Hypoxemia with Sleep in Sickle Cell Anemia-Prevalence, Clinical and Cellular Impact & Response to Therapy: A Multi-Site Prospective Study Accessing New Collaborative Pathways - Sickle cell disease (SCD) arises from a gain-of function mutation of hemoglobin (Hb) in which sickle hemoglobin (HbS) polymerizes, but only after it has delivered its oxygen, and become deoxy-HbS. These polymers wreak havoc inside the red blood cells (RBCs), resulting in rigid, adhesive, and fragile RBCs, then anemia, inflammation, and, with time, progressive vasculopathy. SCD comprises both homozygous sickle cell anemia (SCA, HbSS or HbSb0) and variant (HbSC or HbSb+). We will focus on SCA which is more common and has been historically most affected by low oxygen or ‘hypoxemia’. A decreased oxygen level, measured as a low saturation of Hb (SpO2), likely makes SCA worse due to the central role that deoxy-HbS plays in damage from sickle cell. An association between hypoxemia during sleep and impaired brain, genitourinary, and cardiopulmonary health has been described in children with SCA. Studies of sleep-associated hypoxemia in adults have been less informative, likely due to the inability of even well-designed single site studies to fully describe subtle comorbidities. In this proposal, we will examine the prevalence, impact, and response to treatment of hypoxemia during sleep in adults with SCA, the most severe form of sickle cell disease, at 4 institutions, encompassing dense urban sites (Philadelphia, Newark) and more heterogeneous sites (Birmingham and Chapel Hill, with significant rural outreach). This multi-site study will focus on patient reported outcomes, a cognitive screening test, clinical co-morbidities, routine clinical labs, echocardiograms to identify right to left shunts (which may contribute to this low oxygen), and cellular biomarkers. We want to understand the prevalence of, and impact of treatment for, sleep hypoxemia. A secondary aim will be to identify meaningful short term RBC and plasma biomarkers, which could be helpful in better identifying and managing this comorbidity. Significant barriers to multi-site prospective studies in SCD include a lack of coordination amongst centers, inconsistent and inadequate government and foundation support, and lack of access to a longitudinal prospective national registry. (None of which are true in parallel more supported diseases such as Hemophilia and Cystic Fibrosis). Recently, there has been a sustained effort, by affected individuals living with SCD and their health care communities, to comprehensively address complications from SCD in the modern era. The American Society of Hematology clinical trials network (ASH CTN), which facilitates intra-institution coordination, and the globin research network for data and discovery (GRNDaD) registry, which streamlines longitudinal deidentified data collection at multiple sites, are two new collaborative efforts that we are accessing in order to lower barriers to multi-site studies in SCD. We do not have many treatments for SCD; there is an urgent need to identify modifiable risk-factors, such as occult sleep hypoxemia, in adults. It is possible that evaluation for sleep hypoxemia may be an important part of improved health care for adults with SCA, and this proposal seeks to begin to answer that question.
