脑脊液肿瘤坏死因子-α对鉴别细菌性脑膜炎及病毒性脑膜炎诊断价值：系统综述和Meta分析
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摘要
研究背景
中枢神经系统感染是一类病因明确,由致病微生物引起的神经系统炎症性疾病之一。中枢神经系统感染不仅是神经内科常见疾病之一,在神经外科实践过程中,尤其是颅脑术后病人中,也常可发生中枢神经系统的感染。中枢神经系统感染具有较高的病死率及致残率,早期诊断并及时治疗对改善患者的远期预后具有重要的意义。但是,随着临床诊疗技术的不断发展,在临床诊疗过程中出现了一些新的临床情况,使得对中枢神经系统感染性疾病的诊断出现了新的困难。一方面,随着抗菌药物广泛应用,尤其是经验性抗菌药物治疗的应用,大量中枢神经系统感染患者在可疑感染存在时,已经使用了大量的抗菌药物,这不仅降低中枢神经系统感染性疾病临床表现的典型性,更甚的是影响实验室检查结果的可靠性,对早期中枢神经系统感染性疾病的诊断存在一定的困难；另一方面,随着神经内外科的发展,各种有创治疗手段以及各种颅脑植入物及止血材料的应用,尤其是神经外科颅脑术后的患者,术中的各种植入物引起的异物反应,常常可表现为发热、头痛等中枢神经系统感染性疾病的临床表现,这对术后确实发生了中枢神经系统感染的患者,特别是颅脑术后患者的早期诊断带来困难。因此,早期诊断中枢神经系统感染,鉴别感染病原菌的类型,及时应用有针对性抗菌药物,对中枢神经系统感染患者取得良好预后十分关键。其中实验室检查在早期中枢神经系统感染诊断中占有十分重要的位置,对中枢神经系统感染性疾病的诊断及病原菌的鉴别具有重要的意义。但是,新的临床诊疗情况的出现以及目前临床上广泛使用的实验室检查技术的不足,常常不能满足临床早期诊断需求,给临床诊断带来困难,在指导抗菌药物使用方面有所不足。因此,针对新出现的临床情况,寻找更为特异及敏感的实验室检测方法成为十分迫切的任务。
肿瘤坏死因子-α (Tumor Necrosis Factor-α, TNF-α)是由体内免疫细胞(主要巨噬细胞)和其他组织细胞共同分泌的,具有广泛生物活性的细胞因子,在抗肿瘤、抗感染等方面有重要的作用。在中枢神经系统中,TNF-α主要由巨噬细胞分泌,除此以外,在中枢神经系统组织内不仅星形细胞、脑组织血管内皮细胞和小胶质细胞等均可产生TNF-α,神经元亦可产生TNF-α。当外来的各种刺激,尤其是细菌脂多糖(Lipopolysaccharides, LPS)的刺激,能引起体内相应的细胞分泌大量的TNF-α,在炎症发生的早期起着重要的抗感染作用。通过对TNF-α的研究,发现TNF-α主要由病原体本身的固有成分刺激中枢神经组织细胞产生的,在感染早期大量地分泌,不受抗菌药物使用的影响,而且也不受神经系统有创操作及各种植入物的影响,因此,大量的研究集中在脑脊液TNF-α含量检测在中枢神经系统感染性疾病早期诊断作用方面,并且证实TNF-α含量的改变在中枢神经系统感染性疾病的早期诊断及感染病原体鉴别方面具有十分重要的意义,尤其是在应对新出现的临床情况这方面,显示出其独特的优势。大量关于TNF-α的研究,均发现脑脊液TNF-α在细菌性脑膜炎患者中显著升高,而在病毒性脑膜炎及无颅内感染患者中却无明显改变,这可作为诊断及鉴别诊断的指标之一。然而,有关脑脊液TNF-α在诊断细菌性脑膜炎及其与病毒性脑膜炎鉴别的各个研究中存在着样本量小、灵敏度及特异度差异较大的问题,如何在现有资料上,将各个研究结果统一起来,是本文急需解决的问题。
因此,本文采用Meta分析方法综合定量评价脑脊液TNF-α在诊断细菌性脑膜炎及其与病毒性脑膜炎鉴别诊断中的价值,为在临床上应用及推广提供循证医学证据。
目的
收集已发表的国内外文献,通过Meta分析比较在细菌性脑膜炎及病毒性脑膜炎脑脊液中TNF-α含量的改变,以综合定量地评价脑脊液TNF-α对鉴别细菌性脑膜炎及病毒性脑膜炎中的诊断价值,为中枢神经系统感染性疾病早期诊断及感染病原体的鉴别,提供新的临床诊断手段,为在临床上应用及推广提供循证医学证据。
材料与方法
本文主要遵循诊断性Meta分析的相关指南进行资料收集及分析,并遵守诊断性Meta分析研究报告规范。
我们对Pubmed, EMBASE、The Cochrane Library、CBM、CNKI、维普、万方数据库和相关综述的参考文献进行了全面检索,时间截止到2012年9月30日。文献入选标准为：(1)研究对象包括细菌性脑膜炎及病毒性脑膜炎患者；(2)可直接或间接获得脑脊液TNF-α应用于鉴别诊断的真阳性、假阳性、真阴性及假阴性值；(3)能直接或间接获得脑脊液TNF-α诊断的阳性阈值。排除标准：(1)研究对象仅包含细菌性脑膜炎或病毒性脑膜炎患者之一；(2)无法获取TNF-α应用于鉴别诊断的相关数据。提取资料包括一般信息：作者、年代、国家、研究人群年龄、样本量、脑脊液TNF-α检测方法及其阳性阈值。诊断指标信息：真阳性、假阳性、真阴性及假阴性值。
采用系统评价中评价诊断性研究质量的Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Reviews (QUADAS)质量评分标准对纳入文献进行质量评价。由2名评价员单独筛选文献,提取相关数据并评价文献质量,遇有分歧时讨论解决。使用Meta-Disc1.4软件进行Meta分析。提取各独立研究的真阳性、假阳性、真阴性及假阴性值,绘制综合受试者工作特征曲线(Summary Receiver Operating Characteristics, SROC曲线),估计各个试验总的诊断精度。通过计算灵敏度对数与(1-特异度)对数的Spearman目关系数、X2、I2评价纳入文献的异质性(包括阈值效应及非阈值效应)。当异质性存在时使用随机效应模型,无异质性时采用固定效应模型来计算所纳入研究的合并灵敏度、特异度、阳性似然比、阴性似然比以及诊断性比值比等指标。根据研究变量(国家、人群年龄、TNF-α检测方法)对纳入研究进行分组后行亚组分析,并绘制SROC曲线,亚组之间曲线下面积(Area Under The Curve, AUC)的比较采用Z检验。将纳入文献逐一排除,通过对排除前后的SROC曲线下面积AUC值的比较采用Z检验,以对纳入文献行敏感性分析。
结果
本研究共纳入21篇文献,共涉及558例细菌性脑膜炎及651例病毒性脑膜炎患者。其中,英文文献有10篇,中文文献有11篇。研究对象为儿童的文献有14篇,研究对象包含成人的文献有7篇。研究中TNF-α的检测方法采用Elisa的有13篇,采用放射免疫法有6篇,采用免疫发光法及化学发光法各1篇。纳入研究中TNF-α诊断的阳性阈值最小为6.7pg/mL，最大为35ng/mL,中位值为100pg/mL。
1.文献质量评价结果
所有研究都包含了细菌性脑膜炎及病毒性脑膜炎2种疾病,研究中的所有患者均接受了相同的金标准试验,没有中途退出研究的患者。研究中TNF-α的检测均独立于金标准,且获得的临床资料与实际应用获得的一致。只有5个研究描述了患者的纳入及排除标准。4个研究对金标准未进行详细阐述,不清楚能否准确区分细菌性脑膜炎与病毒性脑膜炎。9个研究中金标准与TNF-α的检测是同时进行的,没有时间间隔。21个研究中TNF-α的检测方法可重复,而所有研究均未对金标准的操作进行详细描述。6个研究中的金标准与TNF-α检测的双盲法不清楚。6个研究没有对中间试验结果进行解释。总的来说,在所有的21篇纳入的研究中,其中的15篇文献,在14个评分条目中,“是”的结果占了11个以上,余下的6篇文献中,只有1篇文献,在14个评分条目中,“否”的结果有3个条目,余下5篇纳入文献,均“不清楚”结果为多。因此,纳入的21篇文献总体质量不错。
2. Meta分析异质性检验结果
阈值效应异质性检验：灵敏度对数与(1-特异度)对数的Spearman相关系数=0.049,P=0.834,提示所纳入研究不存在阈值效应。非阈值效应异质性检验：Cochran-Q=31.93,P=0.0441<0.05,合并灵敏度的X2=54.67,I2=63.4%；合并特异度的X2=48.87,I2=59.1%。可见,纳人研究之间存在非阈值效应引起的异质性。
3.Meta分析结果
3.1纳入研究的合并效应量
脑脊液TNF-α对细菌性脑膜炎鉴别诊断的合并灵敏度为0.80(95%CI:0.76-0.83),合并特异度为0.92(95%CI:0.89-0.94),合并阳性似然比为7.55(95%CI：5.26-10.83),合并阴性似然比为0.26(95%CI:0.21-0.32),合并诊断比值比为38.52(95%CI:23.08-64.29),SROC曲线下面积AUC=0.9267(SE=0.0132), Q*=0.8612(SE=0.0156)。
3.2亚组分析
按照研究国家(中国、外国)、人群年龄(小龄儿童、大龄儿童及成人)、TNF-α检测方法(Elisa、非Elisa方法)的不同对纳入研究进行分组。亚组分析结果显示：(1)以国家为分组依据的亚组分析中,中国亚组所包含的12个研究间存在异质性(I2=74%>50%)；外国亚组所包含的9个研究结果间同质(I2=0.0%)。通过对这两个亚组间曲线下面积AUC值的比较采用Z检验,结果Z=0.3606,P=0.7183；(2)以人群年龄为分组依据的亚组分析中,小龄儿童亚组所包含的14个研究结果之间具有明显的异质性(I2=72.4%>50%)；包含成人的亚组中7个研究结果之间同质(I2=0.0%)。通过对这两个亚组间曲线下面积AUC值的比较采用Z检验,结果Z=0.6712,P=0.5020：(3)以检测方法为分组依据的亚组分析中,Elisa亚组中包含的13个研究结果间同质(I2=37.0%<50%)；非Elisa亚组中包含的8个研究结果间同质(I2=35.4.0%<50%)。通过对这两个亚组间曲线下面积AUC值的比较采用Z检验,结果Z=0.9210,P=0.3570。在所有亚组间曲线下面积AUC值的比较,P值均大于0.05,这表示在诊断效能上,亚组间无统计学差异。说明不论采用何种检测方法,脑脊液TNF-α对中国及外国人群,对儿童及成人细菌性脑膜炎与病毒性脑膜炎患者具有同等的鉴别诊断价值。
3.3敏感性分析
将纳入文献逐一排除后重新进行Meta分析,排除后SROC曲线AUC值无显著变化,说明变纳入的21篇文献稳定性好,结果可信。
结论
1.对纳入21篇文献总的Meta分析结果,经SROC曲线证实,脑脊液TNF-α在鉴别细菌性及病毒性脑膜炎中具有较高的灵敏度和特异度,可作为重要的筛查和诊断指标。
2.经亚组分析提示,脑脊液TNF-α在鉴别细菌性及病毒性脑膜炎中的作用与人种及人群的年龄无关,能在国内外、成人及儿童中广泛推广应用。
Background:
The central nervous system infection (CNSI) is a kind of etiology clear, inflammatory disease caused by pathogenic microorganism in the nervous system. It is one of the common disease in neurology, especially in patients with craniocerebral surgery. It has high mortality and morbidity, so it is important to be diagnosed early and be treated timely to improve the long-term prognosis of the patients. However, follow-up the development of clinical diagnosis and treatment technology, new clinical cases makes diagnosis of the central nervous system infection difficult. On one hand, with the wide application of antibacterial drugs, a large number of patients with suspected infection, have been used for a large number of antibacterial drugs, which not only cover the clinical manifestations of central nervous system infection, moreover affect the reliability of laboratory results of the central nervous system infection, so it makes difficult to diagnose central nervous system infection. On the other hand, along with the development of neurology, all kinds of invasive treatments and brain implants and hemostatic materials applications, especially in patients with craniocerebral surgery, can cause foreign body reaction, which has the same clinical manifestations of central nervous system infection, such as fever and headache. So it also makes the early diagnosis of central nervous system infection very difficult. Laboratory examination plays an important role in the diagnosis and differential diagnosis of central nervous system infection. However, with the emergence of new clinical situation, the traditional laboratory test because of its shortcomings, far cannot meet the needs of current clinical diagnosis. Therefore, in view of the emergence of new clinical situation, looking for a more specific and sensitive laboratory detection method become a very pressing task.
TNF alpha,which secreted by immune cells (macrophages) and other cells in the body tissue, has a broad range of biological activity in antitumor and anti-infection.In the central nervous system, the TNF alpha mainly secreted by macrophages. Besides, not only astrocytes, vascular endothelial cells and microglia can produce TNF alpha, neurons can also produce TNF alpha. When the brain tissue suffers from a variety of external stimulation, especially the stimulation of bacterial lipopolysaccharide, brain tissue can secrete a large number of TNF alpha, in order to resist invasion of pathogen. TNF alpha plays an important role in the early stage of infection. Through the researches of TNF alpha, it is found that when the tissue cells just only suffers by the pathogen itself or its Secretion, the tissue cells can secrete a large number of TNF alpha in the early stage of infection. And it is not affected by the application of antibiotics and invasive manipulation of the brain. So a lot researches have been achieved to prove that when the bacterial meningitis occurs, the level of TNF alpha in cerebrospinal fluid will significantly increase, but when the virus meningitis occurs, the level of TNF alpha in cerebrospinal fluid will not increase so much. However, the researches of TNF alpha about the diagnosis of brain infection have some questions, just like small sample size, different diagnosis of sensitivity and specificity and so on.
So, this article aims to Comprehensively assess the researches of TNF alpha about the diagnosis of brain infection by Meta analysis, in order to provide theoretical basis for the clinical application and promotion.
Objective
We collected the literatures about the diagnostic value of CSF TNF alpha to identify bacterial meningitis and viral meningitis at home and abroad, and evaluated its diagnostic value with Meta analysis. Through that, it can provide a new way to diagnose central nervous system infection and identify causative agent. Besides it can also provide theoretical basis to guide the clinical application
Methods and materials
This study was conducted following the Meta-analysis of observational studies in epidemiology guidelines, simultaneously conforming to most of the preferred reporting items for systematic reviews and Meta-analyses guidelines.
We performed an electronic search of PubMed, EMBASE, the Cochrane library, CBM, CNKI, VIP and Wanfang from inception of each database to September2012. We included studies if they met all the following criteria:(1)Object of the researches include two groups, one includes the patients with bacterial meningitis and the other includes the patients with viral meningitis;(2)It can be directly or indirectly to obtain all the diagnosis information of TNF alpha in cerebrospinal fluid,just like True-Positives, False-Positives, True-Negatives and False-Negatives;(3) It can be directly or indirectly to obtain the diagnosis of positive predictive value. We excluded studies if they met all the following criteria:(1) Object of the researches just only include one group;(2)It can not obtain the diagnosis information.
The quality of included studies were assessed based on the Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Reviews (QU ADAS) for quality of diagnostic studies in Meta-analyses. This article use the Meta-Disc1.4software for Meta analysis. We obtain the data such as True-Positives, False-Positives, True-Negatives and False-Negatives from all the researches, and draw the Summary receiver operating characteristic(SROC), in order to estimated the total diagnostic test accuracy. Through calculating Spearman correlation, X2and I2to evaluate whether there is heterogeneity, and then decide using which to do the Meta analysis, random effects model or fixed effect model. At the same time, we will do the Sensitivity analysis and subgroup analysis of the include researches.
Results
Twenty-one studies were included in our Meta-analysis involving558patients with bacterial meningitis and651patients with virus meningitis, including11english researches and10chinese researches, and14researches for the children,7researches for the adult. And13researches use the Elisa detection,6researches use radioimmunoassay,1research use immunochemiluminometric assays,1research use chemiluminescence.
1. Results of quality evaluation of literature
All studies included2kinds of disease, bacterial meningitis and viral meningitis. All patients received the same standard test. And no patient gives up from all the studies. Only5studies describe the standard of into and out of the test of the patients.4studies don't describe the standard test. The test of TNF alpha with the standard test or control test is carried out at the same time. TNF alpha testing method in all studies can be repeated. In all, all studies included have good quality.
2. Results of heterogeneity test
Spearman correlation is0.049and P=0.834. It says that there is no threshold effect in all studies. Cochran-Q=31.93, P=0.0441<0.05, X2of merger of sensitivity is54.67,and I2=63.4%. X2of merger of specificity is48.87,and I2=59.1%. We cloud say that there has heterogeneity among the studies.
3. Result of Meta-analyses
3.1Risults of effectsize
The information about TNF alpha to differential diagnosis bacterial meningitis and virus meningitis includes the following index:Sensitivity=0.80(95%CI:0.76to0.83),specificity=0.92(95%CI:0.89-0.94), likelihood ratio positive=.55(95%CI:5.26-10.83),likelihood ratio negative=0.26(95%CI:0.21-0.32) diagnostic odds ratio=38.52(95%CI:23.08-64.29) and the AUC of SROC=0.9267(SE=0.0132), Q*=0.8612(SE=0.0156).
3.2Results of subgroup analysis
According to the country (China or foreign country), age (children or adults), method of TNF alpha test, we divided all the studies into some groups. Through the subgroup analysis, we cloud know that there is no different between all the groups, no matter between Chinese and foreigners, or between children and adults.
3.3Results of sensitivity analysis
We removed the included studies one by one, and then do the Meta-analyses again. And we find that the AUC of Summary receiver operating characteristic (SROC) don't change much. That is to say that the quality of all included studies is reliable.
Conclusion
1. TNF alpha in Cerebrospinal fluid has a highly accurate sensitivity and specificity with a strong ROC curve, which makes it a new marker to differentiate bacterial meningitis from viral meningitis.
2. According to the results of subgroup analysis, we know that this way of diagnosis can be spreaded in all people, no matter Chinese or foreigners, children or adults.
中枢神经系统感染是一类病因明确,由致病微生物引起的神经系统炎症性疾病之一。中枢神经系统感染不仅是神经内科常见疾病之一,在神经外科实践过程中,尤其是颅脑术后病人中,也常可发生中枢神经系统的感染。中枢神经系统感染具有较高的病死率及致残率,早期诊断并及时治疗对改善患者的远期预后具有重要的意义。但是,随着临床诊疗技术的不断发展,在临床诊疗过程中出现了一些新的临床情况,使得对中枢神经系统感染性疾病的诊断出现了新的困难。一方面,随着抗菌药物广泛应用,尤其是经验性抗菌药物治疗的应用,大量中枢神经系统感染患者在可疑感染存在时,已经使用了大量的抗菌药物,这不仅降低中枢神经系统感染性疾病临床表现的典型性,更甚的是影响实验室检查结果的可靠性,对早期中枢神经系统感染性疾病的诊断存在一定的困难；另一方面,随着神经内外科的发展,各种有创治疗手段以及各种颅脑植入物及止血材料的应用,尤其是神经外科颅脑术后的患者,术中的各种植入物引起的异物反应,常常可表现为发热、头痛等中枢神经系统感染性疾病的临床表现,这对术后确实发生了中枢神经系统感染的患者,特别是颅脑术后患者的早期诊断带来困难。因此,早期诊断中枢神经系统感染,鉴别感染病原菌的类型,及时应用有针对性抗菌药物,对中枢神经系统感染患者取得良好预后十分关键。其中实验室检查在早期中枢神经系统感染诊断中占有十分重要的位置,对中枢神经系统感染性疾病的诊断及病原菌的鉴别具有重要的意义。但是,新的临床诊疗情况的出现以及目前临床上广泛使用的实验室检查技术的不足,常常不能满足临床早期诊断需求,给临床诊断带来困难,在指导抗菌药物使用方面有所不足。因此,针对新出现的临床情况,寻找更为特异及敏感的实验室检测方法成为十分迫切的任务。
肿瘤坏死因子-α (Tumor Necrosis Factor-α, TNF-α)是由体内免疫细胞(主要巨噬细胞)和其他组织细胞共同分泌的,具有广泛生物活性的细胞因子,在抗肿瘤、抗感染等方面有重要的作用。在中枢神经系统中,TNF-α主要由巨噬细胞分泌,除此以外,在中枢神经系统组织内不仅星形细胞、脑组织血管内皮细胞和小胶质细胞等均可产生TNF-α,神经元亦可产生TNF-α。当外来的各种刺激,尤其是细菌脂多糖(Lipopolysaccharides, LPS)的刺激,能引起体内相应的细胞分泌大量的TNF-α,在炎症发生的早期起着重要的抗感染作用。通过对TNF-α的研究,发现TNF-α主要由病原体本身的固有成分刺激中枢神经组织细胞产生的,在感染早期大量地分泌,不受抗菌药物使用的影响,而且也不受神经系统有创操作及各种植入物的影响,因此,大量的研究集中在脑脊液TNF-α含量检测在中枢神经系统感染性疾病早期诊断作用方面,并且证实TNF-α含量的改变在中枢神经系统感染性疾病的早期诊断及感染病原体鉴别方面具有十分重要的意义,尤其是在应对新出现的临床情况这方面,显示出其独特的优势。大量关于TNF-α的研究,均发现脑脊液TNF-α在细菌性脑膜炎患者中显著升高,而在病毒性脑膜炎及无颅内感染患者中却无明显改变,这可作为诊断及鉴别诊断的指标之一。然而,有关脑脊液TNF-α在诊断细菌性脑膜炎及其与病毒性脑膜炎鉴别的各个研究中存在着样本量小、灵敏度及特异度差异较大的问题,如何在现有资料上,将各个研究结果统一起来,是本文急需解决的问题。
因此,本文采用Meta分析方法综合定量评价脑脊液TNF-α在诊断细菌性脑膜炎及其与病毒性脑膜炎鉴别诊断中的价值,为在临床上应用及推广提供循证医学证据。
目的
收集已发表的国内外文献,通过Meta分析比较在细菌性脑膜炎及病毒性脑膜炎脑脊液中TNF-α含量的改变,以综合定量地评价脑脊液TNF-α对鉴别细菌性脑膜炎及病毒性脑膜炎中的诊断价值,为中枢神经系统感染性疾病早期诊断及感染病原体的鉴别,提供新的临床诊断手段,为在临床上应用及推广提供循证医学证据。
材料与方法
本文主要遵循诊断性Meta分析的相关指南进行资料收集及分析,并遵守诊断性Meta分析研究报告规范。
我们对Pubmed, EMBASE、The Cochrane Library、CBM、CNKI、维普、万方数据库和相关综述的参考文献进行了全面检索,时间截止到2012年9月30日。文献入选标准为：(1)研究对象包括细菌性脑膜炎及病毒性脑膜炎患者；(2)可直接或间接获得脑脊液TNF-α应用于鉴别诊断的真阳性、假阳性、真阴性及假阴性值；(3)能直接或间接获得脑脊液TNF-α诊断的阳性阈值。排除标准：(1)研究对象仅包含细菌性脑膜炎或病毒性脑膜炎患者之一；(2)无法获取TNF-α应用于鉴别诊断的相关数据。提取资料包括一般信息：作者、年代、国家、研究人群年龄、样本量、脑脊液TNF-α检测方法及其阳性阈值。诊断指标信息：真阳性、假阳性、真阴性及假阴性值。
采用系统评价中评价诊断性研究质量的Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Reviews (QUADAS)质量评分标准对纳入文献进行质量评价。由2名评价员单独筛选文献,提取相关数据并评价文献质量,遇有分歧时讨论解决。使用Meta-Disc1.4软件进行Meta分析。提取各独立研究的真阳性、假阳性、真阴性及假阴性值,绘制综合受试者工作特征曲线(Summary Receiver Operating Characteristics, SROC曲线),估计各个试验总的诊断精度。通过计算灵敏度对数与(1-特异度)对数的Spearman目关系数、X2、I2评价纳入文献的异质性(包括阈值效应及非阈值效应)。当异质性存在时使用随机效应模型,无异质性时采用固定效应模型来计算所纳入研究的合并灵敏度、特异度、阳性似然比、阴性似然比以及诊断性比值比等指标。根据研究变量(国家、人群年龄、TNF-α检测方法)对纳入研究进行分组后行亚组分析,并绘制SROC曲线,亚组之间曲线下面积(Area Under The Curve, AUC)的比较采用Z检验。将纳入文献逐一排除,通过对排除前后的SROC曲线下面积AUC值的比较采用Z检验,以对纳入文献行敏感性分析。
结果
本研究共纳入21篇文献,共涉及558例细菌性脑膜炎及651例病毒性脑膜炎患者。其中,英文文献有10篇,中文文献有11篇。研究对象为儿童的文献有14篇,研究对象包含成人的文献有7篇。研究中TNF-α的检测方法采用Elisa的有13篇,采用放射免疫法有6篇,采用免疫发光法及化学发光法各1篇。纳入研究中TNF-α诊断的阳性阈值最小为6.7pg/mL，最大为35ng/mL,中位值为100pg/mL。
1.文献质量评价结果
所有研究都包含了细菌性脑膜炎及病毒性脑膜炎2种疾病,研究中的所有患者均接受了相同的金标准试验,没有中途退出研究的患者。研究中TNF-α的检测均独立于金标准,且获得的临床资料与实际应用获得的一致。只有5个研究描述了患者的纳入及排除标准。4个研究对金标准未进行详细阐述,不清楚能否准确区分细菌性脑膜炎与病毒性脑膜炎。9个研究中金标准与TNF-α的检测是同时进行的,没有时间间隔。21个研究中TNF-α的检测方法可重复,而所有研究均未对金标准的操作进行详细描述。6个研究中的金标准与TNF-α检测的双盲法不清楚。6个研究没有对中间试验结果进行解释。总的来说,在所有的21篇纳入的研究中,其中的15篇文献,在14个评分条目中,“是”的结果占了11个以上,余下的6篇文献中,只有1篇文献,在14个评分条目中,“否”的结果有3个条目,余下5篇纳入文献,均“不清楚”结果为多。因此,纳入的21篇文献总体质量不错。
2. Meta分析异质性检验结果
阈值效应异质性检验：灵敏度对数与(1-特异度)对数的Spearman相关系数=0.049,P=0.834,提示所纳入研究不存在阈值效应。非阈值效应异质性检验：Cochran-Q=31.93,P=0.0441<0.05,合并灵敏度的X2=54.67,I2=63.4%；合并特异度的X2=48.87,I2=59.1%。可见,纳人研究之间存在非阈值效应引起的异质性。
3.Meta分析结果
3.1纳入研究的合并效应量
脑脊液TNF-α对细菌性脑膜炎鉴别诊断的合并灵敏度为0.80(95%CI:0.76-0.83),合并特异度为0.92(95%CI:0.89-0.94),合并阳性似然比为7.55(95%CI：5.26-10.83),合并阴性似然比为0.26(95%CI:0.21-0.32),合并诊断比值比为38.52(95%CI:23.08-64.29),SROC曲线下面积AUC=0.9267(SE=0.0132), Q*=0.8612(SE=0.0156)。
3.2亚组分析
按照研究国家(中国、外国)、人群年龄(小龄儿童、大龄儿童及成人)、TNF-α检测方法(Elisa、非Elisa方法)的不同对纳入研究进行分组。亚组分析结果显示：(1)以国家为分组依据的亚组分析中,中国亚组所包含的12个研究间存在异质性(I2=74%>50%)；外国亚组所包含的9个研究结果间同质(I2=0.0%)。通过对这两个亚组间曲线下面积AUC值的比较采用Z检验,结果Z=0.3606,P=0.7183；(2)以人群年龄为分组依据的亚组分析中,小龄儿童亚组所包含的14个研究结果之间具有明显的异质性(I2=72.4%>50%)；包含成人的亚组中7个研究结果之间同质(I2=0.0%)。通过对这两个亚组间曲线下面积AUC值的比较采用Z检验,结果Z=0.6712,P=0.5020：(3)以检测方法为分组依据的亚组分析中,Elisa亚组中包含的13个研究结果间同质(I2=37.0%<50%)；非Elisa亚组中包含的8个研究结果间同质(I2=35.4.0%<50%)。通过对这两个亚组间曲线下面积AUC值的比较采用Z检验,结果Z=0.9210,P=0.3570。在所有亚组间曲线下面积AUC值的比较,P值均大于0.05,这表示在诊断效能上,亚组间无统计学差异。说明不论采用何种检测方法,脑脊液TNF-α对中国及外国人群,对儿童及成人细菌性脑膜炎与病毒性脑膜炎患者具有同等的鉴别诊断价值。
3.3敏感性分析
将纳入文献逐一排除后重新进行Meta分析,排除后SROC曲线AUC值无显著变化,说明变纳入的21篇文献稳定性好,结果可信。
结论
1.对纳入21篇文献总的Meta分析结果,经SROC曲线证实,脑脊液TNF-α在鉴别细菌性及病毒性脑膜炎中具有较高的灵敏度和特异度,可作为重要的筛查和诊断指标。
2.经亚组分析提示,脑脊液TNF-α在鉴别细菌性及病毒性脑膜炎中的作用与人种及人群的年龄无关,能在国内外、成人及儿童中广泛推广应用。
Background:
The central nervous system infection (CNSI) is a kind of etiology clear, inflammatory disease caused by pathogenic microorganism in the nervous system. It is one of the common disease in neurology, especially in patients with craniocerebral surgery. It has high mortality and morbidity, so it is important to be diagnosed early and be treated timely to improve the long-term prognosis of the patients. However, follow-up the development of clinical diagnosis and treatment technology, new clinical cases makes diagnosis of the central nervous system infection difficult. On one hand, with the wide application of antibacterial drugs, a large number of patients with suspected infection, have been used for a large number of antibacterial drugs, which not only cover the clinical manifestations of central nervous system infection, moreover affect the reliability of laboratory results of the central nervous system infection, so it makes difficult to diagnose central nervous system infection. On the other hand, along with the development of neurology, all kinds of invasive treatments and brain implants and hemostatic materials applications, especially in patients with craniocerebral surgery, can cause foreign body reaction, which has the same clinical manifestations of central nervous system infection, such as fever and headache. So it also makes the early diagnosis of central nervous system infection very difficult. Laboratory examination plays an important role in the diagnosis and differential diagnosis of central nervous system infection. However, with the emergence of new clinical situation, the traditional laboratory test because of its shortcomings, far cannot meet the needs of current clinical diagnosis. Therefore, in view of the emergence of new clinical situation, looking for a more specific and sensitive laboratory detection method become a very pressing task.
TNF alpha,which secreted by immune cells (macrophages) and other cells in the body tissue, has a broad range of biological activity in antitumor and anti-infection.In the central nervous system, the TNF alpha mainly secreted by macrophages. Besides, not only astrocytes, vascular endothelial cells and microglia can produce TNF alpha, neurons can also produce TNF alpha. When the brain tissue suffers from a variety of external stimulation, especially the stimulation of bacterial lipopolysaccharide, brain tissue can secrete a large number of TNF alpha, in order to resist invasion of pathogen. TNF alpha plays an important role in the early stage of infection. Through the researches of TNF alpha, it is found that when the tissue cells just only suffers by the pathogen itself or its Secretion, the tissue cells can secrete a large number of TNF alpha in the early stage of infection. And it is not affected by the application of antibiotics and invasive manipulation of the brain. So a lot researches have been achieved to prove that when the bacterial meningitis occurs, the level of TNF alpha in cerebrospinal fluid will significantly increase, but when the virus meningitis occurs, the level of TNF alpha in cerebrospinal fluid will not increase so much. However, the researches of TNF alpha about the diagnosis of brain infection have some questions, just like small sample size, different diagnosis of sensitivity and specificity and so on.
So, this article aims to Comprehensively assess the researches of TNF alpha about the diagnosis of brain infection by Meta analysis, in order to provide theoretical basis for the clinical application and promotion.
Objective
We collected the literatures about the diagnostic value of CSF TNF alpha to identify bacterial meningitis and viral meningitis at home and abroad, and evaluated its diagnostic value with Meta analysis. Through that, it can provide a new way to diagnose central nervous system infection and identify causative agent. Besides it can also provide theoretical basis to guide the clinical application
Methods and materials
This study was conducted following the Meta-analysis of observational studies in epidemiology guidelines, simultaneously conforming to most of the preferred reporting items for systematic reviews and Meta-analyses guidelines.
We performed an electronic search of PubMed, EMBASE, the Cochrane library, CBM, CNKI, VIP and Wanfang from inception of each database to September2012. We included studies if they met all the following criteria:(1)Object of the researches include two groups, one includes the patients with bacterial meningitis and the other includes the patients with viral meningitis;(2)It can be directly or indirectly to obtain all the diagnosis information of TNF alpha in cerebrospinal fluid,just like True-Positives, False-Positives, True-Negatives and False-Negatives;(3) It can be directly or indirectly to obtain the diagnosis of positive predictive value. We excluded studies if they met all the following criteria:(1) Object of the researches just only include one group;(2)It can not obtain the diagnosis information.
The quality of included studies were assessed based on the Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Reviews (QU ADAS) for quality of diagnostic studies in Meta-analyses. This article use the Meta-Disc1.4software for Meta analysis. We obtain the data such as True-Positives, False-Positives, True-Negatives and False-Negatives from all the researches, and draw the Summary receiver operating characteristic(SROC), in order to estimated the total diagnostic test accuracy. Through calculating Spearman correlation, X2and I2to evaluate whether there is heterogeneity, and then decide using which to do the Meta analysis, random effects model or fixed effect model. At the same time, we will do the Sensitivity analysis and subgroup analysis of the include researches.
Results
Twenty-one studies were included in our Meta-analysis involving558patients with bacterial meningitis and651patients with virus meningitis, including11english researches and10chinese researches, and14researches for the children,7researches for the adult. And13researches use the Elisa detection,6researches use radioimmunoassay,1research use immunochemiluminometric assays,1research use chemiluminescence.
1. Results of quality evaluation of literature
All studies included2kinds of disease, bacterial meningitis and viral meningitis. All patients received the same standard test. And no patient gives up from all the studies. Only5studies describe the standard of into and out of the test of the patients.4studies don't describe the standard test. The test of TNF alpha with the standard test or control test is carried out at the same time. TNF alpha testing method in all studies can be repeated. In all, all studies included have good quality.
2. Results of heterogeneity test
Spearman correlation is0.049and P=0.834. It says that there is no threshold effect in all studies. Cochran-Q=31.93, P=0.0441<0.05, X2of merger of sensitivity is54.67,and I2=63.4%. X2of merger of specificity is48.87,and I2=59.1%. We cloud say that there has heterogeneity among the studies.
3. Result of Meta-analyses
3.1Risults of effectsize
The information about TNF alpha to differential diagnosis bacterial meningitis and virus meningitis includes the following index:Sensitivity=0.80(95%CI:0.76to0.83),specificity=0.92(95%CI:0.89-0.94), likelihood ratio positive=.55(95%CI:5.26-10.83),likelihood ratio negative=0.26(95%CI:0.21-0.32) diagnostic odds ratio=38.52(95%CI:23.08-64.29) and the AUC of SROC=0.9267(SE=0.0132), Q*=0.8612(SE=0.0156).
3.2Results of subgroup analysis
According to the country (China or foreign country), age (children or adults), method of TNF alpha test, we divided all the studies into some groups. Through the subgroup analysis, we cloud know that there is no different between all the groups, no matter between Chinese and foreigners, or between children and adults.
3.3Results of sensitivity analysis
We removed the included studies one by one, and then do the Meta-analyses again. And we find that the AUC of Summary receiver operating characteristic (SROC) don't change much. That is to say that the quality of all included studies is reliable.
Conclusion
1. TNF alpha in Cerebrospinal fluid has a highly accurate sensitivity and specificity with a strong ROC curve, which makes it a new marker to differentiate bacterial meningitis from viral meningitis.
2. According to the results of subgroup analysis, we know that this way of diagnosis can be spreaded in all people, no matter Chinese or foreigners, children or adults.
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