PEEP as Rescue Therapy for Asthmatics With Elevated BMI

The purpose of this study is to test the effect of increasing lung volume with a simple hand-held device to both prevent, and also to relieve, airway constriction in people with asthma and a BMI ≥ 30 kg/m2. Twenty people with late onset non-allergic asthma and a BMI of ≥ 30 kg/m2 will be recruited. The efficacy of elevating lung volume on both preventing and reversing bronchoconstriction will be tested. Lung volume will be modulated by breathing out against a small level of resistance (positive expiratory pressure).

This study will investigate whether PEEP can prevent and/or reverse bronchoconstriction in asthmatics with a BMI > 30 kg/m2. People with late-onset non-allergic asthma that develops in the setting of obesity do not respond well to conventional asthma medications, likely because all treatments for asthma have been developed to treat early-onset allergic disease in lean patients. There is a critical need to understand the pathophysiology of airway disease in late-onset, non-allergic obese asthmatics, in order to develop therapies to target this disease. Airway hyperresponsiveness (AHR) is a defining characteristic in asthma. Lung function tests in individuals with late onset asthma in the setting of obesity are suggestive of distal airway closure rather than airway narrowing as a cause of hyperresponsiveness; these individuals tend to have more collapsible lung peripheries than obese individuals who do not develop asthma. If late onset asthma in obesity is related to a tendency of airways to close, it should respond to therapies designed to keep airways open, such as Positive End-Expiratory Pressure (PEEP). The purpose of this study is to investigate the efficacy of PEEP on prevention and reversal of bronchoconstriction in obese people with asthma. This will be achieved by investigating the efficacy of PEEP therapy on preventing and reversing bronchoconstriction in response to the inhalation of methacholine, while measuring changes in respiratory impedance using the forced oscillation method. Participants will initially perform a conventional methacholine challenge test. Participants will return for 2 visits in which methacholine will be administered concurrently with varying levels of PEEP (using PEEP to prevent bronchoconstriction) while measuring changes in respiratory impedance using the forced oscillation method. Participants will return for another 2 visits in which PEEP will be administered subsequent to methacholine challenge (using PEEP to reverse bronchoconstriction) while measuring changes in respiratory impedance using the forced oscillation method. These studies will be completed over 5 visits.

Intervention: Positive expiratory pressure (PEEP) 10 will be applied after the administration of methacholine

Intervention: Positive expiratory pressure (PEEP) 10 will be applied during the administration of methacholine

Intervention: Positive expiratory pressure (PEEP) 0 will be applied during the administration of methacholine

Investigators will compare changes in respiratory system impedance across the two levels of PEEP (PEEP 10 and PEEP 0) for participants being exposed to PEEP during methacholine and PEEP after methacholine separately.

Investigators will compare changes in respiratory symptoms across the two levels of PEEP (PEEP 10 and PEEP 0) for participants being exposed to PEEP during methacholine and PEEP after methacholine separately.

Inclusion Criteria: PC20 to methacholine < 16 mg/ml Asthma diagnosis when ≥ 18 years of age Serum Immunoglobulin E < 100 IU/ml Ages ≥ 18 years BMI ≥ 30 kg/m2 Exclusion Criteria: Asthma exacerbation (defined as a hospitalization, ED visit, urgent care visit for asthma or new corticosteroids for asthma) in prior 6 weeks. Forced Expiratory Volume in 1 second < 60 % predicted Other significant disease that in the opinion of the investigator would interfere with study Inability to perform required testing. Smoking within last 6 months. ≥ 20 pack year smoking history Inability to provide informed consent Pregnancy

Results will be published in the archival literature, and this will include a complete description of experimental and analytical methods used. All original experimental data will be stored and available to interested investigators with appropriate regulatory approvals in place.

Al-Alwan A, Bates JH, Chapman DG, Kaminsky DA, DeSarno MJ, Irvin CG, Dixon AE. The nonallergic asthma of obesity. A matter of distal lung compliance. Am J Respir Crit Care Med. 2014 Jun 15;189(12):1494-502. doi: 10.1164/rccm.201401-0178OC.

Chapman DG, Irvin CG, Kaminsky DA, Forgione PM, Bates JH, Dixon AE. Influence of distinct asthma phenotypes on lung function following weight loss in the obese. Respirology. 2014 Nov;19(8):1170-7. doi: 10.1111/resp.12368. Epub 2014 Aug 19.