal efficacious doses of the inhaled corticosteroids can result in significant differences in systemic effects due to differences in their pharmacokinetic profile. The purpose of this study was to evaluate a model to compare systemic activity of inhaled corticosteroids given in topically equipotent doses in children. Systemic effects were measured by 24-hour urinary free cortisol (UFC) and a.m. and p.m. serum osteocalcin. Efficacy was monitored by a.m. and p.m. exhaled nitric oxide (eNO) and a.m. peak expiratory flow (PEF). Twenty-one children, 6-16 years old on inhaled corticosteroids at ≥400 μg/day beclomethasone dipropionate (BDP) equivalent were placed on BDP for a 2-week, open-label, run-in, baseline period. Patients were then randomized into a double-blind, double-dummy, crossover trial for two 3-week periods of equipotent doses of fluticasone propionate (FP) or triamcinolone acetonide (TAA) as defined by the NHLBI Expert Panel Report 2. At the end of baseline and each treatment phase patients wer...

The National Asthma Education and Prevention Program's Expert Panel Report 3 (EPR3), Guidelines for the Diagnosis and Management of Asthma, provides recommendations for initial assessment of asthma severity based on both impairment and risk domains. Subsequently, the follow-up visits are designed to assess asthma control and to adjust the therapy to the lowest effective dose of inhaled corticosteroids (ICSs) or various combinations for optimal control. EPR3 recommends considering step down in therapy if patient is well controlled for 3 consecutive months, which may lead to discontinuation of daily medications for patients receiving low dose ICSs or other controller monotherapy. In addition, patients and parents have a tendency to stop the daily medications after having a period of controlled asthma. In these situations, the challenge is to find the best way to discontinue daily medications in patients with mild or intermittent asthma whose daily or weekly impairment is under good control but may still be at risk for asthma exacerbations. The question is, “May another regimen other than daily use of ICSs be used in these patients who become asymptomatic with appropriate treatment to decrease the risk of asthma exacerbation?”

Asthma is characterized by inflammation of proximal and distal airways. As new formulations of extrafine aerosol particles have become available, targeting small airways for the management of asthma has been investigated. As new studies attempt to explore the correlation between small airway dysfunction and clinical outcomes in asthma, well-designed clinical trials are needed to compare targeted and standard therapy for asthma management especially in pediatric patients.

The use of inhaled glucocorticoids for persistent asthma causes a temporary reduction in growth velocity in prepubertal children. The resulting decrease in attained height 1 to 4 years after the initiation of inhaled glucocorticoids is thought not to decrease attained adult height.We measured adult height in 943 of 1041 participants (90.6%) in the Childhood Asthma Management Program; adult height was determined at a mean (±SD) age of 24.9±2.7 years. Starting at the age of 5 to 13 years, the participants had been randomly assigned to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4 to 6 years. We calculated differences in adult height for each active treatment group, as compared with placebo, using multiple linear regression with adjustment for demographic characteristics, asthma features, and height at trial entry.Mean adult height was 1.2 cm lower (95% confidence interval [CI], -1.9 to -0.5) in the budesonide group than in the placebo group (P=0.001) and was 0.2 cm lower (95% CI, -0.9 to 0.5) in the nedocromil group than in the placebo group (P=0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (-0.1 cm for each microgram per kilogram of body weight) (P=0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (-1.3 cm; 95% CI, -1.7 to -0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants.The initial decrease in attained height associated with the use of inhaled glucocorticoids in prepubertal children persisted as a reduction in adult height, although the decrease was not progressive or cumulative. (Funded by the National Heart, Lung, and Blood Institute and the National Center for Research Resources; CAMP ClinicalTrials.gov number, NCT00000575.).

Inhaled corticosteroids (ICSs) are used extensively in the treatment of asthma and chronic obstructive pulmonary disease (COPD) due to their broad antiinflammatory effects. They improve lung function, symptoms, and quality of life and reduce exacerbations in both conditions but do not alter the progression of disease. They decrease mortality in asthma but not COPD. The available ICSs vary in their therapeutic index and potency. Although ICSs are used in all age groups, younger and smaller children may be at a greater risk for adverse systemic effects because they can receive higher mg/kg doses of ICSs compared with older children. Most of the benefit from ICSs occurs in the low to medium dose range. Minimal additional improvement is seen with higher doses, although some patients may benefit from higher doses. Although ICSs are the preferred agents for managing persistent asthma in all ages, their benefit in COPD is more controversial. When used appropriately, ICSs have few adverse events at low to medium doses, but risk increases with high-dose ICSs. Although several new drugs are being developed and evaluated, it is unlikely that any of these new medications will replace ICSs as the preferred initial long-term controller therapy for asthma, but more effective initial controller therapy could be developed for COPD.

OBJECTIVE: To evaluate studies comparing metered dose inhalers with holding chambers to nebulizers in the emergency department for the treatment of asthma exacerbation. DATA SOURCE: Primary articles and systematic review provided by the Cochrane Airways Review Group of the Cochrane Library identified by MEDLINE search (1966–February 2004) and through secondary sources. DATA SYNTHESIS: The Cochrane review included 21 randomized clinical trials conducted in hospital emergency departments comparing clinical outcomes following β2 agonist administration via a nebulizer or a metered dose inhaler with holding chamber. Although the relative risk ratio of hospital admission with metered dose inhaler and holding chamber did not differ in children or in adults compared to the nebulizer delivery, none of the individual studies reviewed were powered to detect a difference in the rate of hospital admission. Specific factors in the treatment of acute asthma such as assessment of severity, appropriate outcome selection, appropriate dose selection, and appropriate delivery systems need to be considered to critically evaluate the literature. CONCLUSION: Although available randomized clinical trials suggest equivalency of metered dose inhaler plus holding chambers and nebulized delivery of inhaled β2 agonists, these trials are biased to show no difference in response. There is no data to support the advantage of one method over the other in mild to moderate asthmatic patients either clinically or economically.

The aim of this study was to characterize the 24-h and diurnal variability of urinary protein excretion and identify the prevalence of orthostatic proteinuria (OP) in healthy children. Upright, supine, and 24-h total urinary protein (UrTP) and creatinine clearance (CrCl) were measured in 91 healthy children ages 6–19 years. Urinary protein and creatinine excretions were calculated and examined by gender, age, Tanner stage, and body mass index (BMI). Orthostatic proteinuria (OP) was defined as a 24-h UrTP >100 mg/m2 with a normal supine UrTP (10 years and BMI >85%. In children with OP, a first morning UPcr shows a value in the normal range, whereas a random daytime UPcr is elevated. There exists a diurnal variability in urinary protein excretion that is exaggerated in participants with OP. UPcr reliably estimates 24-h UrTP. Using current pediatric criteria, OP is very common, particularly in boys. A normal first morning UPcr ratio indicates that a child with elevated random urinary protein has OP.

Objective. To determine the safety of long-term (36 months) administration of an inhaled corticosteroid (budesonide) on hypothalamic-pituitary-adrenal (HPA) axis function in children with mild to moderate asthma.Methods. This was an ancillary study of the Childhood Asthma Management Program (CAMP). Sixty-three children who had mild to moderate asthma and were enrolled in CAMP underwent evaluation of HPA axis function before and 12 and 36 months after receiving continuous therapy with either an inhaled anti-inflammatory agent (budesonide 400 μg/day or nedocromil 16 mg/day) or placebo. HPA axis function was assessed by serum cortisol levels 30 and 60 minutes after 0.25 mg of adrenocorticotrophic hormone (ACTH) and 24-hour urinary free cortisol excretion.Results. There were no differences in serum cortisol levels after ACTH stimulation between treatment groups, regardless of time after ACTH administration or months of follow-up. Urinary cortisol excretion per body surface area was similar in both treatment groups at 36 months, after adjusting for age at randomization, race, gender, and clinic. Cumulative inhaled corticosteroid exposure did not influence serum cortisol response to ACTH or urinary free cortisol excretion at 36 months.Conclusions. We found no effects of chronic budesonide treatment at a dose of 400 μg/day on HPA axis function in children with mild to moderate asthma and demonstrated the absence of a cumulative effect on HPA axis function over a 3-year period.

Diagnosis and management of asthma in preschool children are challenging. The Expert Panel Report 3 has recommendations for specific illness phenotypes to start long-term controller medication to reduce risk and impairment in children ages 0–4-year old. The use of daily-inhaled corticosteroids has shown to be effective in preschool children with persistent asthma, but there are also reports of growth retardation. For children with recurrent or intermittent wheezing without symptoms in between episodes, the intermittent use of controller medications may be an option for certain phenotypes. This review will discuss the available data on use of intermittent controller medications in preschool children with wheezing.