Asthma
Conditions
Keywords
Asthma Progression, Airway Wall Thickness, Corticosteroid Resistance, Biomarkers, Pulmonary Physiology
Brief summary
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.
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).
Interventions
None listed
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
National Jewish Health
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
16 Years to 40 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Airway Wall Thickness | Measured at Year 2 | Segmental average airway wall thickness |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Protease/Antiprotease | 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. |
Countries
United States
Participant flow
Recruitment details
The NHLBI Childhood Asthma Management Program (CAMP) and CAMP Continuation Studies afforded a unique opportunity to investigate four newly described, distinct patterns of airway obstruction associated with childhood asthma, including two that have been associated with significant and potentially irreversible loss in pulmonary function.
Pre-assignment details
Analysis of serial pulmonary function measures in participants in CAMP and CAMPCS over time showed 4 patterns of airway obstruction developing during childhood and adolescence based on measurements of pre-bronchodilator FEV1/FVC at the time of enrollment in CAMP and again at the end of the observational phase.
Participants by arm
| Arm | Count |
|---|---|
| Persistent Obstruction This group represents those that have persistent obstruction from baseline at entry into the NHLBI CAMP study until end of the CAMP Continuation study, 9 years later. | 20 |
| Late Obstruction in Pulmonary Physiology This group represents those that had normal pulmonary function from baseline at entry into the NHLBI CAMP study and then has evidence of obstruction, as defined by FEV1/FVC criteria, at end of the CAMP Continuation study, 9 years later. | 8 |
| Late Normal in Pulmonary Physiology This group represents those that has evidence of obstruction, as defined by FEV1/FVC criteria, from baseline at entry into the NHLBI CAMP study and then has normal pulmonary function at end of the CAMP. | 9 |
| Persistent Normal in Pulmonary Physiology This groups has normal pulmonary function at the time of entry into the CAMP study and normal pulmonary function 9 years later. | 18 |
| Total | 55 |
Baseline characteristics
| Characteristic | Late Obstruction in Pulmonary Physiology | Late Normal in Pulmonary Physiology | Persistent Obstruction | Persistent Normal in Pulmonary Physiology | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 8 Participants | 17 Participants | 15 Participants | 46 Participants |
| Age, Continuous | 18.9 years STANDARD_DEVIATION 2 | 20.8 years STANDARD_DEVIATION 2.4 | 20.0 years STANDARD_DEVIATION 2.1 | 19.9 years STANDARD_DEVIATION 2 | 20.0 years STANDARD_DEVIATION 2.1 |
| Region of Enrollment United States | 8 participants | 9 participants | 20 participants | 18 participants | 55 participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 8 Participants | 11 Participants | 27 Participants |
| Sex: Female, Male Male | 6 Participants | 3 Participants | 12 Participants | 7 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 7 | 0 / 9 | 0 / 18 |
| serious Total, serious adverse events | 0 / 20 | 0 / 7 | 0 / 9 | 0 / 18 |
Outcome results
Primary
Airway Wall Thickness
Segmental average airway wall thickness
Time frame: Measured at Year 2
Population: There were 43 participants with Chest CT data; 1 was excluded from the analysis due to incidental finding of an anatomical congenital anomaly.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Persistent Obstruction | Airway Wall Thickness | 1.5 mm | Standard Deviation 0.2 |
| Late Obstruction | Airway Wall Thickness | 1.5 mm | Standard Deviation 0.2 |
| Late Normal | Airway Wall Thickness | 1.4 mm | Standard Deviation 0.1 |
| Persistent Normal | Airway Wall Thickness | 1.6 mm | Standard Deviation 0.3 |
Comparison: Is there a difference in airway wall thickness among the 4 groups?p-value: 0.2ANOVA
Secondary
Protease/Antiprotease
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.
Time frame: Measured at Year 2
Population: 54 participants had induced sputum data but 1 was excluded due to congenital anatomical anomaly (bronchial atresia).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Persistent Obstruction | Protease/Antiprotease | 34.1 ratio | Standard Deviation 58.8 |
| Late Obstruction | Protease/Antiprotease | 29.3 ratio | Standard Deviation 31.3 |
| Late Normal | Protease/Antiprotease | 9.9 ratio | Standard Deviation 8.4 |
| Persistent Normal | Protease/Antiprotease | 12.1 ratio | Standard Deviation 9 |