Investigating parasitism-induced immune dysregulation and susceptibility to acute rheumatic fever in children

项目总结 风湿性心脏病(RHD)是年轻人后天心脏病发病率和死亡率的主要原因 全世界。风湿性心脏病是急性风湿热(ARF)的一种并发症，由链球菌咽喉(致病)引起 化脓性链球菌)。虽然链球菌咽喉炎在儿科人群中很常见，但只有一小部分人 的患者将进展为ARF和RHD的严重临床并发症。目前，我们不能 预测哪些儿童会发展为更严重的疾病形式。流行病学与临床病理学 风湿性心脏病的定义是复杂和模糊的。风湿性心脏病在美国的发病率自 20世纪初，尽管链球菌性咽喉炎的发病率一直保持不变。在高收入国家，即使在 链球菌性咽喉没有得到适当的治疗，ARF和RHD是极其罕见的。相反，风湿性心脏病和链球菌性咽喉炎 这两个问题在低收入和中等收入国家仍然是严重的问题。有趣的是，最初的下降 临床病例在实施常规青霉素使用之前被记录下来。然而，这种下降确实是， 与实施更严格的卫生做法和减轻儿童负担相对应 寄生虫感染。许多小岛屿发展中国家，如马拉维，继续与寄生虫感染的沉重负担作斗争。 以及他们人口中的风湿性心脏病。寄生虫感染会导致几个系统性的健康问题，如营养 缺陷、认知障碍和对继发感染的易感性增加。最重要的是，确定 寄生虫感染使免疫图谱向Th2先天和适应性反应倾斜。我们相信这一点 寄生虫感染引起的免疫应答失衡是ARF和RHD发生的驱动因素 患有链球菌性咽喉炎的人。本研究旨在探讨混合感染在免疫调节中的作用。 胃肠道寄生虫在链球菌性咽喉炎向急性肾功能衰竭的进展。我们假设呈现给我们的孩子 马拉维高度流行地区的ARF通常会与一种或多种寄生虫合并感染。 与年龄匹配的对照组相比，从而提供了寄生虫诱导的免疫改变的证据 反应导致对ARF和严重疾病的易感性增加。这项研究的总体目标是 确定ARF和RHD患者的寄生虫合并感染是否显著更高，并确定 免疫特征。我们的目标如下：(1)确定儿童寄生虫感染的流行率 马拉维卫生保健中心的急性风湿热患者与年龄匹配的对照组比较(2) 与年龄匹配的对照组相比，检查ARF儿童免疫失调的程度。我们的整体 这项研究的预期结果是，我们将确定寄生虫负担与ARF和 解释会增加严重疾病风险的扭曲的免疫模式。这项研究将产生重要的数据 为更大规模的前瞻性研究提供信息，以确定公共卫生干预和治疗战略的目标。我们 相信这是确定ARF和RHD根本原因的重要的第一步。

PROJECT SUMMARY Rheumatic heart disease (RHD) is the leading cause of acquired cardiac morbidity and mortality in young people worldwide. RHD, a complication of acute rheumatic fever (ARF), develops as a result of strep throat (causative agent Streptococcus pyogenes). While strep throat is common in pediatric populations, only a small percentage of infected patients will progress to the severe clinical complications of ARF and RHD. Currently, we cannot predict which children will progress to the more severe form of disease. The epidemiology and clinical pathology of RHD is complex and ill-defined. The incidence of RHD in the United States has sharply declined since the early 1900s, though the incidence of strep throat has remained constant. In high-income countries, even when strep throat is not appropriately treated, ARF and RHD are extremely rare. Conversely, RHD and strep throat both remain significant problems in low and middle-income countries (LMIC). Interestingly, the initial decline in clinicial cases was noted prior to the implementation of regular penicilin use. This decline does, however, correspond with implementation of more rigorous hygiene practices and the reduced burden of childhood parasitic infections. Many LMICs, such as Malawi, continue to struggle with a high burden of parasitic infections and RHD within their population. Parasitic infections cause several systemic health problems such as nutritional deficiencies, cognitive impairment, and increased susceptibility to secondary infections. Most importantly, certain parasitic infections skew the immune profile towards Th2 innate and adaptive responses. We believe that this skewed immune response due to parasitic infection is a driving factor in the development of ARF and RHD in people with strep throat. This study aims to investigate the role of immune modulation due to co-infection with gastrointestinal parasites in the progression of strep throat to ARF. We hypothesize that children presenting with ARF in a highly endemic region of Malawi will more commonly have a co-infection with one or more parasite when compared to age-matched controls, thereby providing evidence that a parasite-induced altered immune response leads to increased susceptibility to ARF and severe disease. The overall goal of this study is to determine if parasite co-infection is significantly higher in ARF and RHD patients and to determine alterations to the immune profile. Our aims are as follows: (1) Identify the prevalence of parasite infections in children with acute rheumatic fever who present to health care centers in Malawi compared to age-matched controls, (2) Examine the extent of immune dysregulation in children with ARF compared to age-matched controls. Our overall expected outcome from this study is that we will identify a correlation between parasite burden and ARF and explain the skewed immune profiles that increase risk of severe disease. This study will generate important data to inform larger prospective studies to identify targets for public health intervention and treatment strategies. We believe this is an important first step in identifying underlying causes of ARF and RHD.