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1.  Classification of childhood asthma phenotypes and long-term clinical responses to inhaled anti-inflammatory medications 
Background
Although recent studies have identified the presence of phenotypic clusters in asthmatic patients, the clinical significance and temporal stability of these clusters have not been explored.
Objective
Our aim was to examine the clinical relevance and temporal stability of phenotypic clusters in children with asthma.
Methods
We applied spectral clustering to clinical data from 1041 children with asthma participating in the Childhood Asthma Management Program. Posttreatment randomization follow-up data collected over 48 months were used to determine the effect of these clusters on pulmonary function and treatment response to inhaled anti-inflammatory medication.
Results
We found 5 reproducible patient clusters that could be differentiated on the basis of 3 groups of features: atopic burden, degree of airway obstruction, and history of exacerbation. Cluster grouping predicted long-term asthma control, as measured by the need for oral prednisone (P < .0001) or additional controller medications (P = .001), as well as longitudinal differences in pulmonary function (P < .0001). We also found that the 2 clusters with the highest rates of exacerbation had different responses to inhaled corticosteroids when compared with the other clusters. One cluster demonstrated a positive response to both budesonide (P = .02) and nedocromil (P = .01) compared with placebo, whereas the other cluster demonstrated minimal responses to both budesonide (P = .12) and nedocromil (P = .56) compared with placebo.
Conclusion
Phenotypic clustering can be used to identify longitudinally consistent and clinically relevant patient subgroups, with implications for targeted therapeutic strategies and clinical trials design.
PMCID: PMC4047642  PMID: 24892144
Childhood asthma; asthma phenotypes; inhaled corticosteroids; cluster analysis; asthma classification; longitudinal study
2.  Do oral corticosteroids reduce the severity of acute lower respiratory tract illnesses in preschool children with recurrent wheezing? 
The Journal of allergy and clinical immunology  2013;131(6):10.1016/j.jaci.2013.01.034.
Background
Oral corticosteroids (OCSs) are recommended for severe wheezing episodes in children. However, limited evidence supports this intervention in preschool children with outpatient wheezing illnesses.
Objective
We sought to investigate whether OCSs reduce symptom scores during acute lower respiratory tract illnesses (LRTIs) in preschool children with recurrent wheeze
Methods
We performed post hoc and replication analyses in 2 outpatient cohorts of children aged 1 to 5 years with episodic wheezing participating in clinical trials. We compared symptom scores during LRTIs that were or were not treated with OCSs, adjusting for differences in disease and episode severity covariates.We stratified episodes by severity by using a propensity model. The primary outcome was the area under the curve (AUC) of total symptom scores among the more severe episodes.
Results
Two hundred fifteen participants from the Acute Intervention Management Strategies trial experienced 798 acute LRTIs, 112 of which were defined as severe based on propensity scores. The AUCs of total symptom scores did not differ between the episodes that were (n = 70) and were not (n = 42) treated with OCSs (P = .46) nor was there an OCS treatment effect on individual symptom scores. Similar analyses of the Maintenance Versus Intermittent Inhaled Corticosteroids in Wheezing Toddlers trial, involving 278 participants with 133 severe LRTIs, confirmed the above findings (P =.46 for AUC of total symptoms score comparison).
Conclusion
In 2 separate cohorts of preschool children with episodic wheezing, OCS treatment during clinically significant LRTIs did not reduce symptom severity during acute LRTIs, despite asthma controller medication use during most episodes. These findings need to be confirmed in a prospective randomized controlled trial.
doi:10.1016/j.jaci.2013.01.034
PMCID: PMC3810170  PMID: 23498594
Oral corticosteroids; episodic wheezing; preschool children
3.  ITGB5 and AGFG1 variants are associated with severity of airway responsiveness 
BMC Medical Genetics  2013;14:86.
Background
Airway hyperresponsiveness (AHR), a primary characteristic of asthma, involves increased airway smooth muscle contractility in response to certain exposures. We sought to determine whether common genetic variants were associated with AHR severity.
Methods
A genome-wide association study (GWAS) of AHR, quantified as the natural log of the dosage of methacholine causing a 20% drop in FEV1, was performed with 994 non-Hispanic white asthmatic subjects from three drug clinical trials: CAMP, CARE, and ACRN. Genotyping was performed on Affymetrix 6.0 arrays, and imputed data based on HapMap Phase 2, was used to measure the association of SNPs with AHR using a linear regression model. Replication of primary findings was attempted in 650 white subjects from DAG, and 3,354 white subjects from LHS. Evidence that the top SNPs were eQTL of their respective genes was sought using expression data available for 419 white CAMP subjects.
Results
The top primary GWAS associations were in rs848788 (P-value 7.2E-07) and rs6731443 (P-value 2.5E-06), located within the ITGB5 and AGFG1 genes, respectively. The AGFG1 result replicated at a nominally significant level in one independent population (LHS P-value 0.012), and the SNP had a nominally significant unadjusted P-value (0.0067) for being an eQTL of AGFG1.
Conclusions
Based on current knowledge of ITGB5 and AGFG1, our results suggest that variants within these genes may be involved in modulating AHR. Future functional studies are required to confirm that our associations represent true biologically significant findings.
doi:10.1186/1471-2350-14-86
PMCID: PMC3765944  PMID: 23984888
Asthma; Airway hyperresponsiveness; Genome-wide association study; ITGB5; AGFG1
4.  Key findings and clinical implications from The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study 
Patients with severe or difficult-to-treat asthma are an understudied population but account for considerable asthma morbidity, mortality, and costs. The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study was a large, 3-year, multicenter, observational cohort study of 4756 patients (n = 3489 adults ≥18 years of age, n = 497 adolescents 13-17 years of age, and n = 770 children 6-12 years of age) with severe or difficult-to-treat asthma. TENOR's primary objective was to characterize the natural history of disease in this cohort. Data assessed semiannually and annually included demographics, medical history, comorbidities, asthma control, asthma-related health care use, medication use, lung function, IgE levels, self-reported asthma triggers, and asthma-related quality of life. We highlight the key findings and clinical implications from more than 25 peer-reviewed TENOR publications. Regardless of age, patients with severe or difficult-to-treat asthma demonstrated high rates of health care use and substantial asthma burden despite receiving multiple long-term controller medications. Recent exacerbation history was the strongest predictor of future asthma exacerbations. Uncontrolled asthma, as defined by the 2007 National Heart, Lung, and Blood Institute guidelines’ impairment domain, was highly prevalent and predictive of future asthma exacerbations; this assessment can be used to identify high-risk patients. IgE and allergen sensitization played a role in the majority of severe or difficult-to-treat asthmatic patients.
doi:10.1016/j.jaci.2012.04.014
PMCID: PMC3622643  PMID: 22694932
TENOR; severe or difficult-to-treat asthma; asthma control; asthma exacerbations; burden; medication; quality of life; allergy; IgE
5.  Elevated Exhaled Nitric Oxide Levels Increases Risk of Respiratory Tract Illness in Preschool Children with Moderate to Severe Intermittent Wheezing 
Background
The fractional concentration of exhaled nitric oxide (FeNO) is a noninvasive marker for airway inflammation but requires further study in pre-school children to determine its clinical relevance.
Objective
To determine whether the risk of respiratory tract illnesses (RTI), disease burden and atopic features are related to FeNO in preschool children with moderate-to-severe intermittent wheezing.
Methods
We determined FeNO using the off-line tidal breathing technique in 89 children, 12–59 months old, with moderate-severe intermittent wheezing. Risk of RTI was determined by comparing participants with baseline FeNO >75th percentile (24.4ppb) to those with FeNO ≤75th percentile using Cox regression analysis.
Results
The risk of RTI was significantly higher in children with FeNO >24.4ppb relative to those with lower FeNO values (adjusted RR= 3.8, 95% CI: 1.74–8.22; p=0.0008). FeNO levels >24ppb were associated with a greater number of positive skin tests to aeroallergens (p=0.03), but not with other atopic characteristics or historic parameters of illness burden.
Conclusion
Elevated FeNO in preschool children with moderate-to-severe intermittent wheezing was associated with an increased risk of RTI during a one-year follow-up. In addition, higher FeNO was associated with aeroallergen sensitization.
doi:10.1016/S1081-1206(10)60162-7
PMCID: PMC3652587  PMID: 19739422
Preschool children; exhaled nitric oxide; respiratory tract illness; wheezing
6.  Effect of Inhaled Glucocorticoids in Childhood on Adult Height 
The New England journal of medicine  2012;367(10):904-912.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.1056/NEJMoa1203229
PMCID: PMC3517799  PMID: 22938716
7.  Integration of Mouse and Human Genome-Wide Association Data Identifies KCNIP4 as an Asthma Gene 
PLoS ONE  2013;8(2):e56179.
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
doi:10.1371/journal.pone.0056179
PMCID: PMC3572953  PMID: 23457522
8.  Adherence to inhaled corticosteroids: An ancillary study of the Childhood Asthma Management Program clinical trial 
Background
Information comparing subjective and objective measurements of adherence to study medications and the effects of adherence on treatment-related differences in asthma clinical trials are limited.
Objective
We sought to compare subjective and objective measurements of children’s adherence to inhaled corticosteroids or placebo and to determine whether adherence to study medications modified treatment-related differences in outcomes.
Methods
In an ancillary study conducted in 3 of 8 Childhood Asthma Management Program Clinical Centers, adherence was assessed by using self-reported and objective data in 5- to 12-year-old children with mild or moderate asthma who were randomly assigned to 200 μg of inhaled budesonide twice per day (n = 84) or placebo (n = 56) for 4 years. The κ statistic was used to evaluate agreement between self-reported adherence (daily diary cards) and objectively measured adherence (number of doses left in study inhalers). Multivariable analyses were used to determine whether adherence to study treatment modified treatment-related differences in outcomes.
Results
Adherence of less than 80% was seen in 75% of 140 children when adherence was measured objectively but only in 6% of children when measured by means of self-report. There was poor agreement between objective and subjective measurements of adherence of at least 80% (κ = 0.00; 95% CI, −0.05 to 0.04); self-reported adherence over the 4-year period generally overestimated objectively measured adherence (93.6% vs 60.8%, P < .0001). There was little evidence to indicate that adherence modified treatment-related differences in outcomes.
Conclusion
Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.
doi:10.1016/j.jaci.2011.10.030
PMCID: PMC3350797  PMID: 22104610
Asthma; adherence; compliance; children; lung growth; inhaled corticosteroids; budesonide; clinical trial
9.  Growth of Preschool Children at High Risk for Asthma Two Years after Discontinuation of Fluticasone 
Background
The effect on linear growth of daily long-term inhaled corticosteroid (ICS) therapy in preschool-aged children with recurrent wheezing is controversial.
Objective
To determine the effect of daily ICS given for 2 years on linear growth in preschool children with recurrent wheezing.
Methods
Children ages 2 and 3 years with recurrent wheezing and positive modified asthma predictive indices were randomized to a two-year treatment period of fluticasone propionate CFC (176 mcg/day) or masked-placebo delivered by valved chamber with mask and then followed 2 years off study medication. Height growth determined by stadiometry was compared between treatment groups.
Results
In the study cohort as a whole, the fluticasone group did not have significantly less linear growth than the placebo-group [change in height from baseline difference (ΔHt) of −0.2 cm (95% CI, −1.1, 0.6)] two years after discontinuation of study treatment. In post-hoc analyses, children 2 years old and who weighed < 15 kg at enrollment treated with fluticasone had less linear growth compared to placebo [ΔHt of −1.6 cm (95% CI, −2.8, −0.4), p=0.009].
Conclusion
Linear growth was not significantly different in high-risk, recurrent wheezing preschool age children treated with CFC fluticasone 176 mcg/day compared to placebo 2 years after fluticasone is discontinued. However, post-hoc subgroup analyses revealed that children who are younger in age and of lesser weight relative to the entire study cohort had significantly less linear growth, possibly due to a higher relative fluticasone exposure.
doi:10.1016/j.jaci.2011.06.027
PMCID: PMC3224818  PMID: 21820163
Asthma predictive index; atopy; clinical trials; early childhood asthma; fluticasone; inhaled corticosteroids; intermittent wheezing; linear growth; research network
10.  Most Nocturnal Asthma Symptoms Occur Outside of Exacerbations and Associate with Morbidity 
Background
Although nocturnal awakenings help categorize asthma severity and control, their clinical significance has not been thoroughly studied.
Objective
To determine the clinical consequences of nocturnal asthma symptom(s) requiring albuterol in children with mild-to-moderate persistent asthma outside of periods when oral corticosteroids were used for worsening asthma symptoms.
Methods
285 children ages 6 to 14 years with mild-to-moderate persistent asthma were randomized to receive one of three controller regimens and completed daily symptom diaries for 48 weeks. Diary responses were analyzed for the frequency and consequences of nocturnal asthma symptoms requiring albuterol.
Results
Nocturnal asthma symptoms requiring albuterol occurred in 72.2% of participants at least once and in 24.3% ≥13 times. 81.3% of nocturnal symptoms occurred outside of exacerbation periods and were associated the next day with the following events: albuterol use (56.9% of days preceded by nocturnal symptoms versus 18.1% of days not preceded by nocturnal symptoms, Relative Risk (RR) 2.3, 95%CI: 2.2,2.4), school absence (5.0% versus 0.3%, RR 10.6, 95%CI: 7.8,14.4), and doctor contact (3.7% versus 0.2%, RR 8.8, 95%CI:6.1,12.5). Similar findings were noted during exacerbation periods (RR 1.7 for albuterol use, 5.5 for school absence, and 4.9 for doctor contact). Nocturnal symptoms did not predict the onset of exacerbations.
Conclusion
Nocturnal symptoms requiring albuterol in children with mild-to-moderate persistent asthma receiving controller therapy occurred predominantly outside of exacerbation periods. Despite being poor predictors of exacerbations, they were associated with increases in albuterol use, school absences, and doctor contacts the day after nocturnal symptom occurrences.
doi:10.1016/j.jaci.2011.07.018
PMCID: PMC3408598  PMID: 21855126
asthma; nocturnal symptoms; exacerbation
11.  Assessment of asthma control and asthma exacerbations in the epidemiology and natural history of asthma: outcomes and treatment regimens (TENOR) observational cohort 
Current Respiratory Care Reports  2012;1(4):259-269.
Patients with severe or difficult-to-treat asthma account for substantial asthma morbidity, mortality, and healthcare burden despite comprising only a small proportion of the total asthma population. TENOR, a multicenter, observational, prospective cohort study was initiated in 2001. It enrolled 4,756 adults, adolescents and children with severe or difficult-to-treat asthma who were followed semi-annually and annually for three years, enabling insight to be gained into this understudied population. A broad range of demographic, clinical, and patient self-reported assessments were completed during the follow-up period. Here, we present key findings from the TENOR registry in relation to asthma control and exacerbations, including the identification of specific subgroups found to be at particularly high-risk. Identification of the factors and subgroups associated with poor asthma control and increased risk of exacerbations can help physicians design individual asthma management, and improve asthma-related health outcomes for these patients.
doi:10.1007/s13665-012-0025-x
PMCID: PMC3485530  PMID: 23136642
Severe asthma; Difficult-to-treat asthma; Asthma control; Exacerbation
12.  Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene 
PLoS Genetics  2012;8(7):e1002824.
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after administration of a β2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through GWAS.
Author Summary
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function before and after the administration of short-acting β2-agonists, common medications used for asthma treatment. We performed a genome-wide association study of BDR with 1,644 white asthmatic subjects from six drug clinical trials and attempted to replicate these findings in 1,051 white subjects from two independent cohorts. The most significant associated variant was near the SPATS2L gene. We knocked down SPATS2L mRNA in human airway smooth muscle cells and found that β2-adrenergic receptor levels increased, suggesting that SPATS2L may be a regulator of BDR. Our results highlight the promise of pursuing GWAS results that do not necessarily reach genome-wide significance and are an example of how results from pharmacogenetic GWAS can be studied functionally.
doi:10.1371/journal.pgen.1002824
PMCID: PMC3390407  PMID: 22792082
13.  Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing 
The New England journal of medicine  2011;365(21):1990-2001.
BACKGROUND
Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy.
METHODS
We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy.
RESULTS
The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen.
CONCLUSIONS
A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year.
doi:10.1056/NEJMoa1104647
PMCID: PMC3247621  PMID: 22111718
14.  Cost-Effectiveness Analysis of Fluticasone vs. Montelukast in Children with Mild-Moderate Persistent Asthma in the Pediatric Asthma Controller Trial 
Background
Cost-effectiveness analyses of asthma controller regimens for adults exist, but similar evaluations exclusively for children are few.
Objective
To compare the cost-effectiveness of two commonly used asthma controllers, fluticasone and montelukast, with data from the Pediatric Asthma Controller Trial.
Methods
We compared the cost-effectiveness of low-dose fluticasone with montelukast in a randomized controlled multi-center clinical trial in children with mild-moderate persistent asthma. Analyses were also conducted on subgroups based on phenotypic factors. Effectiveness measures included a) the number of asthma-control days, b) the percentage of participants with an increase over baseline of FEV1≥12%, and c) the number of exacerbations avoided. Costs were analyzed from both a US health care payer's perspective and a societal perspective.
Results
For all cost-effectiveness measures studied, fluticasone cost less and was more effective than montelukast; e.g., fluticasone treatment cost $430 less in mean direct cost (P<0.01) and had 40 more asthma control days (P<0.01) during the 48 week study period. Considering sampling uncertainty, fluticasone cost less and was more effective at least 95% of the time. For the high eNO phenotypic subgroup (eNO≥25ppb) and more responsive PC20 subgroup (PC20<2 mg/mL), fluticasone was cost-effective compared with montelukast for all cost-effectiveness measures; whereas not all the effectiveness measures were statistically different for the other two phenotypic subgroups.
Conclusion
For children with mild-moderate persistent asthma, low dose fluticasone had lower cost and higher effectiveness compared with montelukast, especially in those with more airway inflammation as indicated by elevated levels of eNO and more responsivity to methacholine.
doi:10.1016/j.jaci.2010.10.035
PMCID: PMC3061816  PMID: 21211651
Cost-effectiveness analysis; childhood asthma; fluticasone; montelukast; PACT
15.  Urinary Leukotriene E4 /Exhaled Nitric Oxide Ratio and Montelukast Response in Childhood Asthma 
Background
A subset of children with asthma respond better to leukotriene receptor antagonists (LTRA) than to inhaled corticosteroids (ICS). Information is needed to identify children with these preferential responses.
Objective
To determine whether the ratio of urinary leukotriene E4 to fractional exhaled nitric oxide (LTE4: FENO) delineates children with preferential responsiveness to montelukast (MT) compared to fluticasone propionate (FP) therapy.
Methods
Data from 318 children with mild to moderate asthma enrolled in 2 NHLBI CARE network studies (CLIC and PACT) were analyzed. The association between LTE4: FENO ratios at baseline and improved lung function or asthma control days (ACDs) with MT and FP therapy was determined and phenotypic characteristics related to high ratios was assessed.
Results
LTE4: FENO ratios were associated with a greater response to MT than FP therapy for forced expiratory volume in 1 second (FEV1) measurements (2.1% increase per doubling of ratio, p=0.001) and for ACDs per week (0.3 increase, p= 0.009) in the CLIC study. In PACT, the ratio was associated with greater FEV1 responsiveness to MT than FP therapy (0.6% increase, p= 0.03). In a combined study analysis, LTE4: FENO ratios were associated with greater response to MT than FP therapy for FEV1 (0.8% increase, p=0.0005) and ACDs (0.3 increase, p=0.008). Children with LTE4: FENO ratios at or above the 75th percentile were likely (p<0.05) to be younger, female and exhibit lower levels of atopic markers and methacholine reactivity.
Conclusion
LTE4: FENO ratios predict a better response to MT than FP therapy in children with mild to moderate asthma.
Clinical Implications
In children with mild to moderate asthma, the LTE4: FENO ratio is associated with a better response to montelukast compared to fluticasone therapy.
Capsule Summary
Data from 318 children with mild to moderate asthma enrolled in 2 NHLBI network studies (CLIC and PACT) were analyzed. Urinary LTE4: FENO ratios predicted a better response to MT than FP therapy.
doi:10.1016/j.jaci.2010.07.008
PMCID: PMC2935914  PMID: 20816189
asthma; biomarkers; fluticasone propionate; inhaled corticosteroids; leukotriene E4; montelukast
16.  In Utero Smoke Exposure and Impaired Response to Inhaled Corticosteroids in Children with Asthma 
Background
Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in asthmatic children.
Objectives
To explore whether IUS exposure is associated with increased airway responsiveness among children with asthma, and whether IUS modifies the response to treatment with inhaled corticosteroids (ICS).
Methods
To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma we performed a repeated-measures analysis of methacholine PC20 data from the Childhood Asthma Management Program (CAMP), a four-year, multicenter, randomized double masked placebo controlled trial of 1041 children ages 5–12 comparing the long term efficacy of ICS with mast cell stabilizing agents or placebo.
Results
Although improvement was seen in both groups, asthmatic children with IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared to unexposed children (p=.01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC20 compared to untreated children (1.25 fold-increase, 95% CI 1.03, 1.50, p=.02) the beneficial effects of budesonide were attenuated among children with a history of IUS exposure (1.04 fold-increase, 95% CI 0.65, 1.68, p=.88).
Conclusions
IUS reduces age-related improvements in airway responsiveness among asthmatic children. Moreover, IUS appears to blunt the beneficial effects of ICS use on airways responsiveness. These results emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.
doi:10.1016/j.jaci.2010.06.016
PMCID: PMC2937829  PMID: 20673983
asthma; in utero smoke exposure; airway responsiveness; inhaled corticosteroids
17.  Serum Vitamin D Levels and Severe Asthma Exacerbations in the Childhood Asthma Management Program Study 
Background
Asthma exacerbations, most often due to respiratory tract infections, are the leading causes of asthma morbidity and comprise a significant proportion of asthma-related costs. Vitamin D status may play a role in preventing asthma exacerbations.
Objectives
To assess the relationship between serum vitamin D levels and subsequent severe asthma exacerbations.
Methods
We measured 25-hydroxyvitamin D (25(OH)D) levels in serum collected from 1,024 mild to moderate persistent asthmatic children at the time of enrollment in a multi-center clinical trial of children randomized to receiving budesonide, nedocromil, or placebo (as-needed beta-agonists), the Childhood Asthma Management Program. Using multivariable modeling we examined the relationship between baseline vitamin D level and the odds of any hospitalization or emergency department (ED) visit over the 4 years of the trial.
Results
35% of all subjects were vitamin D insufficient, as defined by a level ≤ 30 ng/ml 25(OH)D. Mean vitamin D levels were lowest in African-American subjects, and highest in whites. After adjusting for age, sex, BMI, income, and treatment group, insufficient vitamin D status was associated with a higher odds of any hospitalization or ED visit (odds ratio [OR] 1.5 [95% confidence interval [CI]: 1.1 – 1.9] P =0.01).
Conclusion
Vitamin D insufficiency is common in this population of North American children with mild to moderate persistent asthma, and is associated with higher odds of severe exacerbation over a four year period.
doi:10.1016/j.jaci.2010.03.043
PMCID: PMC2902692  PMID: 20538327
Asthma; Vitamin D; inhaled corticosteroids; asthma exacerbations
18.  Signs and Symptoms that Precede Wheezing in Children with a Pattern of Moderate-to-Severe Intermittent Wheezing 
The Journal of pediatrics  2009;154(6):877-81.e4.
Objectives
To examine parent-observed signs and symptoms as antecedents of wheezing in preschool children with prior moderate to severe wheezing episodes, as well as to determine the predictive capacity of these symptom patterns for wheezing events.
Study Design
Parents (n = 238 ) of children 12–59 months of age with moderate-to-severe intermittent wheezing enrolled in a year-long clinical trial completed surveys that captured signs and symptoms at the start of respiratory tract illnesses. Sensitivity, specificity, negative predictive value, and positive predictive values for each symptom leading to wheezing during that respiratory tract illness were calculated.
Results
The most commonly reported first symptom categories during the first respiratory tract illness were “nose symptoms” (41%), “significant cough” (29%), and “insignificant cough” (13%). The most reliable predictor of subsequent wheezing was “significant cough”, which had specificity of 78% and positive predictive value of 74% for predicting wheezing.
Conclusions
“Significant cough” is the most reliable antecedent of wheezing during a respiratory tract illness. It may be useful to consider individualized symptom patterns as a component of management plans intended to minimize wheezing episodes.
doi:10.1016/j.jpeds.2008.12.029
PMCID: PMC3086348  PMID: 19324370
19.  Predictors of Remitting, Periodic, and Persistent Childhood Asthma 
Background
The course of mild to moderate persistent asthma in children is not clearly established.
Objective
To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence.
Methods
The Childhood Asthma Management Program (CAMP) was a 4.3-year randomized, double-masked, multicenter trial in children with mild to moderate persistent asthma that compared continuous therapy with either budesonide or nedocromil, each to placebo, followed by 4 years observational follow-up period. Asthma activity during the observation period included remitting (no asthma activity in the last year), persistent (asthma activity in every quarter), and periodic asthma (neither remitting nor persistent).
Results
Asthma was identified as remitting in 6%, periodic in 39%, and persistent in 55% of the 909 participants, with no effect noted from earlier anti-inflammatory treatment during the CAMP trial. Within all three asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting vs. persistent asthma were lack of allergen sensitization and exposure to indoor allergens [OR=3.23, p<0.001], milder asthma [OR=2.01, p=0.03], older age [OR=1.23, p=0.01], less airway hyperresponsiveness (higher log methacholine FEV1 PC20 [OR=1.39, p=0.03]), higher pre-bronchodilator FEV1 % predicted [OR=1.05, p=0.02], and lower FVC % predicted [OR=0.96, p=0.04].
Conclusion
Remission of asthma in adolescence is infrequent and not impacted by 4 years of anti-inflammatory controller therapy. Factors such as sensitization and exposure, low lung function, and airway greater hyperresponsiveness decrease the likelihood of remitting asthma.
doi:10.1016/j.jaci.2009.10.037
PMCID: PMC2844768  PMID: 20159245
Remission; Natural history; Persistent asthma
20.  Factors Associated with Asthma Exacerbations During a Long-term Clinical Trial of Controller Medications in Children 
Background
Asthma exacerbations are a common cause of critical illness in children.
Objective
To determine factors associated with exacerbations in children with persistent asthma.
Methods
Regression modeling was used to identify historical, phenotypic, treatment, and time-dependent factors associated with the occurrence of exacerbations, defined by need for oral corticosteroids, emergency or hospital care in the 48-week Pediatric Asthma Controller Trial (PACT) study. Children aged 6–14 with mild to moderate persistent asthma were randomized to receive either fluticasone propionate 100 mcg BID (FP monotherapy), combination fluticasone 100 mcg AM and salmeterol BID, or montelukast 5 mg once daily.
Results
Of the 285 participants randomized, 48% had 231 exacerbations. Using a multivariate analysis, which included numerous demographic, pulmonary, and inflammatory parameters, only a history of an asthma exacerbation requiring a systemic corticosteroid in the past year (odds ratio 2.10, p<0.001) was associated with a subsequent exacerbation during the trial. During the trial, treatment with montelukast vs. FP monotherapy (OR 2.00, p=0.005), season (spring, fall, or winter vs. summer, p=<0.001), and average seasonal 5% reduction in AM peak expiratory flow (PEF) (OR 1.21, p=0.01) were each associated with exacerbations. Changes in worsening of symptoms, beta-agonist use, and low PEF track together before an exacerbation, but have poor positive predictive value of exacerbation.
Conclusion
Children with mild to moderate persistent asthma with prior exacerbations are more likely to have a repeat exacerbation despite controller treatment. Inhaled corticosteroids are superior to montelukast at modifying the exacerbation risk. Available physiologic measures and biomarkers, and diary card tracking are not reliable predictors of asthma exacerbations.
doi:10.1016/j.jaci.2008.08.021
PMCID: PMC3024439  PMID: 19014765
Airway inflammation; Asthma; Bronchial hyperresponsiveness; Childhood asthma; Exacerbations
21.  Step-up Therapy for Children with Uncontrolled Asthma While Receiving Inhaled Corticosteroids 
The New England journal of medicine  2010;362(11):975-985.
BACKGROUND
For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.
METHODS
We randomly assigned 182 children (6 to 17 years of age), who had uncontrolled asthma while receiving 100 µg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 µg of fluticasone twice daily (ICS step-up), 100 µg of fluticasone plus 50 µg of a long-acting beta-agonist twice daily (LABA step-up), or 100 µg of fluticasone twice daily plus 5 or 10 mg of a leukotriene-receptor antagonist daily (LTRA step-up). We used a triple-crossover design and a composite of three outcomes (exacerbations, asthma-control days, and the forced expiratory volume in 1 second) to determine whether the frequency of a differential response to the step-up regimens was more than 25%.
RESULTS
A differential response occurred in 161 of 165 patients who were evaluated (P<0.001). The response to LABA step-up therapy was most likely to be the best response, as compared with responses to LTRA step-up (relative probability, 1.6; 95% confidence interval [CI], 1.1 to 2.3; P = 0.004) and ICS step-up (relative probability, 1.7; 95% CI, 1.2 to 2.4; P = 0.002). Higher scores on the Asthma Control Test before randomization (indicating better control at baseline) predicted a better response to LABA step-up (P = 0.009). White race predicted a better response to LABA step-up, whereas black patients were least likely to have a best response to LTRA step-up (P = 0.005).
CONCLUSIONS
Nearly all the children had a differential response to each step-up therapy. LABA step-up was significantly more likely to provide the best response than either ICS or LTRA step-up. However, many children had a best response to ICS or LTRA step-up therapy, highlighting the need to regularly monitor and appropriately adjust each child’s asthma therapy. (ClinicalTrials.gov number, NCT00395304.)
doi:10.1056/NEJMoa1001278
PMCID: PMC2989902  PMID: 20197425
22.  Clinical Predictors and Outcomes of Consistent Bronchodilator Response in the Childhood Asthma Management Program 
Background
Among asthmatics, bronchodilator response (BDR) to inhaled ß2- adrenergic agonists is variable, and the significance of a consistent response over time is unknown.
Objective
We assessed baseline clinical variables and determined the clinical outcomes associated with a consistently positive BDR over 4 years in children with mild-moderate persistent asthma.
Methods
In the 1,041 participants in the Childhood Asthma Management Program (CAMP), subjects with a change in FEV1 of 12% or greater (and 200mLs) after inhaled ß2 agonist at each of their yearly follow-up visits (consistent BDR) were compared with those who did not have a consistent BDR.
Results
We identified 52 children with consistent BDR over the 4-year trial. Multivariable logistic regression modeling demonstrated that baseline pre-bronchodilator FEV1 (OR=0.71, p<0.0001), log 10 IgE level (OR=1.97, p=0.002), and lack of treatment with inhaled corticosteroids (OR=0.31, p=0.009) were associated with a consistent BDR. Individuals who had a consistent BDR had more hospital visits (p=0.007), required more prednisone bursts (p=0.0007), had increased nocturnal awakenings due to asthma (p<0.0001), and missed more days of school (p=0.03) than non-responders during the 4-year follow-up.
Conclusions
We have identified predictors of consistent BDR and determined that this phenotype is associated with poor clinical outcomes.
doi:10.1016/j.jaci.2008.09.004
PMCID: PMC2947830  PMID: 18848350
asthma; consistent bronchodilator response; outcomes
23.  Long-Term Budesonide or Nedocromil Treatment, Once Discontinued, Does Not Alter the Course of Mild to Moderate Asthma in Children and Adolescents 
The Journal of pediatrics  2009;154(5):682-687.
Objectives
To determine whether long-term, continuous use of inhaled anti-inflammatory medications affects asthma outcomes in children with mild-moderate asthma after use is discontinued.
Study design
Of 1,041 participants in the Childhood Asthma Management Program randomized clinical trial, 941 (90%) were followed to determine whether 4.3 years of twice daily budesonide or nedocromil (each compared with placebo) affected subsequent asthma outcomes during a 4.8 year post-trial period in which treatment was managed by the participant's physician.
Results
The groups treated continuously during the trial with either budesonide or nedocromil did not differ from placebo in lung function, control of asthma, or psychological status at the end of 4.8 years of post-trial follow-up; however, the decreased mean height in the budesonide group relative to the placebo group at the end of the trial (1.1 cm, P=0.005) remained statistically significant (0.9 cm, P=0.01) after an additional 4.8 years and was more pronounced in girls (1.7 cm; P=0.001) than boys (0.3 cm; P=0.49). Participants used inhaled corticosteroids during 30% of the post-trial period in all groups.
Conclusions
Clinically meaningful improvements in control of asthma and improvements in airway responsiveness achieved during continuous treatment with inhaled corticosteroids do not persist after continuous treatment is discontinued.
doi:10.1016/j.jpeds.2008.11.036
PMCID: PMC2942076  PMID: 19167726
24.  Patient Characteristics Associated with Improved Outcomes with Use of an Inhaled Corticosteroid in Preschool Children at Risk for Asthma 
Background
Maintenance inhaled corticosteroid (ICS) therapy in preschool children with recurrent wheezing at high-risk for development of asthma produces multiple clinical benefits. However, determination of baseline features associated with ICS responsiveness may identify children most likely to benefit from ICS treatment.
Objective
To determine if demographic and atopic features predict response to ICS in preschool children at high-risk for asthma.
Methods
Two years of treatment with an ICS, fluticasone propionate (88mcg twice daily), was compared to matching placebo in a double-masked, randomized, multi-center study of 285 two and three year olds at high-risk for asthma development. Baseline demographic and atopic features were related to clinical outcomes in a post-hoc subgroup analysis.
Results
Multivariate analysis demonstrated significantly greater improvement with fluticasone compared to placebo in terms of episode-free days among males, Caucasians, participants with an emergency department (ED) visit or hospitalization within the past year, and those who experienced more symptomatic days at baseline. Children with aeroallergen sensitization experienced greater benefits in terms of oral corticosteroid use, urgent care and ED visits, and use of supplemental controller medications.
Conclusions
More favorable responses to ICS compared to placebo in high-risk preschool children over a 2-year period were more likely in those with a ED visit or hospitalization for asthma within the past year, children with aeroallergen sensitization, males and Caucasians.
Capsule Summary
A favorable response to ICS compared to placebo in high-risk toddlers over a 2-year period was more likely in children with a prior ED visit or hospitalization for asthma, aeroallergen sensitization, males, and Caucasians.
doi:10.1016/j.jaci.2008.12.1120
PMCID: PMC2909590  PMID: 19230959
childhood asthma; inhaled corticosteroids; response
25.  Relationship Between Infant Weight Gain and Later Asthma 
Like obesity, the prevalence of asthma has increased over the past several decades. Accelerated patters of infant growth have been associated with obesity and its co-morbidities. We aimed to determine if infant weight gain pattern is associated with asthma development later in childhood. Birth weight, growth, pulmonary function, and symptom data were collected in a trial of 2–3 year old children at-risk for asthma randomized to a two-year treatment with inhaled corticosteroids or placebo followed by a one year observation period off study medication. Patterns of infant weight gain between birth and study enrollment were categorized as accelerated, average, or decelerated. Regression analyses were used to test the effects of infant weight gain pattern prior to study enrolment on outcomes during the observation year and at study conclusion while adjusting for demographics, baseline symptom severity, study treatment, and atopic indicators. Among the 197 study participants, early life weight gain pattern was not associated with daily asthma symptoms or lung function at the study’s conclusion. However, both prednisone courses (P=.01) and urgent physician visits (P<.001) were significantly associated with weight gain pattern with fewer exacerbations occurring amongst those with a decelerated weight gain pattern. We conclude that early life patterns of weight change were associated with subsequent asthma exacerbations, but were not associated with asthma symptoms or pulmonary function during the preschool years for these children at-risk for asthma.
doi:10.1111/j.1399-3038.2009.00926.x
PMCID: PMC2887600  PMID: 19725894
Asthma; Weight Gain; Infant

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