Imaging Study of the Lungs During an Allergic Asthma Attack

Redistribution of Pulmonary Perfusion During Bronchoconstriction in Asthma

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.

Study Overview

• Status: Completed
• Conditions: Asthma; Atopy
• Intervention / Treatment: Biological: Standardized Cat Allergen Extract and Standardized Dust Mite Allergen; Radiation: Computed Tomography imaging, functional Positron Emission Tomography imaging; Drug: Nebulized methacholine inhalation

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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Allergic asthmatic

Biological: 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 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.; Other Names: •Reagents from Greer will be used:; •Standardized Cat Hair Extract; •Standardized mite extract-Dermatophagoides farinae; •Standardized mite extract-Dermatophagoides pteronyssinus; Radiation: Computed 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; Drug: Nebulized 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.; Other Names: MethaPharm Provocholine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	3 hours after allergen administration
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).	7 hours after allergen administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	3 hours after allergen administration
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.	7 hours after allergen administration

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: R. Scott Harris, MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: February 15, 2012
• First Submitted That Met QC Criteria: March 2, 2012
• First Posted (Estimate): March 7, 2012

Study Record Updates

• Last Update Posted (Actual): November 22, 2017
• Last Update Submitted That Met QC Criteria: October 19, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Keywords: Asthma; Allergen Challenge; Blood flow; Cat allergen; Dust mite allergen; Airway Hyper-responsiveness; Positron Emission Tomography - Computed Tomography; Nitrogen isotopes
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Cholinergic Agonists; Respiratory System Agents; Miotics; Parasympathomimetics; Bronchoconstrictor Agents; Muscarinic Agonists; Methacholine Chloride
• Other Study ID Numbers: 2007P002386; 1R01HL086717-01A2 (U.S. NIH Grant/Contract)