With the overall goal of understanding the mechanisms by which inhaled corticosteroids lead to systemic clinical benefits in individuals with Sickle Cell Disease (SCD) who do not have asthma, we have assembled a team of experts in hematology, pulmonology, immunology and SCD patient engagement with state-of-the-art capabilities for phenotyping pulmonary and systemic inflammation, vascular injury, functional status and patient reported outcomes. In SCD, sickling is caused by de-oxygenation of blood and reversed in the lung. Pulmonary inflammation interferes with re-oxygenation and potentiates further sickling, hemolysis, inflammation and vaso- occlusion. Over the last decade, our group and others demonstrated that pulmonary inflammation is present in SCD mice, that symptoms of episodic cough or wheeze (ECW) occur in half of SCD patients who do not meet criteria for a diagnosis of asthma and that ECW is a risk factor for increased SCD-related pain and death. In a pilot trial, inhaled steroids reduced systemic inflammation, hemolysis and daily pain with trends towards substantial reductions in healthcare utilization. Our global hypothesis is that inhaled steroids improve systemic inflammation and vascular injury in non-asthmatic SCD patients with ECW. To test this hypothesis, we will complete the following aims: AIM 1A: Compare pulmonary inflammation profiles in non-asthmatic SCD patients with and without ECW and, AIM 1B: Determine the effect of inhaled steroids on pulmonary inflammation in non-asthmatic SCD patients with ECW. AIM 2: Determine the effect of inhaled steroids on peripheral blood inflammatory and hemolytic signatures in non-asthmatic individuals with SCD and ECW. AIM 3: Establish a safety protocol for using inhaled steroids in an urban SCD clinical trial setting for 1 year. We will analyze induced sputum and blood using mass cytometry by time of flight (CyTOF - which has several advantages over flow cytometry) and multiplex assays, to define patterns of pulmonary and systemic inflammation that underlie the clinical phenomenon of ECW in SCD and to determine the effects of inhaled steroids on those inflammatory patterns. Once complete, we will use the knowledge gained to design a phase III trial of inhaled steroids for non-asthmatic individuals with SCD.