Leonard B. Bacharier

Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report

Asthma is the leading chronic disease among children in most industrialized countries. However, the evidence base on specific aspects of pediatric asthma, including therapeutic strategies, is limited and no recent international guidelines have focused exclusively on pediatric asthma. As a result, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams to find a consensus to serve as a guideline for clinical practice in Europe as well as in North America. This consensus report recommends strategies that include pharmacological treatment, allergen and trigger avoidance and asthma education. The report is part of the PRACTALL initiative ** , which is endorsed by both academies.

Heterogeneity of severe asthma in childhood: Confirmation by cluster analysis of children in the National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program

BACKGROUND Asthma in children is a heterogeneous disorder with many phenotypes. Although unsupervised cluster analysis is a useful tool for identifying phenotypes, it has not been applied to school-age children with persistent asthma across a wide range of severities. OBJECTIVES This study determined how children with severe asthma are distributed across a cluster analysis and how well these clusters conform to current definitions of asthma severity. METHODS Cluster analysis was applied to 12 continuous and composite variables from 161 children at 5 centers enrolled in the Severe Asthma Research Program. RESULTS Four clusters of asthma were identified. Children in cluster 1 (n = 48) had relatively normal lung function and less atopy. Children in cluster 2 (n = 52) had slightly lower lung function, more atopy, and increased symptoms and medication use. Cluster 3 (n = 32) had greater comorbidity, increased bronchial responsiveness, and lower lung function. Cluster 4 (n = 29) had the lowest lung function and the greatest symptoms and medication use. Predictors of cluster assignment were asthma duration, the number of asthma controller medications, and baseline lung function. Children with severe asthma were present in all clusters, and no cluster corresponded to definitions of asthma severity provided in asthma treatment guidelines. CONCLUSION Severe asthma in children is highly heterogeneous. Unique phenotypic clusters previously identified in adults can also be identified in children, but with important differences. Larger validation and longitudinal studies are needed to determine the baseline and predictive validity of these phenotypic clusters in the larger clinical setting.

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.

International consensus on (ICON) pediatric asthma

Asthma is the most common chronic lower respiratory disease in childhood throughout the world. Several guidelines and/or consensus documents are available to support medical decisions on pediatric asthma. Although there is no doubt that the use of common systematic approaches for management can considerably improve outcomes, dissemination and implementation of these are still major challenges. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), recently formed by the EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus on (ICON) Pediatric Asthma. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences, thus providing a concise reference. The principles of pediatric asthma management are generally accepted. Overall, the treatment goal is disease control. To achieve this, patients and their parents should be educated to optimally manage the disease, in collaboration with healthcare professionals. Identification and avoidance of triggers is also of significant importance. Assessment and monitoring should be performed regularly to re‐evaluate and fine‐tune treatment. Pharmacotherapy is the cornerstone of treatment. The optimal use of medication can, in most cases, help patients control symptoms and reduce the risk for future morbidity. The management of exacerbations is a major consideration, independent of chronic treatment. There is a trend toward considering phenotype‐specific treatment choices; however, this goal has not yet been achieved.

Molecular mechanisms of IgE regulation

IgE antibody plays an important role in allergic diseases. IgE synthesis by B cells requires two signals. The first signal is delivered by the cytokines IL-4 or IL-13, which target the Cepsilon gene for switch recombination. The second signal is delivered by interaction of the B cell surface antigen CD40 with its ligand (CD40L) expressed on activated T cells. This activates deletional switch recombination. We review the molecular mechanisms of IL-4 and CD40 signaling that lead to IgE isotype switching and discuss the implications for intervening to abort or suppress the IgE antibody response.

Socioeconomic Status, Stress, and Immune Markers in Adolescents with Asthma

Objective Previous research has demonstrated links between low socioeconomic status (SES) and clinical asthma outcomes, as well as links between stress and asthma. The objective of this study was to test whether adolescents with asthma from different SES backgrounds differed in biological profiles relevant to asthma, including immune and cortisol measures. The second objective was to test whether psychological stress and control beliefs could explain these differences. Materials and Methods Adolescents with persistent asthma from either low (N = 18) or high (N = 12) SES neighborhoods were interviewed about their stress experiences (chronic stress, acute life events, interpretations of ambiguous life events) and control beliefs. Blood was drawn to assess immune (cytokines, eosinophils, IgE) and neuroendocrine (cortisol) markers associated with asthma. Results Adolescents in the low SES group had significantly higher levels of a stimulated cytokine associated with a Th-2 immune response (IL-5), higher levels of a stimulated cytokine associated with a Th-1 immune response (IFN-&ggr;), and marginally lower morning cortisol values compared with the high SES group. Low SES adolescents also had greater stress experiences and lower beliefs about control over their health. Statistical mediational analyses revealed that stress and control beliefs partially explained the relationship between SES and IL-5/IFN-&ggr;. Conclusion Our finding that low SES was associated with elevations in certain immune responses (IL-5/IFN-&ggr;) in adolescents with asthma suggests the importance of further exploration into relationships between SES and Th-2/Th-1 responses in asthma. Our findings also suggest that psychological stress and control beliefs may provide one explanation for links between SES and immune responses in childhood asthma.

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.

Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.

IMPORTANCE In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency. OBJECTIVE To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels. DESIGN, SETTING, AND PARTICIPANTS The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institutes AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized. INTERVENTIONS Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained. MAIN OUTCOMES AND MEASURES The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care). RESULTS Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]). CONCLUSIONS AND RELEVANCE Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01248065.

Severity of Respiratory Syncytial Virus Bronchiolitis Is Affected by Cigarette Smoke Exposure and Atopy

Objective. Respiratory syncytial virus (RSV) bronchiolitis is a common cause of hospitalizations in children and has been increasingly identified as a risk factor in the development of asthma. Little is known about what determines the severity of RSV bronchiolitis, which may be helpful in the initial assessment of these children. Design. We evaluated a variety of environmental and host factors that may contribute to the severity of RSV bronchiolitis in the RSV Bronchiolitis in Early Life prospective cohort study. Severity of bronchiolitis was based on the quantization of lowest O2 saturation and the length of stay. These factors included the childs and familys demographics, presence of household allergens (dust mite, cat, dog, and cockroach), peripheral blood eosinophil count, immunoglobulin E level, infant feeding, prior illnesses, exposure to intrauterine and postnatal cigarette smoke, and family history of atopy. Patients. We prospectively enrolled 206 hospitalized infants, all under 12 months old (4.0 ± 3.3 months old), with their first episode of severe RSV bronchiolitis (mean O2 saturation: 91.6 ± 7.3%; length of stay: 2.5 ± 2.5 days; presence of radiographic opacities: 75%). Patients were excluded for a variety of reasons including previous wheezing, regular use of bronchodilator or antiinflammatory medications, any preexisting lung disease including asthma, chronic lung disease of prematurity/bronchopulmonary dysplasia, or cystic fibrosis; gastroesophageal reflux disease on medical therapy; or congenital anomalies of the chest or lung. Results. Age was found to be a significant factor in the severity of infection. The younger an infant was, the more severe the infection tended to be as measured by the lowest oxygen (O2) saturation. We also found that infants exposed to postnatal cigarette smoke from the mother had a lower O2 saturation than those not exposed. However, there was no significant difference in RSV bronchiolitis severity between infants exposed only to intrauterine smoke and those infants never exposed to cigarette smoke. Infants with a family history of atopy, especially a maternal history of asthma or hay fever, had a higher O2 saturation. Although a history of maternal atopy seemed to be protective, there was no association between allergens and bronchiolitis severity, although 25% of households had elevated allergen levels. Black infants demonstrated less severe RSV bronchiolitis than their white counterparts. Multivariate analysis revealed age, race, maternal atopy, and smoking to be associated with severity of RSV bronchiolitis. Conclusion. The severity of RSV bronchiolitis early in life seems modified by postnatal maternal cigarette smoke exposure and atopy and age of the infant, not by levels of allergens in the home environment.

Daily or Intermittent Budesonide in Preschool Children with Recurrent Wheezing

BACKGROUND Daily inhaled glucocorticoids are recommended for young children at risk for asthma exacerbations, as indicated by a positive value on the modified asthma predictive index (API) and an exacerbation in the preceding year, but concern remains about daily adherence and effects on growth. We compared daily therapy with intermittent therapy. METHODS We studied 278 children between the ages of 12 and 53 months who had positive values on the modified API, recurrent wheezing episodes, and at least one exacerbation in the previous year but a low degree of impairment. Children were randomly assigned to receive a budesonide inhalation suspension for 1 year as either an intermittent high-dose regimen (1 mg twice daily for 7 days, starting early during a predefined respiratory tract illness) or a daily low-dose regimen (0.5 mg nightly) with corresponding placebos. The primary outcome was the frequency of exacerbations requiring oral glucocorticoid therapy. RESULTS The daily regimen of budesonide did not differ significantly from the intermittent regimen with respect to the frequency of exacerbations, with a rate per patient-year for the daily regimen of 0.97 (95% confidence interval [CI], 0.76 to 1.22) versus a rate of 0.95 (95% CI, 0.75 to 1.20) for the intermittent regimen (relative rate in the intermittent-regimen group, 0.99; 95% CI, 0.71 to 1.35; P=0.60). There were also no significant between-group differences in several other measures of asthma severity, including the time to the first exacerbation, or adverse events. The mean exposure to budesonide was 104 mg less with the intermittent regimen than with the daily regimen. CONCLUSIONS A daily low-dose regimen of budesonide was not superior to an intermittent high-dose regimen in reducing asthma exacerbations. Daily administration led to greater exposure to the drug at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; MIST ClinicalTrials.gov number, NCT00675584.).