The Principal Investigator, Dr. Goldstein, has the long-term goal of pursuing independent investigation in the field of pediatric pulmonology and asthma pathogenesis. Receipt of a Mentored Patient-Oriented Research Career Development Award will facilitate the career development of Dr. Goldstein by extending her knowledge of infant pulmonary function testing and adding new skills in airway biology. The learning objectives set out in this revised proposal, combined with the support of her Mentor, Dr. Marc Hershenson, as well as members of her newly-constituted Advisory Committee, will foster Dr. Goldstein?s progression to independent lines of investigation into the mechanisms of infant lung diseases.
The Specific Aims i n this proposal will extend earlier inquiries by Dr. Goldstein into bronchodilator responsiveness in normal infants to the study of infants with moderate to severe persistent wheezing. 1. Quantify airway function, airway inflammation and allergic sensitization in infants with moderate or severe persistent wheezing. We will perform baseline spirometry using the raised volume rapid thoracoabdominal compression technique. Bronchodilator responsiveness will be assessed by changes in maximal flows following bronchodilator. Functional residual capacity will be assessed plethysmographically and fractional lung volumes calculated to assess air trapping. To determine the potential contributions of various risk factors for recurrent wheezing, parents will complete a respiratory history questionnaire. Airway inflammation will be assessed by measurement of exhaled hydrogen peroxide, serum soluble intercellular adhesion molecule (ICAM-1) and interleukin-2 receptor (IL-2R) levels. Allergic sensitization will be assessed by measuring serum IgE and the response of peripheral blood monocytes to aeroallergens. 2. Evaluate the response to inhaled corticosteroid therapy in infants with moderate or severe persistent wheezing. Patients with evidence of reduced airflow, air trapping or bronchodilator responsiveness will receive either daily low dose inhaled corticosteroid therapy or placebo. Respiratory function and airway inflammation will be reassessed one month after the start of the treatment period, as described above. To determine whether changes in airway function correlate with respiratory symptoms, parents will complete a symptom diary before and during the treatment period. 3. Determine the long-term pulmonary outcome in patients with infantile wheezing. Subjects previously tested as infants will undergo standard pulmonary function testing (spirometry and plethysmography) at five years of age. Bronchodilator response will be assessed by changes in maximal flow following bronchodilator. Parents will also complete a symptom diary and respiratory history questionnaire.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-F (F1))
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Rothgeb, Ann E
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Debley, Jason; Stanojevic, Sanja; Filbrun, Amy G et al. (2012) Bronchodilator responsiveness in wheezy infants and toddlers is not associated with asthma risk factors. Pediatr Pulmonol 47:421-8