Severe, corticosteroid-insensitive asthma is observed in ~ 10% of the asthma population but accounts for the majority of the morbidity, mortality and cost associated with the disease. For nearly 10 years our group has studied airway redox disturbances in adults and children with asthma through the NIH/NHLBI Severe Asthma Research Program (SARP). Through innovative metabolomics and redox biochemistry, methodologies that are a strength and unique to our collaborative efforts, we identified clinically relevant phenotypes of asthma. The phenotypes are defined by biomarkers specific to underlying biochemical mechanistic abnormalities, including eosinophil-mediated oxidation, depletion of antioxidants and protective airway S-nitrosothiols, and airway acidification. Here, we propose to study a new component that is informative for longitudinal assessment of severe asthma phenotypes: gender effects. Severe asthma affects boys more than girls;however, severe asthma in adults is a disease of women. The age-dependent change in gender predilection is one of the largest signals in severe asthma epidemiology, but remains understudied. We reason that identification of the metabolic mechanism(s) underlying onset of severe asthma in young women during adolescence, and resolution of severe asthma in boys, will reveal fundamental pathophysiology of severe asthma. Importantly, we aim to develop clinical testing procedures to accurately assign metabolic asthma phenotypes;and to follow patients in each phenotype to uncover clinical longitudinal outcomes. At the conclusion of the project, we anticipate that we will have 1) developed clinically relevant tests to identify severe asthma phenotypes;2) determined the longitudinal outcome of the phenotypes;and 3) identified the mechanisms underlying the preponderance of women in the severe asthma population.

Public Health Relevance

Severe asthma is a major public health challenge. Whereas only 10 to 15% of all asthmatics have severe asthma, these patients account for a relatively large fraction of the total health care costs attributed to asthma. This application will focus on the development or clinically relevant metabolic tests to identify subphenotypes of adults and children with severe asthma and will lead to new targeted innovative treatments.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Cooperative Clinical Research--Cooperative Agreements (U10)
Project #
5U10HL109250-05
Application #
8680348
Study Section
Special Emphasis Panel (ZHL1-CSR-K (M2))
Program Officer
Noel, Patricia
Project Start
2011-08-08
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
$713,516
Indirect Cost
$173,192
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Teague, W Gerald; Phillips, Brenda R; Fahy, John V et al. (2018) Baseline Features of the Severe Asthma Research Program (SARP III) Cohort: Differences with Age. J Allergy Clin Immunol Pract 6:545-554.e4
Ash, Samuel Y; Rahaghi, Farbod N; Come, Carolyn E et al. (2018) Pruning of the Pulmonary Vasculature in Asthma. The Severe Asthma Research Program (SARP) Cohort. Am J Respir Crit Care Med 198:39-50
Reichard, Andrew; Wanner, Nicholas; Stuehr, Eric et al. (2018) Quantification of airway fibrosis in asthma by flow cytometry. Cytometry A 93:952-958
Wisniewski, Julia A; Muehling, Lyndsey M; Eccles, Jacob D et al. (2018) TH1 signatures are present in the lower airways of children with severe asthma, regardless of allergic status. J Allergy Clin Immunol 141:2048-2060.e13
Asosingh, Kewal; Weiss, Kelly; Queisser, Kimberly et al. (2018) Endothelial cells in the innate response to allergens and initiation of atopic asthma. J Clin Invest 128:3116-3128
Wong-McGrath, Kelly; Denlinger, Loren C; Bleecker, Eugene R et al. (2018) Internet-Based Monitoring in the Severe Asthma Research Program Identifies a Subgroup of Patients With Labile Asthma Control. Chest 153:378-386
DeBoer, Mark D; Phillips, Brenda R; Mauger, David T et al. (2018) Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma. BMC Pulm Med 18:58
Phipatanakul, Wanda; Mauger, David T; Sorkness, Ronald L et al. (2017) Effects of Age and Disease Severity on Systemic Corticosteroid Responses in Asthma. Am J Respir Crit Care Med 195:1439-1448
Duvall, Melody G; Barnig, Cindy; Cernadas, Manuela et al. (2017) Natural killer cell-mediated inflammation resolution is disabled in severe asthma. Sci Immunol 2:
Denlinger, Loren C; Phillips, Brenda R; Ramratnam, Sima et al. (2017) Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med 195:302-313

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