Severe asthma is a heterogeneous disease with distinct clinical phenotypes characterized by differences in susceptibility to exacerbation, loss of lung function, chronic mucus hypersecretion, and refractoriness to anti- inflammatory therapy. Our objectives are to define severe asthma phenotypes at the molecular and cellular level longitudinally in order to predict prognosis, identify novel treatment targets, and guide targeted therapy. Our overarching hypothesis is that differences in clinical presentation, outcomes, and response to therapy in severe asthma are driven by: 1) distinct types of airway inflammation and remodeling developed and maintained by specific molecular pathways; 2) microbial colonization or infection; 3) genetic/epigenetic factors. Aim 1 proposes a shared longitudinal protocol to identify and validate phenotypic characteristics of severe asthma based on underlying pathobiology and pathophysiology. Our protocol incorporates a two- phase design with an initial six-month phase of supervised guideline-based therapy to document baseline clinical and molecular phenotypes, the stability of these phenotypes over time, and response to standardized therapy. This initial phase will be followed by a 2.5 year follow-up phase to document exacerbation frequency and rate of loss of lung function. Aim 2 will explore mechanisms of pathologic mucus in severe asthma in two sub-aims that will both use rheology to quantify the viscoelastic properties of induced sputum from patients with chronic severe asthma. We will identify subgroups of severe asthmatics with chronic mucus hypersecretion and abnormal mucus rheology, determine the clinical and biological characteristics of these subgroups, and explore in ex vivo studies the role of multimeric lectins as cross-linkers of mucin polymers and potential targets of glycomimetic therapy. Included in the lectins we will study will be Aspergillus fumigatus lectin, a fucose binding lectin that we hypothesize to have a pathogenic role in the mechanism of mucus plug formation in Allergic Bronchopulmonary Aspergillosis, an important subtype of severe asthma. Severe asthma occurs in 5-10% of asthmatics and accounts for much of the public health burden of the disease. Patients with severe asthma have unmet therapeutic needs because many respond sub-optimally to currently available treatments. To improve treatment for severe asthma it will be necessary to have a better understanding of the mechanisms of disease to guide targeted therapy.