发热伴血小板减少综合征布尼亚病毒感染病例的前瞻性队列研究

Severe fever with thrombocytopenia syndrome (SFTS) is a novel emerging infectious disease that was discovered during 2009 in the middle east of China. The disease usually presents as fever, thrombocytopenia, and leukocytopenia, with an average case-fatality rate around 12% and up to 30% in some areas. The causative agent of SFTS was identified to be a novel bunyavirus named SFTS virus (SFTSV), a novel phlebovirus in the Bunyaviridae family. Recent case report in Korea, Japan and XX demonstrated its potential wide spread outside of China, therefore indicating the imminent public health impact of this reemerging disease. After the identification of the infection, the clinical manifestations, laboratory findings and outcomes of SFTS for patients have been disclosed to some extent, but the immunological characteristics of the infection remained largely unknown. To gain a better insight into the host immunological responses, we are designed to perform a 4-year prospective study on confirmed SFTSV infected cases to acquire the dynamic changes in cellular immunity by flow cytometer technique, to prospectively observe the specific Abs using micro-neutralization assay (MNA) and enzyme linked immunosorbent assay (ELISA), to measure the memory B cell and T cell responses in patients recovering from SFTS by means of enzyme-linked immunospot (ELISPOT). The study might help to acquire their immune response dynamics over the entire hospitalization duration and correlated these patterns with clinical, virological, haematological, and treatment findings , to elucidate the impact of host immune responses on disease pathogenesis. To determine the long term protection that was elicited by the SFTSV infection, these patients were also followed up to obtain a long term humoral response. These information on immunity and pathogenesis might help to provide a comprehensive basis for specific drug or vaccine design.

发热伴血小板减少综合征（SFTS），是出现在我国的一种新型布尼亚病毒（SFTSV）通过血液感染的新发传染病，主要临床表现为急性发热、血小板和白细胞减少、胃肠道症状。大约12%住院病例进展为多器官功能障碍后死亡。作为一种新发传染病，SFTSV感染后临床发生、发展和转归等自然史尚不清楚。本课题利用我国特有的现场优势，选择病原学确诊的临床病例建立随访队列，进行为期四年的前瞻性观察，对病例急性期细胞免疫水平及其与临床预后之间的关系进行研究；对病例体液免疫水平进行长时间持续性观察，掌握IgM、IgG抗体和中和性抗体动态变化规律和持续时间；结合病例临床表现和转归评价体液免疫和细胞免疫在病原体感染中的作用，揭示病例免疫变化和转归的影响因素；评价记忆性T、B细胞的免疫应答规律，综合分析SFTSV感染后保护性免疫持久性。研究结果预期可为深入了解疾病的致病机理，指导临床治疗方案，疫苗研制和有效使用提供科学依据

发热伴血小板减少综合征（SFTS），是出现在我国的一种新型布尼亚病毒（SFTSV）通过蜱叮咬感染人的新发传染病， SFTSV感染后临床发生、发展和转归等自然史尚不清楚。课题通过四年的队列随访，开展 SFTSV感染病例细胞免疫和体液免疫特征的前瞻性观察及临床转归的危险因素研究。取得的进展包括：建立了目前为止规模最大的SFTS随访病例队列，获得 SFTSV感染病例体液免疫反应动态变化趋势。 发现IgM在发病第四周达到高峰，随后急剧下降，直到六个月仍能低水平检出。IgG抗体水平在发病第6个月达到最大值，随后下降。第9个月阳性率87.3%，感染3年后显著降低。IgG抗体阳转时间平均为发病后6 周。第6个月阳性检出率最高（89.1%），随后下降。第9、18、30、36个月时阳性率分别为87.3%， 87.2%， 84%， 75%。应用数学模型估计IgG抗体的半衰期为发病后11个月。感染后44个月， IgG抗体可能消失。应用随机模型估计抗体产生时间、高峰水平、持续时间等的影响因素。发现有基础疾病史、病情危重及高龄患者的免疫应答水平显著低于其他患者。IgM和IgG抗体的水平与病毒载量之间显著负相关。在IgG水平达到高峰前的六个月内，重症、高龄、高病毒载量的患者产生较低水平的IgG抗体。研究结果发表在Vaccine杂志。.此外，利用建立的病例队列，评价了利巴韦林的治疗效果,未发现其对降低该病死亡率和病毒载量有明显作用。确认了SFTSV与立克次体复合感染的病例，并揭示其较重的临床预后。通过代谢组流行病学与临床RCT研究，确认精氨酸代谢通路下调与病毒感染及临床预后有关，补充精氨酸可提供部分改善临床。揭示内皮细胞过度激活及功能障碍是SFTS的致病机制之一。.项目执行期间共发表标注资助号的SCI论文14篇，影响因子总计139分，最高影响因子25分。培养硕士研究生5名，联合培养博士研究生4名。研究结果可为深入了解疾病的致病机理，指导临床治疗方案，疫苗研制和有效使用提供科学依据。