Sickle Cell Anemia, Splenic Pathology, and Hydroxyurea in Sub-Saharan Africa

项目总结/摘要 研究：与美国患有镰状细胞性贫血（SCA）的儿童相反， 在撒哈拉以南非洲，患有SCA的儿童在5岁时通常会有脾肿大，但其功能性 状态和临床结果未知。这项研究的长期目标是了解 撒哈拉以南非洲SCA患儿脾肿大的病因、病理生理学和临床后果 非洲本研究的目的是探讨脾肿大的病因和临床效果， 在一项前瞻性治疗试验中， （SPHERE，NCT 03948867）。候选人的辅助试验将收集两个脾脏的连续测量结果， 体积（三维超声）和脾功能（豪厄尔乔利小体，红细胞凹陷， SPHERE队列的观察组和治疗组中的特异性病毒血清学）， 这些特定的目的：1）在治疗前确定与脾肿大相关的因素， （3维体积）与生理学（过滤和免疫功能）和2）研究的变化， 羟基脲治疗期间脾脏体积和功能以及 与未经治疗的参与者相比。这些目标将检验以下假设：1A） 基线脾肿大将出现在10-20%，并与α地中海贫血和既往疟疾相关 感染; 1B）治疗前脾脏大小与功能无关; 2A）脾肿大的发生率将 接受羟基脲治疗的儿童中，与未接受治疗的儿童相比， 脾体积、HbF反应和新疟疾感染; 2B）用羟基脲治疗的脾肿大将 与改善脾过滤功能和保护免疫功能有关。 职业发展计划：Smart博士的长期目标是成为一名独立的研究者，专注于 改善美国和全球镰状细胞病患者的预后。他将致力于以下工作： 在他的K23培训目标：1）获得指导，在低- 通过在坦桑尼亚SCA儿童中进行前瞻性临床试验， 通过教育研讨会和实验室了解脾功能障碍在SCA中的重要性 包括脾脏解剖学和生理学的定量和定性评估的经验;以及3） 通过课程和数据分析获得临床试验设计和先进统计方法的经验。 环境：拟定研究将在辛辛那提儿童医院医学中心进行 （辛辛那提，俄亥俄州）和Bugando医疗中心（姆万扎，坦桑尼亚），他们有着长期的合作伙伴关系， 为临床和转化研究提供了强大的协作环境和基础设施， 杰出的指导，以及在镰状细胞病方面具有专业知识的优秀合作者团队， 免疫学、羟基脲疗法、生物统计学和低资源环境下的临床试验。

PROJECT SUMMARY/ABSTRACT Research: Contrary to children in the US with sickle cell anemia (SCA) who develop dysfunctional, atrophic spleens by 5 years old, children with SCA in sub-Saharan Africa often have splenomegaly, but its functional status and clinical consequences are unknown. The long-term goal of this research is to understand the etiology, pathophysiology, and clinical consequences of splenomegaly in children with SCA in sub-Saharan Africa. The goal of this proposal is to investigate the etiology and clinical effects of splenomegaly both before and after hydroxyurea treatment in a large cohort of children with SCA, enrolled in a prospective treatment trial (SPHERE, NCT03948867). The candidate's ancillary trial will collect serial measurements of both splenic volume (3-dimensional ultrasound) and splenic function (Howell Jolly bodies, pitted red blood cells, and specific viral serologies) in both the observation and the treatment groups of the SPHERE cohort and address these specific aims: 1) identify factors associated with splenomegaly prior to treatment and correlate anatomy (3-dimensional volume) with physiology (filtrative and immunological functions) and 2) investigate changes in splenic volume and function during hydroxyurea treatment as well as laboratory and clinical effects of hydroxyurea compared to untreated participants. These aims will test the following hypotheses: 1A) baseline splenomegaly will be present in 10-20% and associated with alpha thalassemia and previous malaria infections; 1B) pre-treatment splenic size will not correlate with function; 2A) incidence of splenomegaly will double in children receiving hydroxyurea compared to untreated children and be predicted by pre-treatment splenic volume, HbF response, and new malarial infections; 2B) splenomegaly with hydroxyurea treatment will be associated with improved splenic filtrative function and preserved immunological function. Career Development Plan: Dr. Smart's long-term goal is to become an independent investigator focused on improving outcomes for persons with sickle cell disease in the US and globally. He will pursue the following objectives during his K23 training: 1) obtain mentorship in the implementation of rigorous clinical trials in low- resource settings by conducting a prospective clinical trial among children with SCA in Tanzania; 2) understand the significance of splenic dysfunction in SCA through educational seminars and laboratory experience that includes quantitative and qualitative assessments of spleen anatomy and physiology; and 3) gain experience in clinical trial design and advanced statistical methods through coursework and data analysis. Environment: The proposed research will be conducted at Cincinnati Children's Hospital Medical Center (Cincinnati, Ohio) and Bugando Medical Centre (Mwanza, Tanzania) who have a longstanding partnership that provides a strong collaborative environment with infrastructure for clinical and translational research, outstanding mentorship, and an excellent team of collaborators with expertise in sickle cell disease, immunology, hydroxyurea therapy, biostatistics, and clinical trials in low-resource settings.