The Genetics of Severe Asthma in Children

Our primary outcome measure is the development of a near fatal asthma exacerbation. Secondary outcome measures will include the duration of continuously nebulized ADRβ2 agonist therapy and the duration of IV ADRβ2 agonist therapy. Children will be stratified by ADRβ2 genotype at amino acid position 16 and outcomes compared.

We propose to investigate two separate populations in this study: (1) children admitted to the hospital with an acute asthma exacerbation, and (2) children with asthma who have never had an acute near fatal asthma exacerbation. In addition, in order to replicate findings in an independent cohort, we will examine the genotypes of a third cohort of age-matched children without asthma.

For the population of children admitted to the hospital with an acute asthma exacerbation, the following inclusion criteria will be met: (1) admission to the hospital with a primary admission diagnosis of asthma exacerbation and (2) age between 4 years and 18 years. Near fatal asthma exacerbations will be defined as (1) treatment with intubation and mechanical ventilation, (2) presence of respiratory acidosis (arterial pCO2 > 45), or (3) Modified Pulmonary Index Score > 12 after 2 hours of at least 20 mg/hour of continuously nebulized albuterol therapy. Children will be excluded if they have a (1) pre-existing chronic disease (other than asthma) including: (a) bronchopulmonary dysplasia, (b) bronchomalacia, (c) tracheomalacia, (d) laryngomalacia, (e) vocal cord dysfunction, (f) chronic restrictive lung disease, (g) recurrent aspiration pneumonia, or (h) congenital heart disease.

For the population of children with asthma who have never had an acute near fatal asthma exacerbation, the following inclusion criteria will be met: (1) diagnosis of asthma and (2) age between 4 years and 18 years. Children will be excluded if (1) that child ever required admission to the hospital for a near fatal asthma exacerbation and (2) if they have a pre-existing chronic disease (other than asthma) as listed above. We propose to enroll 158 children, recruited from Pulmonary Clinic at the study institution, matched by age, by gender, and by NHLBI asthma classification to the population of children with near fatal asthma exacerbations.

In order to replicate these findings in an independent cohort, we will also examine these genetic markers in a reference group of 80 healthy children without asthma, matched by age, gender and race/ethnicity to the group of children with near fatal asthma exacerbations. The following inclusion criteria will be met for this group: (1) age between 4 and 18 years. Children will be excluded if they have any pre-existing chronic disease. This population of children will be recruited from the Primary Care Clinic at CCMC and if necessary for racial/ethnic matching, from a private practice in suburban Hartford.