Using real-world data to evaluate modern pharmacotherapy treatment regimens and prophylaxis for reducing infections in sickle cell disease

The National Heart, Lung, and Blood Institute awarded Vanderbilt University Medical Center $873,449 on August 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to evaluate modern pharmacotherapy treatment regimens and prophylaxis for reducing infections in sickle cell disease.

The recipient will conduct a population-based retrospective cohort study leveraging the Sickle Cell Data Collection Network (2010–2024) to assess children with sickle cell disease in Georgia, Michigan, and Tennessee. The work uses causal inference methods to test two primary hypotheses: whether the risk of hospitalization for serious infections and infection-related complications is lower among children receiving combined hydroxyurea and antibiotic prophylaxis compared with either treatment alone, and whether combined hydroxyurea with L-glutamine or crizanlizumab reduces infection risk compared with hydroxyurea monotherapy. An exploratory component examines the optimal age for cessation of antibiotic prophylaxis and the impact of adherence gaps on infection outcomes.

Work is performed in Forest Hills, Tennessee. The period of performance extends from August 15, 2026, through May 31, 2031. This is a Project Grant, an assistance type providing direct federal funding to the recipient for specified research activities.

Abstract

Children with sickle cell disease (SCD) are at a heightened risk of serious bacterial and viral infections, which significantly contribute to mortality and complications such as vaso-occlusive episodes, acute chest syndrome, and ischemic cerebrovascular accidents. Despite the reduction of invasive bacterial diseases among children with SCD over the last several decades, the persistently higher rate of infection and infection-related complications underscores the need for a modern, population-based assessment of the current real world treatment landscape, including the combined use of antibiotic prophylaxis with disease modifying therapies such as hydroxyurea (HU), L-glutamine and crizanlizumab. In addition, the changing landscape of invasive infections among children with SCD in the US necessitates a reevaluation of current recommended antibiotic prophylaxis strategies, including the ideal age for cessation and the impact of adherence gaps. To address these knowledge gaps, we propose to leverage the sickle cell data collection (SCDC) network (2010-2024) to identify a longitudinal, population-based retrospective cohort of children with SCD residing in georgia, michigan and tennessee (representing approximately 16% of the SCD population in the US) to conduct a series of studies using robust causal inference methods to evaluate the following hypotheses: hypothesis 1A: the risk of hospitalizations for serious infections and infection-related complications will be lower among those with combined HU use and antibiotic prophylaxis compared with HU or antibiotic prophylaxis only. Exploratory hypothesis 1B: the risk will be lower among those with combined HU and L-glutamine or crizanlizumab use compared with HU only. Hypothesis 2: children with SCD have a higher risk of infections and complications during periods without antibiotic prophylaxis compared to periods with prophylaxis, with increasing risks as the GAP without prophylaxis increases. Hypothesis 3A: children continuing antibiotic prophylaxis after age 5 years have a higher risk of hospitalization for infections and complications during periods without prophylaxis versus with prophylaxis. Exploratory hypothesis 3B: antibiotic prophylaxis among children after age 5 years increases the risk of antibiotic-resistant infections compared to those that do not continue antibiotic prophylaxis. This research aligns with the national heart, lung, and blood institute's strategic vision to improve SCD management and reduce complications associated with the disease. The findings will inform treatment guidelines and contribute to more personalized and effective care to reduce the risk of infections and infection-related complications, thereby improving the quality of life and health outcomes in children with SCD.