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.
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.
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.
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.
Asthma; Airway hyperresponsiveness; Genome-wide association study; ITGB5; AGFG1
asthma; asthma control; asthma guidelines; asthma impairment; asthma risk; asthma severity; biomarkers; genetics; inhaled corticosteroids
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.
TENOR; severe or difficult-to-treat asthma; asthma control; asthma exacerbations; burden; medication; quality of life; allergy; IgE
Over the past 20 years there has been a concerted effort in the United States to reduce morbidity related to chronic disease including asthma. Attention was initially directed towards asthma in response to the recognition that asthma mortality was increasing and that the burden of disease was significant. These efforts to address asthma mortality led to many new initiatives to develop clinical practice guidelines, implement the asthma guidelines into clinical practice, conduct research to fill the gaps in the guidelines, and to continuously revise the asthma guidelines as more information became available. An assessment of our progress shows significant accomplishments in relation to reducing asthma mortality and hospitalizations.
Consequently, we are now at a crossroads in asthma care. Although we have recognized some remarkable accomplishments in reducing asthma mortality and morbidity, the availability of new tools to monitor disease activity, including biomarkers and epigenetic markers, along with information technology systems to monitor asthma control hold some promise in identifying gaps in disease management. These advances should prompt the evolution of new strategies and new treatments to further reduce disease burden. It now becomes imperative to continue a focus on ways to further reduce the burden of asthma and prevent its onset.
Asthma; childhood asthma; asthma therapy; asthma statistics; asthma management; asthma guidelines; asthma disease management; inhaled corticosteroids; long-acting β-adrenergic agonists; leukotriene receptor antagonists; omalizumab; asthma surveillance; asthma mortality; asthma hospitalizations; asthma exacerbations; asthma progression; personalized medicine; public health
Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4+ lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10−16). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV1). Though unadjusted linear models of FEV1 identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV1 and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association.
ancestry; gene expression; population stratification; self-identified race
The National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) recently completed its work after 20 years of collaboration as a multicentre clinical trial network. When formed, its stated mission was to perform multiple controlled clinical trials for treating patients with asthma by dispassionately examining new and existing therapies, and to rapidly communicate its findings to the medical community. The ACRN conducted 15 major clinical trials. In addition, clinical data, manual of operations, protocols and template informed consents from all ACRN trials are available via NHLBI BioLINCC (https://biolincc.nhlbi.nih.gov/studies/). This network contributed major insights into the use of inhaled corticosteroids, short-acting and long-acting ß-adrenergic agonists, leukotriene receptor antagonists, and novel agents (tiotropium, colchicine and macrolide antibiotics). They also pioneered studies of the variability in drug response, predictors of treatment response and pharmacogenetics. This review highlights the major research observations from the ACRN that have impacted the current management of asthma.
Rationale: To date, most studies aimed at discovering genetic factors influencing treatment response in asthma have focused on biologic candidate genes. Genome-wide association studies (GWAS) can rapidly identify novel pharmacogenetic loci.
Objectives: To investigate if GWAS can identify novel pharmacogenetic loci in asthma.
Methods: Using phenotypic and GWAS genotype data available through the NHLBI-funded Single-nucleotide polymorphism Health association-Asthma Resource Project, we analyzed differences in FEV1 in response to inhaled corticosteroids in 418 white subjects with asthma. Of the 444,088 single nucleotide polymorphisms (SNPs) analyzed, the lowest 50 SNPs by P value were genotyped in an independent clinical trial population of 407 subjects with asthma.
Measurements and Main Results: The lowest P value for the GWAS analysis was 2.09 × 10−6. Of the 47 SNPs successfully genotyped in the replication population, three were associated under the same genetic model in the same direction, including two of the top four SNPs ranked by P value. Combined P values for these SNPs were 1.06 × 10−5 for rs3127412 and 6.13 × 10−6 for rs6456042. Although these two were not located within a gene, they were tightly correlated with three variants mapping to potentially functional regions within the T gene. After genotyping, each T gene variant was also associated with lung function response to inhaled corticosteroids in each of the trials associated with rs3127412 and rs6456042 in the initial GWAS analysis. On average, there was a twofold to threefold difference in FEV1 response for those subjects homozygous for the wild-type versus mutant alleles for each T gene SNP.
Conclusions: Genome-wide association has identified the T gene as a novel pharmacogenetic locus for inhaled corticosteroid response in asthma.
polymorphism; genome; pharmacogenomics; glucocorticoid
Last year’s Advances in Pediatric Asthma concluded with the following statement “If we can close these [remaining] gaps through better communication, improvements in the health care system and new insights into treatment, we will move closer to better methods to intervene early in the course of the disease and induce clinical remission as quickly as possible in most children”. This year’s summary will focus on recent advances in pediatric asthma that take steps moving forward as reported in Journal of Allergy and Clinical Immunology publications in 2010.
Some of those recent reports show us how to improve asthma management through steps to better understand the natural history of asthma, individualize asthma care, reduce asthma exacerbations, manage inner city asthma, and some potential new ways to use available medications to improve asthma control. It is clear that we have made many significant gains in managing asthma in children but we have a ways to go to prevent asthma exacerbations, alter the natural history of the disease, and to reduce health disparities in asthma care.
Perhaps new directions in personalized medicine and improved health care access and communication will help maintain steady progress in alleviating the burden of this disease in children, especially young children.
asthma; asthma control; asthma impairment; asthma risk; asthma severity; early intervention in asthma; biomarkers; genetics; inhaled corticosteroids; leukotriene receptor antagonists; long-acting β-adrenergic agonists; omalizumab; personalized medicine; therapeutics
In the past, we viewed lack of response to asthma medications as a rare event. Based on recent studies, we now expect significant variation in treatment response for all asthma medications. However, little information is available about methods to predict favorable treatment response. Research conducted in the National Heart, Lung and Blood Institute (NHLBI) Asthma Clinical Research Network (ACRN) and the NHLBI Childhood Asthma Research and Education (CARE) Network verified this variability in response to several long-term control medications, specifically inhaled corticosteroids (ICS) and leukotriene receptor antagonists (LTRA), in adults and children with mild to moderate persistent asthma. The networks also identified potential methods to utilize patient characteristics, such as age and allergic status, and biomarkers, such as bronchodilator response, exhaled nitric oxide and urinary leukotrienes, to help predict response to ICS and LTRA and to determine which of the two treatments may be more effective in individual patients. This information now assists the clinician in personalizing asthma treatment at the time of initiating long-term control therapy.
Asthma; treatment response; inhaled corticosteroids; leukotriene receptor antagonists; leukotriene modifiers; β-adrenergic agonists
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.
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.
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.
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.
Researchers should use objective rather than self-reported adherence data to identify clinical trial participants with low levels of adherence to study treatment.
Asthma; adherence; compliance; children; lung growth; inhaled corticosteroids; budesonide; clinical trial
The effect on linear growth of daily long-term inhaled corticosteroid (ICS) therapy in preschool-aged children with recurrent wheezing is controversial.
To determine the effect of daily ICS given for 2 years on linear growth in preschool children with recurrent wheezing.
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.
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].
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.
Asthma predictive index; atopy; clinical trials; early childhood asthma; fluticasone; inhaled corticosteroids; intermittent wheezing; linear growth; research network
Although nocturnal awakenings help categorize asthma severity and control, their clinical significance has not been thoroughly studied.
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.
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.
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.
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.
asthma; nocturnal symptoms; exacerbation
Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects.
National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies.
We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health–organized workshop convened in March 2010 and finalized in September 2011.
Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures.
The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories.
Multiallergen screen; fractional exhaled nitric oxide; sputum eosinophils; total eosinophils; IgE; urinary leukotriene E4
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.
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.
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.
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.
Cost-effectiveness analyses of asthma controller regimens for adults exist, but similar evaluations exclusively for children are few.
To compare the cost-effectiveness of two commonly used asthma controllers, fluticasone and montelukast, with data from the Pediatric Asthma Controller Trial.
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.
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.
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.
Cost-effectiveness analysis; childhood asthma; fluticasone; montelukast; PACT
Genome-wide association studies of human gene expression promise to identify functional regulatory genetic variation that contributes to phenotypic diversity. However, it is unclear how useful this approach will be for the identification of disease-susceptibility variants. We generated gene expression profiles for 22 184 mRNA transcripts using RNA derived from peripheral blood CD4+ lymphocytes, and genome-wide genotype data for 516 512 autosomal markers in 200 subjects. We screened for cis-acting variants by testing variants mapping within 50 kb of expressed transcripts for association with transcript abundance using generalized linear models. Significant associations were identified for 1585 genes at a false discovery rate of 0.05 (corresponding to P-values ranging from 1 × 10−91 to 7 × 10−4). Importantly, we identified evidence of regulatory variation for 119 previously mapped disease genes, including 24 examples where the variant with the strongest evidence of disease-association demonstrates strong association with specific transcript abundance. The prevalence of cis-acting variants among disease-associated genes was 63% higher than the genome-wide rate in our data set (P = 6.41 × 10−6), and although many of the implicated loci were associated with immune-related diseases (including asthma, connective tissue disorders and inflammatory bowel disease), associations with genes implicated in non-immune-related diseases including lipid profiles, anthropomorphic measurements, cancer and neurologic disease were also observed. Genetic variants that confer inter-individual differences in gene expression represent an important subset of variants that contribute to disease susceptibility. Population-based integrative genetic approaches can help identify such variation and enhance our understanding of the genetic basis of complex traits.
The assumption that the assessment of FEF25-75 does not provide additional information in asthmatic children with normal FEV1 % predicted has not been adequately tested.
To determine whether the measurement of the FEF25-75 % predicted offers advantages over the FEV1 % predicted and the FEV1/FVC % predicted for the evaluation of childhood asthma.
Methods and Measurements
This is a secondary analysis of data from the “Pediatric Asthma Controller Trial” and the “Characterizing the Response to a Leukotriene Receptor Antagonist and Inhaled Corticosteroid” trials. Pearson correlation coefficients, Pearson partial correlation coefficients, canonical correlations, and receiver operator characteristic (ROC) curves were constructed.
Among 437 children with normal FEV1 % predicted, FEF25-75 % predicted and FEV1/FVC % predicted were (1) positively correlated with log2 methacholine PC20, (2) positively correlated with morning and evening peak expiratory flow % predicted, and (3) negatively correlated with log10 FeNO and bronchodilator responsiveness. Pearson partial correlations and canonical correlations indicated that FEF25-75 % predicted was better correlated with bronchodilator responsiveness and log2 methacholine PC20 than were the FEV1 % predicted or FEV1/FVC % predicted. In the ROC curve analysis, FEF25-75 at 65% predicted had a 90% sensitivity and a 67% specificity for detecting a 20% increase in FEV1 following albuterol inhalation.
FEF25-75 % predicted was well correlated with bronchodilator responsiveness in asthmatic children with normal FEV1. FEF25-75 % predicted should be evaluated in clinical studies of asthma in children, and may be of use in predicting the presence of clinically relevant reversible airflow obstruction.
FEF25-75; bronchodilator responsiveness; asthma; FEV1/FVC; canonical correlations and ROC curves
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.
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.
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.
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.
LTE4: FENO ratios predict a better response to MT than FP therapy in children with mild to moderate asthma.
In children with mild to moderate asthma, the LTE4: FENO ratio is associated with a better response to montelukast compared to fluticasone therapy.
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.
asthma; biomarkers; fluticasone propionate; inhaled corticosteroids; leukotriene E4; montelukast
The course of mild to moderate persistent asthma in children is not clearly established.
To determine the rate and predictors for remitting, periodic, and persistent asthma in adolescence.
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).
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].
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.
Remission; Natural history; Persistent asthma
Asthma exacerbations are a common cause of critical illness in children.
To determine factors associated with exacerbations in children with persistent asthma.
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.
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.
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.
Airway inflammation; Asthma; Bronchial hyperresponsiveness; Childhood asthma; Exacerbations
For children who have uncontrolled asthma despite the use of low-dose inhaled corticosteroids (ICS), evidence to guide step-up therapy is lacking.
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%.
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).
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.)
Among asthmatics, bronchodilator response (BDR) to inhaled ß2- adrenergic agonists is variable, and the significance of a consistent response over time is unknown.
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.
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.
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.
We have identified predictors of consistent BDR and determined that this phenotype is associated with poor clinical outcomes.
asthma; consistent bronchodilator response; outcomes
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.
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.
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.
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.
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.
To determine if demographic and atopic features predict response to ICS in preschool children at high-risk for asthma.
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.
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.
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.
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.
childhood asthma; inhaled corticosteroids; response
Although guidelines recommend anti-inflammatory therapy for persistent asthma, recent studies suggest that 25-35% of asthmatics may not improve lung function with inhaled corticosteroids.
To evaluate potential biomarkers of predicting short term (6-week) response to inhaled corticosteroid with subsequent evaluation of responders and non-responders to asthma control over a longer interval (16 additional weeks).
Eighty-three asthmatic subjects off steroid were enrolled in this multi-center study. Biomarkers and asthma characteristics were evaluated as predictors of inhaled corticosteroid response over a six week trial for changes in FEV1 and methacholine PC20. Following this, an additional four month trial evaluated asthma control.
Although multiple baseline predictors had significant correlations with improvements for short term inhaled steroid success, the only strong correlations (r ≥ ± 0.6) were albuterol reversibility (r=0.83, p<0.001); FEV1/FVC (r=−0.75, p<0.001); and FEV1 % predicted (r=−0.71, p<0.001). Dividing the subjects in the short term inhaled steroid trial into responders (> 5% FEV1 improvement), and non-responders (≤ 5%) determined the longer term need for steroids. For the non-responders, asthma control remained unchanged whether inhaled corticosteroids were continued or were substituted with a placebo, p=0.99. The good short term responders maintained asthma control longer term only if maintained on inhaled steroids (p=0.007).
The short term response to inhaled corticosteroids with regard to FEV1 improvement predicts long term asthma control.
A six week trial of ICS, in patients not currently on steroids, producing a ≥ 5% improvement in FEV1 can predict long term asthma control and the need for continued steroid use.
inhaled corticosteroids; predicting response; therapy; characteristics; biomarkers