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.

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 (88 microg twice daily), was compared with matching placebo in a double-masked, randomized, multicenter study of 285 children 2 and 3 years old 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 than placebo in terms of episode-free days among boys, white subjects, 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 than 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, boys, and white subjects.

Long-term inhaled corticosteroids in preschool children at high risk for asthma.

BACKGROUND: It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma. METHODS: We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 mug twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year. RESULTS: During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P=0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P=0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively. CONCLUSIONS: In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.).

Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing.

BACKGROUND: Acute wheezing illnesses in preschoolers require better management strategies to reduce morbidity. OBJECTIVES: We sought to examine the effectiveness of episodic use of an inhaled corticosteroid and a leukotriene receptor antagonist in preschoolers with intermittent wheezing. METHODS: In a randomized, double-blind, placebo-controlled 12-month trial, 238 children aged 12 to 59 months with moderate-to-severe intermittent wheezing received 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). Proportion of episode-free days (EFDs) during the 12-month trial was the primary outcome. RESULTS: The 3 treatment groups did not differ in proportions of EFDs, with adjusted mean EFDs of 76% (95% CI, 70% to 81%) for budesonide, 73% (95% CI, 66% to 79%) for montelukast, and 74% (95% CI, 65% to 81%) for conventional therapy (P = .66). The 3 groups did not differ in oral corticosteroid use, health care use, quality of life, or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38% [P = .003] and 37% [P = .003], respectively) and interference with activity scores (32% [P = .01] and 40% [P = .001], respectively) that were most evident in those with positive asthma predictive indices. CONCLUSIONS: In preschool children with moderate-to-severe intermittent wheezing, episodic use of either budesonide or montelukast early in RTIs, when added to albuterol, did not increase the proportion of EFDs or decrease oral corticosteroid use over a 12-month period. However, indicators of severity of acute illnesses were reduced, particularly in children with positive asthma predictive indices.

Azithromycin or montelukast as inhaled corticosteroid-sparing agents in moderate-to-severe childhood asthma study.

BACKGROUND: Clinical trials in children with moderate-to-severe persistent asthma are limited. OBJECTIVE: We sought to determine whether azithromycin or montelukast are inhaled corticosteroid sparing. METHODS: The budesonide dose (with salmeterol [50 microg] twice daily) necessary to achieve control was determined in children 6 to 17 years of age with moderate-to-severe persistent asthma. After a budesonide-stable period of 6 weeks, children were randomized in a double-masked, parallel, multicenter study to receive once-nightly azithromycin, montelukast, or matching placebos plus the established controlling dose of budesonide (minimum, 400 microg twice daily) and salmeterol twice daily. Primary outcome was time from randomization to inadequate asthma control after sequential budesonide dose reduction. RESULTS: Of 292 children screened, only 55 were randomized. Inadequate adherence to study medication (n = 80) and improved asthma control under close medical supervision (n = 49) were the major reasons for randomization failure. A futility analysis was requested by the Data Safety Monitoring Board. In data available for analyses, no differences were noted for either treatment compared with placebo in time to inadequate control status (median: azithromycin, 8.4 weeks [95% confidence limit, 4.3-17.3]; montelukast, 13.9 weeks [95% confidence limit, 4.7-20.6]; placebo, 19.1 weeks [95% confidence limit, 11.7-infinity]), with no difference between the groups (log-rank test, P = .49). The futility analysis indicated that even if the planned sample size was reached, the results of this negative study were unlikely to be different, and the trial was prematurely terminated. CONCLUSION: Based on these results, neither azithromycin nor montelukast is likely to be an effective inhaled corticosteroid-sparing alternative in children with moderate-to-severe persistent asthma.

Clinical manifestations of airway malacia in young children.

A case of recurrent respiratory distress, wheezing, and "noisy" breathing in a 6-month-old infant with a normal birth history and chest radiographic evaluation is presented. The distinction between primary and secondary tracheomalacia is outlined. This report emphasizes the importance of clinical history in the evaluation of primary tracheomalacia.

Heterogeneity in response to asthma medications.

PURPOSE OF REVIEW: Evidence for the heterogeneity of response to asthma medications including inhaled corticosteroids and leukotriene receptor antagonists is mounting. beta2-Adrenoceptor gene polymorphisms may contribute to asthma responsiveness to short- and long-acting beta2-agonists. This review examines recent articles describing variability in response to inhaled corticosteroids, leukotriene receptor antagonists and short-acting beta2-agonists specifically in pediatric persistent asthmatics. RECENT FINDINGS: In the late 1990's, differences in the response to a leukotriene receptor antagonist and an inhaled corticosteroid in adults with moderate persistent asthma were first described. Subsequently, similar findings have recently been elucidated in children with mild to moderate persistent asthma. The variability in response to these two classes of control medicines now appears to encompass all ages with persistent asthma. In general, despite the variability in response to these medications, both resulted in improved clinical and physiologic control measures. SUMMARY: Childhood asthma is a complex disease with numerous clinical phenotypes that contribute to response variability to asthma medications.

Leukotriene receptor antagonists--risks and benefits for use in paediatric asthma.

Leukotrienes (LTs) are important mediators of the pathophysiology of asthma, specifically, bronchoconstriction, airway inflammation and oedema and mucus hypersecretion. The LT receptor antagonists (LTRAs) inhibit these potent effects by selectively blocking the cysteinyl LT 1 receptor. These are the first novel therapies for asthma since the introduction of inhaled corticosteroids (ICS) in 1972. Unlike generalised inhibition of airway inflammation by ICS, the LTRAs target inhibition of specific mediators. In general, paediatric data concerning these agents remain quite limited. However, they have demonstrated efficacy against allergen- and exercise-induced bronchospasm in both adults and children. Recently, their potential role for the treatment of viral-induced wheeze in young children has been explored. In multiple, placebo-controlled trials, the LTRAs have demonstrated efficacy for the treatment of mild persistent asthma, additive benefit in the management of symptomatic moderate asthmatics on maintenance ICS and evidence of significant steroid-sparing. Findings from these clinical trials and real-world experience support the use of the LTRAs as controller agents for persistent asthma. Based on their excellent safety profiles, tolerance and ease of administration (including once daily dosing with montelukast), this drug class may offer several important features for use as controller therapy, particularly in asthmatic children as young as 1 year of age, however, this must continue to be reviewed as new paediatric data become available.

Natural history of asthma.

For some children, asthma is a disease whose symptoms seem to remit with time. Numerous children, however, develop disease that is persistent throughout their lifetimes and is associated with more severe symptoms, increased airway reactivity, and loss of lung function. These children typically have a family history of asthma and demonstrate increased airways reactivity and atopy in childhood. A clearer picture of the natural history of asthma in the developing child has been derived from the results of several longitudinal studies. Although some questions have been clarified, several questions still remain. Now that the incidence and severity of asthma seem to be increasing, children born in the last 10 years may experience more severe disease or a different pathophysiology than those born 30 to 40 years ago. New cohort studies are needed to assess this possibility. Additional investigations into the genetics of asthma causation will help elucidate the different phenotypic expressions of this complex disease. Once these different phenotypic groups can be identified early in life, further studies can be performed to explore the impact of therapeutic intervention on the severity of asthma symptoms and loss of lung function.

Neutrophilic airway inflammation and association with bacterial lipopolysaccharide in children with asthma and wheezing.

Asthma is a leading chronic childhood illness in the US. To gain further insight into the pathophysiology of childhood asthma, we studied markers of airway inflammation and possible triggers such as bacterial lipopolysaccharide (LPS) in 18 children with chronic asthma and persistent wheezing who underwent clinically indicated bronchoscopy and bronchoalveolar lavage (BAL). We predominantly found neutrophilic airway inflammation associated with increased levels of IL-8, metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP-1) and MMP-9/TIMP-1 ratio. A significant correlation was found between levels of LPS in BAL and airway neutrophils in BAL from a subgroup of children who had a tendency of increased levels of MMP-9 and TIMP-1, suggesting that increased LPS levels in BAL may contribute to chronic airway inflammation and early remodeling. Our data highlight the importance of defining chronic triggers of early airway inflammation in children and characterizing their inflammation, considering the use of bronchoscopy and BAL. Increased knowledge of airway inflammation in children may help prevent a more severe asthma phenotype and lead to environmental control measures and new treatment strategies to intervene against the establishment of irreversible inflammation.

Thoracoscopic aortopexy for primary tracheomalacia in a 12-year-old.

Aortopexy is the therapeutic modality of choice for severe primary tracheomalacia. The thoracoscopic approach has been used with good results in infants and toddlers, but little information exists on the use of aortopexy in older children. We present the case of a boy with a lifelong history of refractory, a steroid-dependent reactive airway disease, and who was found to have severe primary tracheomalacia. He subsequently underwent thoracoscopic aortopexy with immediate resolution of the tracheomalacia as demonstrated by serial bronchoscopy and long-term resolution of his clinical respiratory symptoms at 1 year.

Severe intermittent wheezing in preschool children: a distinct phenotype.

BACKGROUND: Young children with wheezing predominantly with respiratory tract illnesses experience severe exacerbations separated by extended periods of wellness and may be described as having "severe intermittent wheezing," a diagnostic category not currently recognized in national guidelines. OBJECTIVE: We sought to characterize a cohort of children with recurrent severe wheezing. METHODS: A total of 238 children 12 to 59 months enrolled in the Acute Intervention Management Strategies trial were characterized through comprehensive allergy, asthma, environmental, and quality of life assessments. RESULTS: Asthma symptoms over the period of the preceding year occurred at frequencies consistent with intermittent asthma, as 94.5% of children experienced activity limitation < or = 2 times per month. However, frequent severe exacerbations were common, because 71% experienced > or = 4 wheezing episodes over the period of the preceding year, 95% made at least 1 primary care visit, 52% missed school or daycare, 40% made an emergency department visit, and 8% were hospitalized for wheezing illnesses. Atopic features were common, including eczema (37%), aeroallergen sensitization (46.8%), and positive asthma predictive index (59.7%). Oral corticosteroid use in the previous year (59.7% of the cohort) identified a subgroup with more severe disease documented by a higher incidence of urgent care visits (P = .0048), hospitalizations (P = .0061), aeroallergen sensitization (P = .047), and positive asthma predictive indices (P = .007). CONCLUSION: Among preschool children enrolled in the Acute Intervention Management Strategies trial, a subgroup was identified with severe intermittent wheezing characterized by atopic features and substantial illness-related symptom burden despite prolonged periods of wellness. CLINICAL IMPLICATIONS: Preschool children with recurrent severe wheezing episodes experience significant illness-related morbidity and exhibit features of atopic predisposition.

Leukotriene receptor antagonists.

In the past decade, heightened emphasis has been placed on the importance of inflammation in the pathogenesis of asthma. Although corticosteroids have remained the primary anti-inflammatory agents in the management of the persistent asthmatic, new classes of drugs have recently been added. The leukotriene receptor antagonists (LTRAs) are the first new approach in asthma therapy in the past 25 years and the first class of drugs to target specific components of the inflammatory process. These drugs reverse the primary biological effects of the cysteinyl leukotrienes in relation to the pathogenesis of asthma including bronchoconstriction, mucus hypersecretion, and airway inflammation. The LTRAs have demonstrated efficacy against exercise- and allergen-induced bronchoconstriction, aspirin-sensitive asthma, and additive benefit in symptomatic moderate asthmatics on maintenance inhaled corticosteroids, as well as potential steroid-sparing effects. Finally, although evidence for their role as first-line controller agents for the management of mild persistent asthma has grown stronger in recent years, this role continues to evolve.

Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma.

BACKGROUND: Few studies have characterized the atopic profile of toddler-aged children with recurrent wheezing at high risk of the development of persistent asthma. Objective We sought to determine the atopic profile of toddler-aged children with frequent wheeze at high risk for the development of persistent asthma who either had a parental history of asthma, a personal history of atopic dermatitis, or both. METHODS: Participants enrolled in the Prevention of Early Asthma in Kids study (n = 285) on the basis of a modified Asthma Predictive Index were characterized on the basis of allergy and asthma questionnaire responses and allergy skin puncture test results. RESULTS: The majority of the children (60.7%, n = 148) were sensitized to either food or aeroallergens. Male children were significantly more likely to be sensitized to aeroallergens ( P = .03) and to have a blood eosinophil level of 4% or greater ( P = .03) and a total serum IgE level of greater than 100 IU/mL ( P = .0004). Additionally, eosinophilia and total serum IgE level had the strongest correlation with aeroallergen sensitization. CONCLUSION: The high prevalence of aeroallergen sensitization in this high-risk cohort suggests that aeroallergens might have an important role in the early development of asthma. As such, the Prevention of Early Asthma in Kids cohort appears to be an appropriate cohort in which to test whether early intervention with an inhaled corticosteroid can significantly attenuate, or perhaps even prevent, the allergic march from the initial stages of allergic sensitization to the subsequent development of asthma in toddlers with episodic wheezing.

The Prevention of Early Asthma in Kids study: design, rationale and methods for the Childhood Asthma Research and Education network.

Pediatric asthma remains an important public health concern as its prevalence and cost to the health care system is rising. In order to promote innovative research in asthma therapies, the National Heart, Lung and Blood Institute created the Childhood Asthma Research and Education Network in 1999. As its first study, the steering committee of the Childhood Asthma Research and Education Network designed a randomized clinical trial to determine if persistent asthma could be prevented in children at a high risk to develop the disease. This communication presents the design of its first clinical trial, the Prevention of Asthma in Kids (PEAK) trial and the organization of the Childhood Asthma Research and Education Network that developed and implemented this trial. Studies of the natural history of asthma have shown that, in persistent asthma, the initial asthma-like symptoms and loss of lung function occur predominately during the first years of life. Therefore, in the Prevention of Asthma in Kids study, children 2 and 3 years old with a positive asthma predictive index were randomized to twice daily treatment with fluticasone 88 microg or placebo via metered-dose inhaler and Aerochamber for 2 years. The double blind treatment period was followed by a 1-year observational period. Lung function was measured by spirometry and oscillometry technique at 4-month intervals throughout the study. Bronchodilator reversibility and exhaled nitric oxide (ENO) studies were performed at the end of the treatment and observation periods. The primary outcome measure was the number of asthma-free days. Other secondary outcomes included number of exacerbations, use of asthma medications and lung function. These measures were chosen to reflect the progression of the disease from intermittent wheezing to persistent asthma and measurement of the extent of airflow limitation and airway reactivity.