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An Update on Severe Asthma

The Epidemiology of Severe Asthma: The TENOR Study and SARP (NIH)

Eugene R. Bleecker, MD
Thomas H. Davis Professor of Pulmonary Medicine
Section Head, Pulmonary, Critical Care, Allergy and Immunologic Diseases
Co-Director, Center for Human Genomics
Winston-Salem, NC USA

"Severe Asthma" consists of up to 20% of asthma patients who have frequent and severe symptoms despite aggressive therapy with anti-inflammatory as well as other controller medications. They often have fixed and progressive reductions in pulmonary function that do not reverse completely either after intense acute or long-term therapy. These abnormalities in lung function may reflect structural changes in the airways that have been classified as "airway remodeling". The varied clinical patterns found in severe asthma may reflect genetic differences that regulate bronchial inflammation and interact with environmental stimuli resulting in the characteristic pathophysiologic abnormalities as well as propensity to airway remodeling. In addition, pharmacogenetic responses may alter expected therapeutic responses and influence asthma severity. Thus, it is important to understand and characterize the clinical and inflammatory phenotyes in patients with severe asthma. Specific disease patterns may emerge during this comprehensive phenotype evaluation (including biomarkers), which would allow us to better understand the pathogenesis, development and treatment of more severe asthma.

The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimes (TENOR) study was a two to three year multi-center observational cohort study of asthmatics described as "difficult to treat" by their physicians, sponsored by Genentech and Novartis. It was not a clinical trial but rather a longitudinal cohort study of 4,756 patients (15% African American, 6.4% Hispanic, and 1.5% Asian or Pacific Islanders) with asthma aged 6 or older from 283 clinical centers including managed care, HMO, community and academic centers. Subjects were included if they had physician-characterized difficult-to-treat asthma, and met additional criteria based on frequency of urgent care visits and/or the use of multiple controller medications. In this group of asthmatics , 44.6% met the NHLBI National Asthma Education and Prevention Program (NAEPP) expert panel guidelines for severe persistent asthma, 27.5% for moderate persistent asthma, and 27.8% for mile persistent asthma. All subjects were evaluated initially with comprehensive questionnaires and laboratory testing, and were seen every 6 months during the remaining 2-3 years of the study. Detailed phenotypic information collected includes information on asthma exacerbations, medication use, urgent care visits, quality of life, pulmonary function tests (spirometry with reversibility), total serum IgE levels and history of allergies. Difficult-to-treat or severe asthma is common, representing a significant subset of asthmatics, estimated at 20% of patients with asthma. In addition, these severe asthmatics use disproportionately more healthcare resources.

The NIH (NHLBI) Severe Asthma Research Program (SARP) has characterized over 1000 asthmatics of varying severity (and ~200 normal controls), including over 400 subjects with severe asthma. All subjects underwent detailed clinical, physiologic, inflammatory and in a subset, radiologic phenotyping. In addition, DNA from all SARP subjects is being genotyped using the Illumina 1 million SNP ship for Genome Wide Associations Studies (GWAS) analysis as part of the NHLBI funded STAMPEED project. Investigative bronchoscopies are routinely performed as part of each of the independent SARP research projects.

While the NAEPP expert panel guidelines represent an important approach to classify asthma severity, the guidelines have well recognized problems which limit their use in clinical practice and clinical research. For example, the need to classify severity of patients when they are "off" medications is both impractical and, for the severe of difficult-to-treat asthmatic, can be dangerous. In addition, clinical investigators have recognized that asthmatics labeled "severe" can be characterized by several different clinical patterns of disease expression. In some patients, frequent and severe symptoms occur despite aggressive therapy with anti-inflammatory as well as other controller medications. Other patients with asthma have fixed and progressive reductions in pulmonary function that do not reverse completely either after intense acute or long-term therapy. These abnormalities in lung function may reflect structural changes in the airways that have been classified as "airway remodeling".

The varied clinical patterns found in difficult-to-treat and severe asthma almost certainly reflect genetic differences interacting with environmental factors that regulate bronchial inflammation resulting in characteristic pathophysiologic abnormalities, the propensity for airway remodeling, and different responses to asthma controller therapy. Pharmacogenetic responses may be particularly important in these patients since the more difficult-to-treat asthma patients may not respond as well to controller therapies as do other asthmatics. Thus, it is important to carefully define and characterize the phenotypic characteristics of difficult-to-treat and severe asthma in large population samples throughout the world.


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