SARP: Dissecting subphenotypes and endotypes

In this chapter, the aims and accomplishments of the National Heart, Lung, and Blood Institute SARP are presented with emphasis on the importance of disease heterogeneity within asthma, and within severe asthma. This overview is limited to only some of the research accomplishments since the SARP investigators have published over 100 manuscripts on inflammation, genomics, subphenotypes, biomarkers and imaging in severe asthma. The initial rationale for SARP was to address the unmet needs of patients with severe or refractory asthma by the development of networks of centres to perform standardised in-depth clinical characterisation with collection of multiple samples. To dissect disease heterogeneity in severe asthma, statistical approaches that allow the data to be "grouped" into similar subsets without prior assumptions were utilised. Clinical cluster analysis was performed in SARP 1 and, subsequently, various analyses have addressed disease heterogeneity utilising more than clinical data alone by incorporating biomarkers such as sputum (airway) cells, imaging and response to corticosteroids. The important findings from SARP 3 systemic corticosteroid-induced phenotype emphasises the observed clinical and biologic responses that imply relative resistance to corticosteroids in some patients with severe asthma. Finally, multiple genetic studies have been performed identifying genes and genetic pathways important in asthma susceptibility and severity including genomic studies integrating DNA data with RNA expression from the primary disease organ of interest: lung airways cells. Understanding disease heterogeneity is essential in understanding the pathogenesis and represents the basis for targeted therapies for severe asthma.