Progression of Airway Obstruction in Childhood Asthma

Overview

Distinct patterns of loss in pulmonary function were identified in children with mild to moderate asthma participating in a 10-year observation period during the NHLBI Childhood Asthma Management Program. This loss in pulmonary function is likely related to ongoing inflammation unresponsive to current therapy. This study will measure indicators of airway inflammation which are associated with structural and physiologic changes in the lung and provide insight into mechanisms of asthma progression in adolescence and early adulthood.

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: June 2011

Detailed Description

The Childhood Asthma Management Program Continuation Study/Phase 2 is a 3.25 year observational follow-up study of the children enrolled in the Childhood Asthma Management Program (CAMP) randomized trial. CAMPCS/2 is a multicenter National Heart, Lung and Blood Institute program. The objective of the CAMPCS/2 is to determine the consequences of childhood asthma and its treatment on asthma outcomes in young adulthood. This separate ancillary study will extend the core CAMP/CAMPCS work by focusing on progression of airway obstruction in childhood asthma to evaluate mechanisms of progression and describe the differences in the four separate patterns in airway obstruction that have evolved over time. The four patterns of airway obstruction which have been identified are as follows: (1) abnormal obstruction present in early childhood which remained abnormal (Low/Low group) and (2) initially normal ratios, which worsened into the abnormal range over time (Normal/Low group). These patterns with unfavorable outcomes can be compared to two other patterns with favorable outcomes: (3) initially abnormal ratios improving with time (Low/Normal group) and (4) normal ratios throughout follow-up (Normal/Normal group). Based on these four patterns, three specific hypotheses related to immunology, structure, and physiology are identified: 1. Among school-aged children with mild to moderate asthma, those children with increased airflow limitation (i.e. low FEV1/FVC) at the end of CAMPCS (Normal/Low and Low/Low groups) have elevated markers of inflammation related to proteolysis (i.e. neutrophil elastase, matrix metalloproteinase-9 (MMP9), and tissue inhibitor of metalloproteinase-1 (TIMP1) and neutrophils in sputum). 2. Subjects who show a pattern of early progression and failure to resolve (Low/Low group) have clinical evidence of steroid insensitivity compared to those with slow progression (Normal/Low group). They also have in vitro evidence of steroid resistance compared to the Normal/Low or Normal/Normal groups. This pattern of obstruction may be due to irreversible changes consistent with airway remodeling and inflammation that are relatively refractory to steroid therapy. 3. Children with ongoing airflow limitation (Normal/Low and Low/Low groups) have more prominent structural changes related to increased air trapping and airway thickening compared to those with normal FEV1/FVC at the end of CAMPCS (Low/Normal and Normal/Normal groups). Each participant will be studied at varying times over the 2-year study period. Researchers will complete a collection of sputum, blood, urine, and exhaled breath condensate samples; exhaled nitric oxide; and spirometry from CAMPCS/3 participants, representing each of the four phenotypes (n = 20 for a total of 80).

Arms, Groups and Cohorts

  • Persistent obstruction
    • (pattern of asthma progression)
  • Late obstruction
    • (pattern of asthma progression)
  • Late normal
    • (pattern of asthma progression)
  • Persistent normal
    • (pattern of asthma progression)

Clinical Trial Outcome Measures

Primary Measures

  • Airway Wall Thickness
    • Time Frame: Measured at Year 2
    • Segmental average airway wall thickness

Secondary Measures

  • Protease/Antiprotease
    • Time Frame: Measured at Year 2
    • MMP9/TIMP 1 molar ratio MMP9 is matrix metalloproteinse 9 and is a protease enzyme that is responsible for tissue degradation of extracellular matrix and could be a factor in airway remodeling. TIMP 1 is an abbreviation for tissue inhibitor of metalloproteinase-1 and is an inhibitor of MMP9 and would serve to balance the activity protease activity of MMP9 and this it is an anti-protease. Therefore the ratio of MMP9 and TIMP1 is used to assess the relative balance of protease and antiprotease activity.

Participating in This Clinical Trial

Inclusion Criteria

  • Must be enrolled in the CAMPCS/3 study; individuals enrolled in this study will represent four different patterns of asthma progression, as defined by forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) levels Exclusion Criteria:

  • Unwilling to comply with study procedures – Physical state does not allow the study procedures to be performed (e.g., low pulmonary function for induced sputum, pregnancy for computerized tomography [CT] scan)

Gender Eligibility: All

Minimum Age: 16 Years

Maximum Age: 40 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • National Jewish Health
  • Collaborator
    • National Heart, Lung, and Blood Institute (NHLBI)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Stanley J. Szefler, MD, Principal Investigator, National Jewish Health

References

Childhood Asthma Management Program Research Group; Szefler S, Weiss S, Tonascia J, Adkinson NF, Bender B, Cherniack R, Donithan M, Kelly HW, Reisman J, Shapiro GG, Sternberg AL, Strunk R, Taggart V, Van Natta M, Wise R, Wu M, Zeiger R. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000 Oct 12;343(15):1054-63. doi: 10.1056/NEJM200010123431501.

Covar RA, Spahn JD, Murphy JR, Szefler SJ; Childhood Asthma Management Program Research Group. Progression of asthma measured by lung function in the childhood asthma management program. Am J Respir Crit Care Med. 2004 Aug 1;170(3):234-41. doi: 10.1164/rccm.200308-1174OC. Epub 2004 Mar 17.

Strunk RC, Weiss ST, Yates KP, Tonascia J, Zeiger RS, Szefler SJ; CAMP Research Group. Mild to moderate asthma affects lung growth in children and adolescents. J Allergy Clin Immunol. 2006 Nov;118(5):1040-7. doi: 10.1016/j.jaci.2006.07.053.

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