The Genetics of Respiratory Failure in Bronchiolitis

Bronchiolitis is a potentially severe infection of the airway in infants and children, and among the most frequent diagnoses leading to pediatric intensive care unit admission in infants. This acute infection is caused by an array of viruses, but respiratory syncytial virus (RSV) is the most frequently implicated. The majority of infants hospitalized with bronchiolitis are previously healthy, and half of infants intubated and mechanically ventilated for respiratory failure due to RSV bronchiolitis have no previously identified risk factors. It is likely, therefore, that other factors, particularly genetic heterogeneity of the host, contribute to disease severity. However, no previous study has investigated the association of genetic variants with respiratory failure in children with bronchiolitis. Several categories of candidate genes have emerged as potentially important in the pathogenesis of the disease. Specifically, genetic polymorphisms of surfactants, pattern recognition receptors, receptor adhesion molecules, and cytokines have been examined. The aim is to evaluate these polymorphisms to determine their association with respiratory failure in a cohort of more severely ill children with bronchiolitis.

We propose to conduct a prospective observational study of infants and children admitted with bronchiolitis to determine if genetic polymorphisms in a number of likely candidate immune response related genes are positively associated with respiratory failure in this population. Respiratory failure will be defined as requiring intubation and mechanical ventilation. We plan to enroll two groups of children, those admitted to the ICU with respiratory failure due to bronchiolitis (cases) and those children admitted to the ward with less severe bronchiolitis infection (controls). In special circumstances, we will also enroll pairs of twins who are hospitalized with bronchiolitis (in the ICU or the ward), for whom either one or both twins do not meet inclusion criteria as a case or a control and/or for whom we are not able to obtain a DNA blood sample while hospitalized (twin inpatient population).

Demographic data, and data regarding the hospital treatments and course of these children will be collected. Blood, saliva or sputum for genotyping will also be obtained. If a patient enrolled as a control needs to be intubated, these children cannot be control patients, but instead would be considered cases.

We propose to compare a population of 100 children with respiratory failure due to bronchiolitis to a population of 100 children with bronchiolitis without respiratory failure. Clinical characteristics and genetic markers will be compared. We will also compare clinical characteristics and genetic markers of any twin pairs who are enrolled.

Eligibility Criteria:
Inclusion Criteria, cases:

* admission to the ICU with a primary diagnosis of bronchiolitis
* endotracheally intubated and mechanically ventilated with respiratory failure due to bronchiolitis
* age less than 2 years

Exclusion Criteria, cases:

* pre-existing chronic disease including:

  1. bronchopulmonary dysplasia
  2. congenital heart disease
  3. immune deficiency
* requiring an additional venopuncture for blood collection for genotyping

Inclusion Criteria, controls:

* admission to the hospital with a primary diagnosis of bronchiolitis
* age less than 2 years

Exclusion Criteria, controls:

* pre-existing chronic disease including:

  1. bronchopulmonary dysplasia
  2. congenital heart disease
  3. immune deficiency
* requiring an additional venopuncture for blood collection for genotyping
* requiring non-invasive positive pressure ventilation or high flow nasal cannula
* requiring intubation and mechanical ventilation during the hospitalization