重症肾综合征出血热早期预警参数评估及预后风险模型的构建

发布时间：2018-07-28 10:03

【摘要】：肾综合征出血热（hemorrhagic fever with renal syndrome, HFRS）是由汉坦病毒（Hantanvirus）引起的以发热、出血及肾脏损害为特征的一类自然疫源性疾病。近3年来我国HFRS发病率逐年增高，作为陕西省HFRS高发区的关中地区，由汉滩病毒（hantaan virus，HTNV）感染所致的重症HFRS多发，病死率高。 HTNV是汉坦病毒属的主要血清型，也是陕西地区重症HFRS的主要病原。截止目前，在西安地区仅发现由HTNV感染所致的HFRS病例。HFRS具有全身炎症反应综合征（systemic inflammatory response syndrome，SIRS）的病理生理学特征；典型病理表现为血管渗漏综合征，可导致水肿、休克、出血和急性肾小管间质性肾炎。典型HFRS患者病程多经历五个阶段：发热期、低血压休克期、少尿期、多尿期和恢复期。在一些重症病例，发热期、低血压休克期和少尿期三期可以重叠，且易出现或合并难治性休克、急性肾损伤/肾衰竭（acute kidney injury, AKI/acute renalfailure, ARF）、呼吸衰竭、严重凝血障碍和多脏器功能障碍综合征（multiple organdysfunction syndrome，MODS）。虽然早在20世纪80年代已证明利巴韦林和α干扰素具有抗汉坦病毒的功效，但由于该病早期诊断率低，入住医院的患者大多在第4至第6病日以后，因此治疗时机往往偏晚，用药后难以观察以明确疗效，上述药物迄今仍未在临床广泛应用。早期发现、早期诊断、早期及就近支持治疗仍是HFRS救治的主要原则。虽然国内早在上世纪80年代制定了HFRS的临床分型标准，其在该病防治中起到了十分重要的作用，但因于该分型标准中很多指标均建立在病人主观症状和医生体检的基础上，不仅大多数参数未能量化，难以动态及精确地评估HFRS病情变化及严重程度，而且难以早期预测病情的发展和趋势，合理地指导医师对患者进行有效的治疗干预。随着当代医学检验学、医学影像学和重症监护技术的发展，HFRS救治过程中已经有越来越多的实验室和仪器检查项目和数据可供医师选择和参考，但同其它危重症的诊治一样，如何高效简捷地选择、整合和分析临床上获得的大量HFRS重症患者的检测数据和参数，并用于指导临床治疗，国内外仍缺少相应的研究。因此，进一步深入探索和发现新的重症HFRS早期预警指标，对现有众多的临床及实验室参数进行有效整合和分析，对重症HFRS患者的病情及预后进行早期预判，指导医师采取实时有效的治疗对策，，对提高HFRS危重患者的救治成功率具有重要和实际的意义。本课题正是围绕上述研究方向，评估目前临床常规检测的实验室参数在重症HFRS早期预警及预后评估中的价值；分析危重型HFRS患者的临床特征及预后；尝试构建基于临床及实验室参数的预后风险模型；明确高迁移率族蛋白-1（high mobilitygroup box protein-1，HMGB-1）、脂联素（adiponectin，APN）、铁蛋白（ferritin，FRT）和正五聚素-3（pentraxin3，PTX-3）4个生物标记物在重症HFRS早期预警及预后评估中的价值。 1．重症肾综合征出血热实验室参数早期预警评估及预后风险模型的构建建立HFRS临床诊疗数据库平台，随机调取2008年1月至2012年08月收治的356例典型HFRS患者的临床诊疗数据。结合临床分型标准，将纳入患者分为轻型、中型、重型和危重型四组。将12个患者治疗中常规检测的实验室参数进行分析，包括WBC、HGB、PLT、ALT、AST、ALB、BUN、SCr、UA、PT、APTT和Fib。研究内容包括：回顾性分析上述实验室参数在不同分型HFRS患者急性期的表达变化，评估其在重症HFRS早期预警中的价值；分析各实验室参数与预后的相关性及对预后的影响程度和预测价值；筛选影响预后的独立因素，并构建基于实验室参数的预后风险模型。结果显示： WBC、PLT、AST、ALB、BUN、SCr、PT和APTT等实验室参数在不同分型患者急性期表达水平出现明显变化；WBC、AST、PT和Fib可作为HFRS患者预后的独立影响因子；WBC、AST、PT和Fib联合检测评估HFRS患者预后的效力优于单一参数检测。 2．危重型肾综合征出血热的临床特征及预后风险模型的构建将第一部分中观察的356例HFRS患者中的75例危重型患者纳入本部分研究。结合患者预后，将其分为存活组和死亡组。研究内容包括：回顾性比较存活组与死亡组患者在一般临床特征、人口统计学及流行病学特征、症状、体征、影像学、体液、有创治疗措施及并发症等相关参数的差异；观察患者的累计生存率及28天病死率；分析临床参数与预后的相关性，对预后的影响程度；筛选影响预后的独立因素，并构建基于临床参数的预后风险模型。结果显示：危重型HFRS患者病程第2周的累计生存率为70.7%，28天病死率为36.3%；烦燥不安、球结膜出血、昏迷、心力衰竭、ARDS、脑病和ARF与预后相关性强；ARDS、球结膜出血和昏迷可作为危重型患者预后的独立影响因素。 3．HMGB-1、APN、FRT和PTX-3在重症肾综合征出血热早期预警及预后评估中的价值随机纳入105例2011年10月至2012年12月收治的HFRS患者。抽取患者住院期间急性期静脉血标本93份，恢复期78份，抽取健康对照标本28份，分离出血浆。应用ELISA检测HMGB-1、APN、FRT和PTX-3在不同分型HFRS患者急性期和恢复期的表达水平。研究内容包括：前瞻性观察HMGB-1、APN、FRT和PTX-3四因子在不同分型患者急性期及恢复期的表达变化，与健康对照组的差异；评估其在HFRS早期预警中的价值；分析四因子间的相关性及与预后、实验室参数的相关性；评估四因子对预后的预测价值。结果显示：HMGB-1、APN、FRT和PTX-3在不同分型患者急性期与恢复期表达水平出现明显变化，且与WBC、PLT和ALB相关性强；除APN外，HMGB-1、FRT和PTX-3预测预后的AUC均大于0.800，FRT与PTX-3预测预后的价值高于WBC、PLT和ALB。结论： 1.常规检测WBC、PLT、AST、ALB、BUN、SCr、PT和APTT等实验室指标有助于对重症HFRS进行早期预警；WBC、AST、PT和Fib可作为影响患者预后的独立影响因子；WBC、AST、PT和Fib联合检测较单一参数检测更有助于预测患者的预后； 2. ARDS、球结膜出血和昏迷可作为影响危重型HFRS患者预后的独立影响因素，以此提醒医师时刻警惕致命并发症的发生，密切监测并给予积极的对症支持治疗； 3. HMGB-1、APN、FRT和PTX-3均可作为重症HFRS的早期预警因子；除APN外，检测HMGB-1、FRT和PTX-3有助于评估及预测患者的预后。 4.本课题研究结果表明，联合临床及常规实验室参数检测，探索并将HMGB-1、APN、FRT和PTX-3等生物标记物应用于临床将更有助于重症HFRS的早期预警及预后评估，为HFRS临床分型标准的量化补充，制定新的HFRS临床分级、分度量化标准提供更多循证医学证据。
[Abstract]:Hemorrhagic fever with renal syndrome (HFRS) is a kind of natural epidemic disease characterized by fever, bleeding and kidney damage caused by Hantaan virus (Hantanvirus). In the past 3 years, the incidence of HFRS in China has increased year by year. As the Guanzhong area of the high incidence area of Shaanxi Province, Hantaan virus (Hantaan virus, HTNV) has been found. The severe HFRS caused by infection is high and the mortality rate is high.
HTNV is the main serotype of Hantavirus and is also the main pathogen of severe HFRS in Shaanxi. Up to now, only the HFRS case.HFRS caused by HTNV infection in Xi'an region has the pathophysiological characteristics of systemic inflammatory response syndrome (systemic inflammatory response syndrome, SIRS), and the typical pathological manifestation is vascular leakage. Syndrome, which can lead to edema, shock, bleeding and acute renal tubulointerstitial nephritis. Typical HFRS patients undergo five stages of disease: fever, hypotension, oliguria, polyuria, and recovery. In some severe cases, fever, hypotension, and oliguria, three stages can be overlapped, and easy to occur or combine refractory shock. Acute renal injury / renal failure (acute kidney injury, AKI/acute renalfailure, ARF), respiratory failure, severe coagulopathy and multiple organ dysfunction syndrome (multiple organdysfunction syndrome, MODS).
Although it has been proved in 1980s that Leigh Bhave Lin and IFN have the efficacy of anti hantavirus, but because of the low early diagnosis rate of the disease, most of the patients in the hospital are in the fourth to sixth days of the disease, so the time of treatment is often late, and it is difficult to observe the therapeutic effect after the drug use. Early diagnosis, early and near support therapy is still the main principle of HFRS treatment. Although the clinical classification standards of HFRS were established in 80s of last century, it has played a very important role in the prevention and treatment of the disease, but many of the indicators are based on the subjective symptoms of the patients and the basis of medical examination. On the other hand, most of the parameters are not quantified, and it is difficult to dynamically and accurately assess the changes and severity of the HFRS condition, and it is difficult to predict the development and trend of the disease early and to guide the doctor to intervene effectively in the patients. With the development of contemporary medical examination, medical imaging and intensive care technology, the HFRS treatment process More and more laboratory and instrument inspection projects and data are available for doctors to choose and refer, but like other critical diseases, it is necessary to select, integrate and analyze the data and parameters of a large number of HFRS critically ill patients, and to guide clinical treatment. Therefore, further exploration and discovery of the new early warning indicators for severe HFRS, effective integration and analysis of many existing clinical and laboratory parameters, early judgement on the condition and prognosis of severe HFRS patients, guiding physicians to take real time and effective treatment strategies, to improve the success rate of treatment for critical patients with HFRS Important and practical significance.
This topic is to evaluate the value of the laboratory parameters of clinical routine testing in the early warning and prognosis of severe HFRS, to analyze the clinical characteristics and prognosis of severe HFRS patients, to establish a prognostic risk model based on clinical and laboratory parameters, and to make clear the high mobility group protein -1 (high mob). Ilitygroup box protein-1, HMGB-1), adiponectin (adiponectin, APN), ferritin (ferritin, FRT) and positive five polymer -3 (pentraxin3, PTX-3) 4 biomarkers in the early warning and prognostic evaluation of severe HFRS.
Construction of early warning assessment and prognostic risk model for severe hemorrhagic fever with renal syndrome in 1.
The HFRS clinical diagnosis and treatment database platform was set up to randomly select the clinical data of 356 typical HFRS patients admitted from January 2008 to 2012. According to the clinical classification standard, the patients were divided into four groups of light, medium, heavy and severe. The laboratory parameters of the routine examination in the treatment of 12 patients were analyzed, including WBC, HGB, PLT, A. LT, AST, ALB, BUN, SCr, UA, PT, APTT, and Fib. included: a retrospective analysis of the changes in the expression of the above laboratory parameters in the acute phase of different types of HFRS patients, evaluation of its value in the severe HFRS early warning, the correlation between the parameters of the laboratory and the prognosis and the prognostic value and predictive value of the prognosis; The results show that WBC, PLT, AST, ALB, BUN, SCr, PT, APTT and other laboratory parameters have obvious changes in the acute phase of patients with different types, and WBC, AST, PT and Fib can be used as independent prognostic factors. The prognostic effect of HFRS is better than that of single parameter test.
2. the clinical characteristics and risk model of severe hemorrhagic fever with renal syndrome
356 of the 356 cases of severe severe patients in the first part of the first part were studied in this part. Combined with the prognosis of the patients, they were divided into the survival group and the death group. The study included a retrospective comparison of the general clinical features, demographic and epidemiological characteristics, symptoms, signs, imaging, and fluid, in the survival and death groups. The difference in the parameters related to invasive treatment and complications, the cumulative survival rate and the 28 day mortality rate, the correlation between the clinical parameters and the prognosis, the impact on the prognosis, the screening of independent factors affecting the prognosis, and the construction of a prognostic risk model based on the clinical parameters. The results showed that the course of the patients with severe severe HFRS The cumulative survival rate of second weeks was 70.7%, and the 28 day fatality rate was 36.3%; irritability, conjunctival hemorrhage, coma, heart failure, ARDS, encephalopathy and ARF were associated with the prognosis; ARDS, conjunctival hemorrhage and coma were independent prognostic factors for the prognosis of severe patients.
Value of 3.HMGB-1, APN, FRT and PTX-3 in early warning and prognosis evaluation of severe hemorrhagic fever with renal syndrome
105 cases of HFRS patients admitted from October 2011 to December 2012 were randomly selected. 93 samples of acute venous blood samples were collected during hospitalization, 78 recovered period, 28 healthy control specimens were extracted and hemorrhagic pulp was separated. The expression level of HMGB-1, APN, FRT and PTX-3 in the acute phase and recovery period of different types of HFRS patients was detected by ELISA. The contents included the content of the study. A prospective observation of the changes in the expression of the four factors of HMGB-1, APN, FRT and PTX-3 in the acute and convalescent stages of different types of patients, and the difference from the healthy control group; evaluate its value in the early warning of HFRS; analyze the correlation between the four factors and the correlation with the prognosis and the laboratory parameters; and evaluate the predictive value of the four factor to the prognosis. The expression levels of HMGB-1, APN, FRT and PTX-3 were significantly changed in the acute and recovery stages of different types of patients, and they were closely related to WBC, PLT and ALB. Except APN, HMGB-1, FRT and PTX-3 predicted the prognosis of AUC were greater than 0.800.
Conclusion:
1. routine tests of WBC, PLT, AST, ALB, BUN, SCr, PT and APTT are helpful to early warning of severe HFRS; WBC, AST, PT, and APTT are independent factors affecting the prognosis of patients.
2. ARDS, bulking conjunctiva bleeding and coma can be an independent factor affecting the prognosis of severe HFRS patients, in order to remind physicians to be vigilant for the occurrence of fatal complications, closely monitor and give positive symptomatic support treatment.
3. HMGB-1, APN, FRT and PTX-3 can be used as early warning factors for severe HFRS. Besides APN, detection of HMGB-1, FRT and PTX-3 can help assess and predict the prognosis of patients.
4. the research results show that the application of HMGB-1, APN, FRT and PTX-3 biomarkers in clinical and routine laboratory parameters detection, and the application of biomarkers such as FRT, and PTX-3 will be more helpful to the early warning and prognosis assessment of severe HFRS, for the quantitative supplement of the HFRS clinical classification standards, the formulation of a new HFRS clinical classification, and a more evidence-based criteria for quantitative quantification. Proof of medical evidence.
【学位授予单位】：第四军医大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R512.8

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