Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

/pdf/international-ers-ats-guidelines-on-definition-evaluation-sedelwbk4v.pdf

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Although asthma has been considered as a single disease for years, recent studies have increasingly focused on its heterogeneity. The characterization of this heterogeneity has promoted the concept that asthma consists of multiple phenotypes or consistent groupings of characteristics. Asthma phenotypes were initially focused on combinations of clinical characteristics, but they are now evolving to link biology to phenotype, often through a statistically based process. Ongoing studies of large-scale, molecularly and genetically focused and extensively clinically characterized cohorts of asthma should enhance our ability to molecularly understand these phenotypes and lead to more targeted and personalized approaches to asthma therapy.

/pdf/asthma-phenotypes-the-evolution-from-clinical-to-molecular-1a6ydbpfb2.pdf

Asthma phenotypes: the evolution from clinical to molecular approaches

Rationale: The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma.Objectives: To identify novel asthma phenotypes using an unsupervised hierarchical cluster analysis.Methods: Reduction of the initial 628 variables to 34 core variables was achieved by elimination of redundant data and transformation of categorical variables into ranked ordinal composite variables. Cluster analysis was performed on 726 subjects.Measurements and Main Results: Five groups were identified. Subjects in Cluster 1 (n = 110) have early onset atopic asthma with normal lung function treated with two or fewer controller medications (82%) and minimal health care utilization. Cluster 2 (n = 321) consists of subjects with early-onset atopic asthma and preserved lung function but increased medication requirements (29% on three or more medications) and health care utilizati...

Identification of Asthma Phenotypes Using Cluster Analysis in the Severe Asthma Research Program

Background Measurement of biomarkers has been incorporated within clinical research studies of asthma to characterize the population and associate the disease with environmental and therapeutic effects. Objective National Institutes of Health institutes and federal agencies convened an expert group to propose which biomarkers should be assessed as standardized asthma outcomes in future clinical research studies. Methods We conducted a comprehensive search of the literature to identify studies that developed and/or tested asthma biomarkers. We identified biomarkers relevant to the underlying disease process progression and response to treatment. We classified the biomarkers as either core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at an National Institutes of Health–organized workshop convened in March 2010 and finalized in September 2011. Results Ten measures were identified; only 1, multiallergen screening to define atopy, is recommended as a core asthma outcome. Complete blood counts to measure total eosinophils, fractional exhaled nitric oxide (Feno), sputum eosinophils, urinary leukotrienes, and total and allergen-specific IgE are recommended as supplemental measures. Measurement of sputum polymorphonuclear leukocytes and other analytes, cortisol measures, airway imaging, breath markers, and system-wide studies (eg, genomics, proteomics) are considered as emerging outcome measures. Conclusion The working group participants propose the use of multiallergen screening in all asthma clinical trials to characterize study populations with respect to atopic status. Blood, sputum, and urine specimens should be stored in biobanks, and standard procedures should be developed to harmonize sample collection for clinical trial biorepositories.

/pdf/asthma-outcomes-biomarkers-40zqhal848.pdf

Asthma outcomes: Biomarkers

Asthma, and severe asthma, in particular, is increasingly recognized as a heterogeneous disease. While traditional views of asthma have centered around a childhood onset disease with an allergic component, several large scale network studies are now confirming that severe asthma can present in multiple different ways, only 30-50% of which meet traditional childhood onset allergic criteria. To understand the different groups better, initial studies have attempted to define phenotypes of severe asthma. A phenotype is defined as the integration of different characteristics that are the product of the interaction of the patient's genes with the environment. Both clinical and statistical approaches have identified at least 3-5 phenotypes of severe asthma. However, these phenotypes, in isolation, do not identify the immunopathology that makes these clinical phenotypes distinct or identifies a target population for a specific approach to therapy. As biological characteristics are identified, phenotypes should continue to evolve towards asthma endotypes. The identification of these endotypes, either by matching biology, genetics and therapeutic responses to therapy with clinically or statistically defined phenotypes or through unbiased genetic and genomic approaches, remains limited. Moving forward, this integration of genetics, biology and clinical characteristics should substantially enhance our ability to effectively treat complex heterogeneous diseases, such as severe asthma.

Janice Cook Granroth

Papers

A multivariate analysis of risk factors for the air-trapping asthmatic phenotype as measured by quantitative CT analysis.

Measured by Quantitative CT Analysis the Air-Trapping Asthmatic Phenotype as A Multivariate Analysis of Risk Factors for