The Genetics of Severe Asthma in Children
Condition: Asthma
MeSH terms: Asthma
Study type: Observational

Summary: 
      Near fatal asthma exacerbations are one of the most common causes of critical illness in
      children, accounting for approximately ten thousand intensive care unit (ICU) admissions per
      year in the United States. Even children with intermittent or mild baseline asthma can
      develop these severe exacerbations; however, there are few studies evaluating the risk
      factors associated with the development of near fatal asthma exacerbations in children.
      Inhaled β2-adrenergic receptor (ADRβ2) agonist therapy is the foundation of therapy for acute
      asthma and genetic variations of this receptor have been shown to affect response to ADRβ2
      agonist therapy in this population. The investigators hypothesis is that a child's ADRβ2
      genotype is associated with the development of a near fatal asthma exacerbation.
    

Detailed description: 
      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.

      For the population of children hospitalized with an asthma exacerbation, patients will be
      approached, consented and enrolled upon admission to the hospital. In this observational
      study, patients will be treated according to the current asthma treatment protocol in effect
      at Connecticut Children's Medical Center. This protocol has been previously published 13 and
      titrates therapy based on a clinical asthma score (MPIS) 51 that has been shown to be highly
      reproducible between groups of physicians, nurses and respiratory therapists. This
      around-the-clock adjustment of therapy by nurses and respiratory therapists produces less
      variation in care due to non-medical reasons. This protocol includes thresholds for
      admission/discharge to the hospital and for admission/discharge to the ICU based on MPIS. For
      the populations of children with no history of a near fatal asthma exacerbation and no asthma
      diagnosis, patients will be approached, consented and enrolled upon confirmation of
      eligibility in the Pulmonary Clinic and the Primary Care Clinic.

      Genotyping of the ADRβ2 gene will be performed at the University of Connecticut Health Center
      (UCHC) Clinical and Translational Research Core Lab. Genotyping will be performed either from
      saliva or from whole blood collected during routine blood sampling for clinical care.
      Children will be stratified based on their genotype and outcomes compared. Providers will be
      blinded to genotype at the time of treatment.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Children with asthma
      
Biospecimen description: 
      saliva and blood
    
Keywords: Pediatric; Polymorphism, Genetic; Adrenergic beta-Agonists