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

项目摘要/摘要 研究：与美国患有镰状细胞性贫血(SCA)的儿童相反，后者会出现功能障碍、萎缩 脾到5岁时，撒哈拉以南非洲的SCA儿童经常有脾肿大，但它的功能 病情和临床后果尚不清楚。这项研究的长期目标是了解 撒哈拉以南地区儿童SCA的病因、病理生理学和脾肿大的临床后果 非洲。这项建议的目的是调查脾肿大的病因和临床效果。 在大量SCA儿童接受羟基脲治疗后，参加了前瞻性治疗试验 (球体，NCT03948867)。候选人的辅助试验将收集两个脾的连续测量数据 体积(三维超声)和脾功能(Howell Jolly小体、凹陷红细胞和 特定病毒血清学)在球群和地址的观察组和治疗组中 这些具体目标：1)在治疗前确定与脾肿大相关的因素和相关解剖。 (三维体积)和生理(过滤和免疫功能)和2)调查 羟基脲治疗对脾体积和功能的影响及其实验和临床效果 羟基脲与未经治疗的参与者进行比较。这些目标将检验以下假设：1) 基线脾肿大将出现在10%-20%，并与阿尔法地中海贫血和既往疟疾相关 感染；1B)治疗前的脾大小与功能无关；2A)脾肿大的发生率将 接受羟基脲治疗的儿童比未接受治疗的儿童增加一倍，并可通过治疗前预测 脾体积、HBF反应和新的疟疾感染；2B)羟基脲治疗的脾肿大将 与改善脾滤过功能和保护免疫功能有关。 职业发展计划：斯马特博士的长期目标是成为一名专注于 改善美国和全球镰状细胞疾病患者的预后。他将追求以下目标 在他的K23培训期间的目标：1)在实施严格的临床试验方面获得指导 在坦桑尼亚的SCA儿童中进行前瞻性临床试验的资源设置；2) 通过教育研讨会和实验室了解脾功能障碍在SCA中的意义 经验，包括对脾解剖和生理的定量和定性评估；以及3) 通过课程设计和数据分析获得临床试验设计经验和先进的统计方法。 环境：拟议的研究将在辛辛那提儿童医院医疗中心进行 (俄亥俄州辛辛那提)和布甘多医疗中心(坦桑尼亚姆万扎)建立了长期合作伙伴关系， 为临床和转化性研究提供强大的协作环境和基础设施， 杰出的导师，以及在镰状细胞疾病方面拥有专业知识的优秀合作者团队， 在低资源环境下的免疫学、羟基脲疗法、生物统计学和临床试验。

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.