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

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

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

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

Use of Fractional Exhaled Nitric Oxide to Guide the Treatment of Asthma: An Official American Thoracic Society Clinical Practice Guideline.

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma. Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered. Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidence-based answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations. Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice. Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.

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

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

Lung mechanical properties distinguish children with asthma with normal and diminished lung function.

BACKGROUND: Children with asthma, even those with severe persistent disease, can have forced expiratory volume in 1 second (FEV1 ) values ≥100% of predicted, while others have diminished FEV1 . OBJECTIVE: We sought to characterize the lung mechanical properties underlying these two asthma phenotypes and the mechanisms explaining the paradox of severe asthmatic children, whom when clinically stable can have an FEV1 >100% of predicted, but during an acute bronchospastic episode can experience a life-threatening asthma event. METHODS: Lung mechanics were evaluated in three groups of children: asthmatics with FEV1 ≥100% (HFEV1 ; n = 13), asthmatics with FEV1 ≤80% (LFEV1 ; n = 14) and non-asthmatic controls (n = 10). A linear mixed model was used to examine the relationship between volume and static transpulmonary pressures obtained at total lung capacity (TLC); actual TLC %of predicted and flow; and static transpulmonary pressure and flow. RESULTS: HFEV1 asthmatics had larger airways (FEV1 z-scores 1.12 vs -2.37; P < .05), greater lung volumes (mean % of predicted TLC 134.8% vs 109.6%; P < .05) and lower airway resistance (mean %of predicted Raw 101.9% vs 199.9%; P < .05) compared to the LFEV1 group. Moreover, HFEV1 asthmatics had significantly reduced elastic recoil pressure (pressure-volume curve shifted upward and to the left) and higher lung compliance (0.21 vs 00.9 L/cm H2 O; P < .05) compared to the LFEV1 group. The pressure-flow curves revealed the LFEV1 group to have significantly increased resistance to flow in the upstream segment of the airways at all lung volumes studied compared to HFEV1 . CONCLUSION AND CLINICAL RELEVANCE: HFEV1 asthmatic children display distinct lung mechanical proprieties compared to their LFEV1 asthmatic peers. With loss of elastic recoil pressure, the HFEV1 group could generate normal FEV1 due to proportionally enlarged airways and reduced airway resistance, while airflow limitation in the LFEV1 is due to increased airway resistance. Loss of elastic recoil and interdependence during acute bronchoconstriction episodes may predispose the HFEV1 group to catastrophic reductions in airflow.

Overweight/obesity status in preschool children associates with worse asthma but robust improvement on inhaled corticosteroids.

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.

Genetics and Genomics of Longitudinal Lung Function Patterns in Individuals with Asthma.

RATIONALE: Patterns of longitudinal lung function growth and decline in childhood asthma have been shown to be important in determining risk for future respiratory ailments including chronic airway obstruction and chronic obstructive pulmonary disease. OBJECTIVES: To determine the genetic underpinnings of lung function patterns in subjects with childhood asthma. METHODS: We performed a genome-wide association study of 581 non-Hispanic white individuals with asthma that were previously classified by patterns of lung function growth and decline (normal growth, normal growth with early decline, reduced growth, and reduced growth with early decline). The strongest association was also measured in two additional cohorts: a small asthma cohort and a large chronic obstructive pulmonary disease metaanalysis cohort. Interaction between the genomic region encompassing the most strongly associated single-nucleotide polymorphism and nearby genes was assessed by two chromosome conformation capture assays. MEASUREMENTS AND MAIN RESULTS: An intergenic single-nucleotide polymorphism (rs4445257) on chromosome 8 was strongly associated with the normal growth with early decline pattern compared with all other pattern groups (P = 6.7 × 10-9; odds ratio, 2.8; 95% confidence interval, 2.0-4.0); replication analysis suggested this variant had opposite effects in normal growth with early decline and reduced growth with early decline pattern groups. Chromosome conformation capture experiments indicated a chromatin interaction between rs4445257 and the promoter of the distal CSMD3 gene. CONCLUSIONS: Early decline in lung function after normal growth is associated with a genetic polymorphism that may also protect against early decline in reduced growth groups. Clinical trial registered with www.clinicaltrials.gov (NCT00000575).

Randomized Trial of Once-Daily Fluticasone Furoate in Children with Inadequately Controlled Asthma.

OBJECTIVE: To evaluate the dose-response, efficacy, and safety of fluticasone furoate (FF; 25 µg, 50 µg, and 100 µg), administered once daily in the evening during a 12-week treatment period to children with inadequately controlled asthma. STUDY DESIGN: This was a Phase IIb, multicenter, stratified, randomized, double-blind, double-dummy, parallel-group, placebo- and active-controlled study in children aged 5-11 years with inadequately controlled asthma. The study comprised a 4-week run-in period, 12-week treatment period, and 1-week follow-up period. Children were randomized to receive either placebo once daily, fluticasone propionate (FP) 100 µg twice daily, FF 25 µg, FF 50 µg, or FF 100 µg each once daily in the evening. Primary endpoint was the mean change from baseline in daily morning peak expiratory flow (PEF) averaged over weeks 1-12. Adverse events (AEs) also were investigated. RESULTS: In total, 593 children were included in the intent-to-treat population. The difference vs placebo in change from baseline daily morning PEF averaged over weeks 1-12 was statistically significant for the FF 25, FF 50, FF 100, and FP 100 groups (18.6 L/min, 19.5 L/min, 12.5 L/min, and 14.0 L/min, respectively; P < .001 for all). The incidence of AEs was greater in the FF groups (32%-36%) than in the placebo group (29%); the most frequent AE was cough. CONCLUSION: FF and FP resulted in significant improvements in morning PEF compared with placebo, suggesting that they are effective treatments for children with inadequately controlled asthma. All treatments were well tolerated; no new safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01563029.

Randomised trial of once-daily vilanterol in children with asthma on inhaled corticosteroid therapy.

BACKGROUND: Inhaled corticosteroids (ICS) are effective maintenance treatments for childhood asthma; however, many children remain uncontrolled. Vilanterol (VI) is an inhaled long-acting beta-2 agonist which, in combination with the ICS fluticasone furoate, is being explored as a once-daily treatment for asthma in children. We evaluated the dose-response, efficacy, and safety of once-daily VI (6.25 µg, 12.5 µg and 25 µg) administered in the evening over 4 weeks, on background fluticasone propionate (FP) in children with asthma inadequately controlled on ICS. METHODS: This was a Phase IIb, multicentre, randomised, double-blind, parallel-group, placebo-controlled study in children ages 5-11 years with persistent asthma on ICS and as-needed short-acting beta-agonist. The study comprised a 4-week run-in, 4-week treatment period, and 1-week follow-up. From study start, children replaced their current ICS with open-label FP 100 µg twice daily. Children were randomised to receive placebo, VI 6.25 µg, VI 12.5 µg or VI 25 µg once daily. Primary endpoint was treatment difference between VI 25 and placebo groups in mean change from baseline in evening peak expiratory flow averaged over the 4-week treatment. Secondary endpoints included change from baseline in trough forced expiratory volume in one second (FEV1) at Week 4 and change from baseline in percentage of rescue-free and symptom-free 24-h periods. Safety assessments included incidence of adverse events (AEs) and asthma exacerbations. RESULTS: In total, 456 children comprised the intention-to-treat population. The adjusted treatment difference between VI 25 and placebo groups for the primary endpoint was not statistically significant (p = 0.227) so no statistical inference was made for other VI dose comparisons or other endpoints. No difference in change from baseline in trough FEV1 was observed for any VI treatments versus placebo; however, VI 25 resulted in an additional 0.6 rescue-free days and 0.7 symptom-free days per week versus placebo. The incidence of AEs was slightly higher in the VI groups (28-33 %) versus placebo (22 %). Nine children experienced asthma exacerbations during the treatment period. CONCLUSION: VI plus FP did not result in significant improvements in lung function versus placebo plus FP, but was well tolerated at all doses assessed. TRIAL REGISTRATION: NCT01573767 (ClinicalTrials.gov).

Pivotal efficacy trials of inhaled corticosteroids in asthma.

BACKGROUND: Inhaled corticosteroids (ICSs) are the mainstay of daily controller treatment for persistent and uncontrolled asthma. However, many clinicians are wary of ICSs because of safety concerns. Clinicians need to know the underlying efficacy data that support the use of ICSs to weigh efficacy against safety. OBJECTIVE: To discuss efficacy data from pivotal trials to aid clinicians in their decisions to use ICSs. METHODS: Key efficacy studies were selected to augment discussion. RESULTS: Clinical studies have revealed that ICSs are effective in reducing the risk of exacerbations in both children and adults. ICSs also reduce the risk of hospitalization and asthma-related death, improve asthma symptoms, and improve quality of life. In addition, ICSs improve lung function and airway responsiveness and reduce airway inflammation and remodeling. In young children, ICSs improve daytime and nighttime symptoms, improve lung function, reduce the risk of exacerbations, and reduce the need for rescue medications. To date, evidence is conflicting about whether intermittent ICS treatment is as effective as daily ICS treatment. The possibility of lower efficacy of intermittent therapy needs to be weighed against a reduced risk of slowed growth in children. CONCLUSION: ICSs effectively reduce the risk of exacerbations, hospitalizations, and asthma-related death and improve asthma symptoms, quality of life, lung function, and airway responsiveness. ICSs also reduce airway inflammation and remodeling. Intermittent therapy may not be as effective as daily therapy, and clinicians should weigh reduced efficacy against reduced risk of adverse effects, particularly slowed growth in children.

The chitinase-like protein YKL-40 is not a useful biomarker for severe persistent asthma in children.

BACKGROUND: The chitinase-like protein YKL-40 is thought to play a role in inflammation and tissue remodeling. In adults with severe asthma, YKL-40 is expressed in the airway and YKL-40 levels are elevated in the serum. OBJECTIVE: To compare YKL-40 levels in children with severe persistent asthma with those in adults with severe persistent asthma and to determine whether YKL-40 levels correlate with increasing asthma severity in childhood asthma. METHODS: In this prospective, cross-sectional study, 23 adults and 19 children with severe persistent asthma, 23 children with moderate persistent asthma, and 19 children with mild persistent asthma were enrolled. The following data were collected on each patient: spirometry, exhaled nitric oxide, percutaneous skin testing results to aeroallergens, peripheral eosinophils, serum IgE levels, and serum YKL-40 levels. RESULTS: Compared with adults, children with severe persistent asthma had significantly lower YKL-40 levels, higher values for forced vital capacity and forced expiration volume in 1 second, higher serum IgE levels, and higher exhaled nitric oxide levels. YKL-40 levels did not correlate with increasing asthma severity in the pediatric cohort. CONCLUSION: Severe persistent asthma in childhood is not associated with elevated YKL-40 levels, unlike in adults with severe persistent asthma. YKL-40 is not a useful biomarker for asthma severity in childhood asthma.

Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids.

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 microg of fluticasone twice daily, to receive each of three blinded step-up therapies in random order for 16 weeks: 250 microg of fluticasone twice daily (ICS step-up), 100 microg of fluticasone plus 50 microg of a long-acting beta-agonist twice daily (LABA step-up), or 100 microg 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.)

Predictors for asthma at age 7 years for low-income children enrolled in the Childhood Asthma Prevention Study.

OBJECTIVE: To identify the predictive factors of early childhood wheezing in children of low socioeconomic status. STUDY DESIGN: The Childhood Asthma Prevention Study enrolled 177 low-income children (9-24 months old) with frequent wheezing. At age 7 years, presence of asthma was assessed through caregiver reports of physician diagnosis of asthma (CRPDA) and corroborated by assessment of bronchial hyperresponsiveness (BHR). Lung function, inflammatory markers, and asthma symptom severity were compared for children with ±CRPDA, ±BHR, and asthma. Baseline predictors for CRPDA, BHR, and asthma at 7 years of age were examined. RESULTS: Maternal symptom report strongly differentiated children with +CRPDA (49%) despite comparable airflow measurements (P < .0001), and spirometric lung function measurements were different for +BHR (65%) versus -BHR (P < .005). Univariate analyses revealed different baseline predictors of +CRPDA and +BHR for children at age 7 years. Higher levels of maternal psychological resources were associated with +CRPDA, but not +BHR. Only 39% of children with a history of frequent wheezing met the conservative definition of asthma at age 7 years, with the following significant predictors found: low birth weight, baseline symptom severity, and maternal psychological resources. CONCLUSIONS: This low-income, multi-ethnic group of wheezing infants represents a unique population of children with distinct characteristics and risks for persistent asthma. Determination of asthma status at 7 years of age required objective measurement of BHR in addition to CRPDA. The association of maternal psychological resources with +CRPDA may represent a previously unrecognized factor in the determination of asthma status among low-income groups.

Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Daily inhaled corticosteroids are an effective treatment for mild persistent asthma, but some children have exacerbations even with good day-to-day control, and many discontinue treatment after becoming asymptomatic. We assessed the effectiveness of an inhaled corticosteroid (beclomethasone dipropionate) used as rescue treatment. METHODS: In this 44-week, randomised, double-blind, placebo-controlled trial we enrolled children and adolescents with mild persistent asthma aged 5-18 years from five clinical centres in the USA. A computer-generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups: twice daily beclomethasone with beclomethasone plus albuterol as rescue (combined group); twice daily beclomethasone with placebo plus albuterol as rescue (daily beclomethasone group); twice daily placebo with beclomethasone plus albuterol as rescue (rescue beclomethasone group); and twice daily placebo with placebo plus albuterol as rescue (placebo group). Twice daily beclomethasone treatment was one puff of beclomethasone (40 µg per puff) or placebo given in the morning and evening. Rescue beclomethasone treatment was two puffs of beclomethasone or placebo for each two puffs of albuterol (180 µg) needed for symptom relief. The primary outcome was time to first exacerbation that required oral corticosteroids. A secondary outcome measured linear growth. Analysis was by intention to treat. This study is registered with clinicaltrials.gov, number NCT00394329. RESULTS: 843 children and adolescents were enrolled into this trial, of whom 288 were assigned to one of four treatment groups; combined (n=71), daily beclomethasone (n=72), rescue beclomethasone (n=71), and placebo (n=74)-555 individuals were excluded during the run-in, according to predefined criteria. Compared with the placebo group (49%, 95% CI 37-61), the frequency of exacerbations was lower in the daily (28%, 18-40, p=0·03), combined (31%, 21-43, p=0·07), and rescue (35%, 24-47, p=0·07) groups. Frequency of treatment failure was 23% (95% CI 14-43) in the placebo group, compared with 5·6% (1·6-14) in the combined (p=0·012), 2·8% (0-10) in the daily (p=0·009), and 8·5% (2-15) in the rescue (p=0·024) groups. Compared with the placebo group, linear growth was 1·1 cm (SD 0·3) less in the combined and daily arms (p<0·0001), but not the rescue group (p=0·26). Only two individuals had severe adverse events; one in the daily beclomethasone group had viral meningitis and one in the combined group had bronchitis. INTERPRETATION: Children with mild persistent asthma should not be treated with rescue albuterol alone and the most effective treatment to prevent exacerbations is daily inhaled corticosteroids. Inhaled corticosteroids as rescue medication with albuterol might be an effective step-down strategy for children with well controlled, mild asthma because it is more effective at reducing exacerbations than is use of rescue albuterol alone. Use of daily inhaled corticosteroid treatment and related side-effects such as growth impairment can therefore be avoided. FUNDING: National Heart, Lung and Blood Institute.

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 a 4-year 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 3 asthma activity categories, improvements in airway hyperresponsiveness, eosinophilia, and asthma morbidity were observed over time. Features at entry into CAMP associated with remitting versus persistent asthma were lack of allergen sensitization and exposure to indoor allergens (odds ratio [OR], 3.23; P < .001), milder asthma (OR, 2.01; P = .03), older age (OR, 1.23; P = .01), less airway hyperresponsiveness (higher log methacholine FEV(1) PC(20) (OR, 1.39; P = .03), higher prebronchodilator FEV(1) percent predicted (OR, 1.05; P = .02), and lower forced vital capacity percent predicted (OR, 0.96; P = .04). CONCLUSION: Remission of asthma in adolescence is infrequent and not affected 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.

Relationship between infant weight gain and later asthma.

Like obesity, the prevalence of asthma has increased over the past several decades. Accelerated patterns 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- to 3-yr-old children at-risk for asthma randomized to a 2-yr treatment with inhaled corticosteroids or placebo followed by a 1-yr observation period of 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 enrollment 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 = 0.01) and urgent physician visits (p < 0.001) 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 pre-school years for these children at-risk for asthma.

Identifying the components of asthma health status in children with mild to moderate asthma.

BACKGROUND: Weak and inconsistent correlations between measurements of asthma health status suggest that the disease is composed of nonoverlapping components. OBJECTIVE: Factor analysis was used to explore the relationships between measures of asthma morbidity and to identify heterogeneous components of asthma health status in children 5 to 12 years old. Results were compared across time (baseline and 48-month visit) and treatment arms. METHODS: Analyses were conducted in 7 different study windows in a database from a large clinical trial of children with mild to moderate asthma (n = 1041). Measurements of lung function, symptoms, and health care utilization from daily diary cards, serum IgE levels, total eosinophil count, skin test positivity, and airway hyperresponsiveness were included. Data on fractional exhaled nitric oxide and sputum eosinophil cationic protein were included in a subgroup of patients. RESULTS: In each of the study windows, factor analysis identified 5 factors that explained between 50% and 60% of the common variance. Factors identified included (1) inflammatory markers, (2) symptoms/medication use, (3) asthma exacerbations, and measures of lung function, which subdivided into (4) FEV(1) and forced vital capacity, and (5) bronchodilator response and the FEV(1)/forced vital capacity ratio. Exploratory analyses suggest that fractional exhaled nitric oxide account for the atopy/inflammatory marker factor, and sputum measurements account for a sixth, separate factor. CONCLUSION: The consistent identification of a 5-factor structure across time and treatment arms suggests that each of these factors provides independent information in the assessment of asthma.

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 or emergency or hospital care in the 48-week Pediatric Asthma Controller Trial study. Children age 6 to 14 years with mild-to-moderate persistent asthma were randomized to receive either fluticasone propionate 100 microg twice daily (FP monotherapy), combination fluticasone 100 microg AM and salmeterol twice daily, 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 [OR], 2.10; P < .001) was associated with a subsequent exacerbation during the trial. During the trial, treatment with montelukast versus FP monotherapy (OR, 2.00; P = .005), season (spring, fall, or winter vs summer; P < or = .001), and average seasonal 5% reduction in AM peak expiratory flow (OR, 1.21; P = .01) were each associated with exacerbations. Changes in worsening of symptoms, beta-agonist use, and low peak expiratory flow track together before an exacerbation, but have poor positive predictive value of exacerbation. CONCLUSION: Children with mild-to-moderate persistent asthma with previous 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.

Long-term effects of asthma medications in children.

PURPOSE OF REVIEW: This review describes recent studies in children that evaluated long-term outcomes of controller asthma medications. RECENT FINDINGS: The literature is replete with studies demonstrating the immediate profound effects of inhaled corticosteroids on symptom control, reduction in morbidity and mortality rates, improvement in lung function, bronchial hyperresponsiveness, and inflammatory markers. Recent evidence supports that even this most effective class of medication does not alter the progression of recurrent wheeze to asthma, and that its effects on decline in lung function are limited. The lack of evidence supporting the superiority of lower dose inhaled corticosteroids combined with a long-acting beta-agonist over a full dose inhaled corticosteroid with respect to long-term efficacy measures and growth effects suggests that monotherapy with acceptable inhaled corticosteroid dose is the preferred treatment in children with mild to moderate persistent asthma. Montelukast has been shown to significantly reduce asthma exacerbations and lower use of supplemental inhaled corticosteroids compared with placebo. SUMMARY: There is mounting evidence that the currently available medications for childhood asthma have a substantial impact on multiple dimensions of asthma control. No drug in our current armamentarium, however, has been found to alter the natural progression of childhood asthma nor halt progressive airway damage in the more susceptible children.

Bronchoprovocation Testing in Asthma: An Update.

Bronchial hyperresponsiveness (BHR) is defined as a heightened bronchoconstrictive response to airway stimuli. It complements the cardinal features in asthma, such as variable or reversible airflow limitation and airway inflammation. Although BHR is considered a pathophysiologic hallmark of asthma, it should be acknowledged that this property of the airway is dynamic, because its severity and even presence can vary over time with disease activity, triggers or specific exposure, and with treatment. In addition, it is important to recognize that there is a component that is not reflective of a specific disease entity.