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

撒哈拉以南非洲地区的镰状细胞性贫血、脾脏病理学和羟基脲

• 批准号: 10040082
• 负责人: Luke Smart
• 金额: $ 16.96万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-21 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10040082
• 关键词: 18 year old; 3-Dimensional; 5 year old; Address; Adult; Affect; Africa; Africa South of the Sahara; African; Age; Age-Months; Anatomy; Atrophic; Attention; Biometry; Cell Adhesion; Child; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Country; Data; Data Analyses; Development Plans; Diagnosis; Disease; Dose; Enrollment; Environment; Erythrocytes; Etiology; Event; Fetal Hemoglobin; Filtration; Frequencies; Functional disorder; Future; Goals; Guidelines; Hematological Disease; Immune response; Immunology; Incidence; Infection; Inflammation; Inherited; Knowledge; Laboratories; Life; Malaria; Maximum Tolerated Dose; Measurement; Medical center; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Neonatal Screening; Ohio; Organ; Outcome; Palpable; Participant; Pathology; Patients; Pediatric Hospitals; Penicillins; Persons; Physiology; Predisposition; Prevalence; Prevention program; Prophylactic treatment; Publishing; Research; Research Personnel; Resources; Risk; Risk Factors; Safety; Serologic tests; Sickle Cell; Sickle Cell Anemia; Spleen; Splenomegaly; Statistical Methods; Stroke; Stroke prevention; Tanzania; Testing; Time; Toxic effect; Training; Transfusion; Translational Research; Ultrasonography; United States Food and Drug Administration; Vaccination; Vaccines; Viral; Work; alpha thalassemia minor; alpha-Thalassemia; base; blood rheology; career development; clinical effect; clinical infrastructure; cohort; collaborative environment; effective therapy; evidence base; experience; functional status; hydroxyurea; immune function; improved; improved outcome; laboratory experience; malaria infection; mortality; peripheral blood; preservation; programs; prospective; response; safety and feasibility; screening program; treatment comparison; treatment group; treatment trial

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.

项目摘要/摘要 研究：与美国的儿童患有镰状细胞贫血（SCA），他们患有功能失调，萎缩 5岁的脾脏，撒哈拉​​以南非洲有SCA的儿童经常有脾肿大，但其功能性 状态和临床后果尚不清楚。这项研究的长期目标是了解 撒哈拉以下儿童脾肿大的病因，病理生理学和临床后果 非洲。该提议的目的是研究脾肿大的病因和临床作用 在大量SCA儿童中羟基脲治疗后，参加了一项前瞻性治疗试验 （Sphere，NCT03948867）。候选人的辅助试验将收集两种脾 体积（3维超声）和脾功能（Howell Jolly身体，斑点红细胞和 特定的病毒血清学）在球体队列的观察和治疗组中均可和地址 这些具体目的：1）在治疗前确定与脾肿大相关的因素并将其关联解剖 （3维体积）具有生理学（过滤和免疫功能），2）研究 羟基脲处理期间的脾气和功能以及实验室和临床作用 与未经治疗的参与者相比，羟基脲。这些目标将检验以下假设：1a） 基线脾肿大的存在为10-20％，并且与α丘脑贫血和先前的疟疾有关 感染； 1B）治疗前的脾脏大小与功能无关； 2a）脾肿大的发病率将 与未经治疗的儿童相比，接受羟基脲的儿童双重 脾气暴躁，HBF反应和新的疟疾感染； 2b）羟基脲处理的脾肿大将 与改善脾脏滤过功能和保留的免疫功能有关。 职业发展计划：Smart博士的长期目标是成为专注于的独立调查员 改善美国和全球患有镰状细胞疾病的人的结果。他将追求以下 目标在他的K23培训期间：1）在低 - 通过对坦桑尼亚SCA儿童进行前瞻性临床试验，资源环境； 2） 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 经验包括脾解剖学和生理学的定量和定性评估； 3） 通过课程和数据分析获得临床试验设计和高级统计方法的经验。 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Bugando医疗中心（坦桑尼亚姆万萨），他们长期合作 为临床和转化研究提供了强大的协作环境， 杰出的指导，以及一支拥有镰状细胞病专业知识的合作者团队， 低资源环境中的免疫学，羟基脲治疗，生物统计学和临床​​试验。