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

项目摘要 风湿性心脏病（RHD）是年轻人获得性心脏病发病率和死亡率的主要原因 国际吧风湿性心脏病是急性风湿热（ARF）的并发症，由于链球菌性咽喉炎（致病性） 化脓性链球菌（Streptococcus pyogenes）。虽然链球菌性咽喉炎在儿科人群中很常见， 的感染患者将发展为严重的ARF和RHD临床并发症。目前，我们不能 预测哪些孩子会发展成更严重的疾病。流行病学和临床病理学 风湿性心脏病是一个复杂的和不明确的。自2000年以来，美国风湿性心脏病的发病率急剧下降。 早在1900年代，虽然链球菌咽喉炎的发病率一直保持不变。在高收入国家，即使 链球菌性咽喉炎没有得到适当的治疗，ARF和RHD非常罕见。相反，风湿性心脏病和链球菌性咽喉炎 在低收入和中等收入国家，这两个问题仍然很严重。有趣的是，最初的下降 在定期使用青霉素之前就注意到了临床病例。然而，这种下降确实， 与实施更严格的卫生习惯和减轻儿童负担相一致 寄生虫感染许多低收入国家，如马拉维，继续在寄生虫感染的沉重负担中挣扎， 和风湿性心脏病寄生虫感染会引起几种全身性健康问题，如营养不良， 缺乏，认知障碍和继发感染的易感性增加。最重要的是，某些 寄生虫感染使免疫特征偏向Th2先天性和适应性应答。我们认为这 寄生虫感染引起的免疫反应不平衡是ARF和RHD发展的驱动因素， 喉咙发炎的人本研究的目的是探讨由于合并感染， 胃肠道寄生虫在链球菌性咽喉炎发展为急性肾功能衰竭中的作用我们假设， 在马拉维的一个高度流行地区，ARF更常见的是与一种或多种寄生虫合并感染 当与年龄匹配的对照组相比时，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。本研究的总体目标是 确定ARF和RHD患者的寄生虫合并感染是否显著更高，并确定 免疫系统我们的目标如下：（1）确定儿童寄生虫感染的流行情况， 与年龄匹配的对照组相比，在马拉维的卫生保健中心就诊的急性风湿热患者，（2） 与年龄匹配的对照组相比，检查ARF儿童的免疫失调程度。我们的整体 这项研究的预期结果是，我们将确定寄生虫负荷和ARF之间的相关性， 解释了增加严重疾病风险的免疫失衡。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策略的目标。我们 我相信这是确定ARF和RHD潜在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.