Asthma, Atopy
Conditions
Keywords
Asthma, Allergen Challenge, Cat allergen, Dust mite allergen, Airway Hyper-responsiveness, Positron Emission Tomography - Computed Tomography, Nitrogen isotopes, Blood flow
Brief summary
Asthma is a disease of rapidly increasing incidence that already affects more than 17 million people in the United States alone. It has long been known that areas of severely reduced airflow occur in asthma and contribute significantly to the impairment of gas exchange in this disease. However, the extent to which local blood flow changes during an asthmatic attack is unclear. The purpose of this study is using Positron Emission Tomography - Computed Tomography imaging to evaluate how the blood flow changes in the lungs during an asthma attack induced by allergens.
Detailed description
Asthma is a disease of rapidly increasing incidence that already affects more than 17 million people in the United States alone. It is of major importance to understand the mechanisms responsible for underlying mechanical and physiological changes that occur during asthma exacerbations. The effect of asthma on the pulmonary vasculature is virtually unknown. It has long been known that areas of severely reduced airflow occur in asthma and contribute significantly to the impairment of gas exchange in this disease. However, the extent to which local blood flow changes during an asthmatic attack is unclear. This proposal is designed to evaluate the relevance of potential mechanisms responsible for the blood flow defects seen in our Positron Emission Tomography studies of subjects with asthma and identify factors modifying that perfusion distribution. With this knowledge, it is hoped that a more focused basic research is motivated to understand the fundamental mechanisms behind these processes ultimately targeted to improved asthma therapy. Comparing these measures in healthy subjects and asthmatics patients may lead to methods to improve patient care.
Interventions
BIOLOGICALStandardized Cat Allergen Extract and Standardized Dust Mite Allergen
The route of administration will be topical application of the titrated allergen via nebulized droplets to the lungs. The starting dose of allergen will be 3 dose dilutions below the estimated provocative concentration of allergen that causes a 20% fall in Forced Expired Volume in 1 second delivered for 5 minutes at tidal breathing, followed by Forced Expired Volume in 1 second at 10-minute intervals until the lowest Forced Expired Volume in 1 second is established. If the percent of Forced Expired Volume in 1 second fall is \< 20%, the next concentration is given, until the Forced Expired Volume in 1 second falls ≥ 20 percent. When this happens the Forced Expired Volume in 1 second will be followed at 10, 20, 30, 45, and 60 minutes, then hourly for 7 hours. The early asthmatic response is the maximum percent of Forced Expired Volume in 1 second fall between 0 and 3 hours and the late asthmatic response between 3 and 7 hours post allergen challenge.
RADIATIONComputed Tomography imaging, functional Positron Emission Tomography imaging
Physiology study using Computed Tomography and Positron Emission Tomography imaging with Nitrogen-13 saline as radiotracer; images obtained during the early and late phases after allergen challenge
DRUGNebulized methacholine inhalation
Standard methacholine challenge performed once to determine the subject's dose that causes a 20% fall in Forced Expired Volume in 1 second from baseline.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Massachusetts General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Mild asthma is defined in the National Institutes of Health 2002 guidelines for the Diagnosis and Management of Asthma. Briefly, people with mild asthma are defined as those with symptoms greater than 2 times a week but less than once per day with normal Forced Expired Volume in 1 second (\> 80% predicted) * Clinical history of allergic symptoms to cat or dust mite allergen and demonstrated skin reactivity * Life-long absence of cigarette smoking (defined as a lifetime total of less than 5 pack-years); none in 5 years * Willing and able to give informed consent * Expressed the desire to participate in an interview with the principal investigator
Exclusion criteria
* Women of childbearing potential who are documented to be pregnant (based on blood testing) or who are nursing. * The presence of spontaneous asthmatic episode or clinical evidence of upper respiratory tract infection within the previous 6 weeks. * Participation in research study involving a drug or biologic during the 30 days prior to the study. * Intolerance to albuterol, atropine, or lidocaine. * Antihistamines within 7 days of the screening visit. * Known exposure to agents that are associated with pulmonary disease (i.e. asbestos, silica). * Presence of other known pulmonary disease, coronary disease, congestive heart failure, ventricular arrhythmias, history of a cerebrovascular accident, renal failure (or creatinine \> 1.5, if known), history of anaphylaxis, cirrhosis or presence of a significant disease, which in the opinion of the principal investigator, would pose a significant risk for the subject or confound the results of the study. * Use of systemic steroids, increased use of inhaled steroids, beta blockers and mono-amine oxidase inhibitors or a visit for an asthma exacerbation within 1 month of the screening visit. * A history of asthma-related respiratory failure requiring intubation. * A history of hospitalization for asthma. * Subjects with a high possibility of poor compliance with the study as judged by the principal investigator. * History of contrast dye allergy. * Unresponsive to bronchodilator agents. * Quantitative skin prick test at or below a dilution level of standardized cat allergen extract of 1:2048 (4.88 bioequivalent allergy unit/ml)for subjects being challenged with cat allergen. * Quantitative skin prick test at or below a dilution level of standardized mite allergen extract of 1:2048 (4.88 bioequivalent allergy unit/ml)for subjects being challenged with either mite allergen. * Subjects who, by participating in one of these studies, will have a cumulative radiation dose exceeding the maximum yearly recommended dose for a research subject (50 milliSieverts). * Previous participation in one of the protocols in this proposal. * Contraindication to methacholine challenge testing (Forced Expired Volume in 1 second \< 50% predicted or \< 1L, heart attack or stroke in last 3 months, uncontrolled hypertension, or known aortic aneurysm). * Body Mass Index \> 32
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in the Ratio of Mean-normalized Perfusion Within Ventilation Defective Regions Relative to Outside | 3 hours after allergen administration | Blood flow relative to the mean blood flow of the lung (mean normalized perfusion) inside areas that have reduced ventilation (Vdefs) relative to outside the Vdefs. Or, another way of writing this is: (Blood flow inside Vdefs/mean blood flow of the lung)/(Blood flow outside Vdefs/mean blood flow of the lung). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Coefficient of Variation Squared of Perfusion | 3 hours after allergen administration | Coefficient of variation squared of the perfusion in the imaged lung. This measures the overall heterogeneity of perfusion in the imaged lung. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited using an IRB approved advertisement from December 2012 - January 2013. Potential subjects completed two screening visits, during which the informed consent was obtained, clinical assessment, spirometry, methacholine challenge and allergic skin tests were performed. All screening visits took place at our pulmonary clinics.
Pre-assignment details
This is a single group design study. Subjects were instructed to withhold their asthma and allergy medications before the screening and bronchial allergen challenge tests. The duration of the medication withholding depended on which medications they were using at that time.
Participants by arm
| Arm | Count |
|---|---|
| Allergic Asthmatic Standardized Cat Allergen Extract and Standardized Dust Mite Allergen: The route of administration will be topical application of the titrated allergen via nebulized droplets to the lungs. The starting dose of allergen will be 3 dose dilutions below the estimated PC20-allergen delivered for 5 minutes at tidal breathing, followed by FEV1 at 10-minute intervals until the lowest FEV1 is established. If the %FEV1 fall is \< 20%, the next concentration is given, until the FEV1 falls ≥ 20%. When this happens the FEV1 will be followed at 10, 20, 30, 45, and 60 minutes, then hourly for 7 hours. The early asthmatic response is the maximum %FEV1 fall between 0 and 3 hours and the late asthmatic response between 3 and 7 hours post allergen challenge.CT imaging, functional PET imaging: Physiology study using CT and PET imaging with Nitrogen-13 (13NN) saline as radiotracer; images obtained during the early and late phases after allergen challenge. Nebulized methacholine inhalation: Standard | 7 |
| Total | 7 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not meet all eligibility criteria | 1 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Allergic Asthmatic |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 22.7 years STANDARD_DEVIATION 5.08 |
| Region of Enrollment United States | 7 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Percentage Change in the Ratio of Mean-normalized Perfusion Within Ventilation Defective Regions Relative to Outside
Blood flow relative to the mean blood flow of the lung (mean normalized perfusion) inside areas that have reduced ventilation (Vdefs) relative to outside the Vdefs. Or, another way of writing this is: (Blood flow inside Vdefs/mean blood flow of the lung)/(Blood flow outside Vdefs/mean blood flow of the lung).
Time frame: 3 hours after allergen administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allergic Asthmatic | Percentage Change in the Ratio of Mean-normalized Perfusion Within Ventilation Defective Regions Relative to Outside | -17.8 percentage | Standard Deviation 5.1 |
Primary
Percentage Change in the Ratio of Mean-normalized Perfusion Within Ventilation Defective Regions Relative to Outside
Blood flow relative to the mean blood flow of the lung (mean normalized perfusion) inside areas that have reduced ventilation (Vdefs) relative to outside the Vdefs. Or, another way of writing this is: (Blood flow inside Vdefs/mean blood flow of the lung)/(Blood flow outside Vdefs/mean blood flow of the lung).
Time frame: 7 hours after allergen administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allergic Asthmatic | Percentage Change in the Ratio of Mean-normalized Perfusion Within Ventilation Defective Regions Relative to Outside | -26.3 percentage | Standard Deviation 9.8 |
Secondary
Coefficient of Variation Squared of Perfusion
Coefficient of variation squared of the perfusion in the imaged lung. This measures the overall heterogeneity of perfusion in the imaged lung.
Time frame: 3 hours after allergen administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allergic Asthmatic | Coefficient of Variation Squared of Perfusion | 0.11 unitless | Standard Deviation 0.03 |
Secondary
Coefficient of Variation Squared of Perfusion
Coefficient of variation squared of the perfusion in the imaged lung. This measures the overall heterogeneity of perfusion in the imaged lung.
Time frame: 7 hours after allergen administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Allergic Asthmatic | Coefficient of Variation Squared of Perfusion | 0.15 unitless | Standard Deviation 0.07 |