Defining childhood severe falciparum malaria for intervention studies.
Defining childhood severe falciparum malaria for intervention studies.
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DOI：
10.1371/journal.pmed.0040251
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发表时间：
2007-08
期刊：
影响因子：
15.8
通讯作者：
Marsh K
中科院分区：
文献类型：
--
作者：
Bejon P;Berkley JA;Mwangi T;Ogada E;Mwangi I;Maitland K;Williams T;Scott JA;English M;Lowe BS;Peshu N;Newton CR;Marsh K
旨在预防儿童严重恶性疟疾的干预措施的临床试验需要明确的终点。国际上接受的严重疟疾的定义是敏感的，适合临床目的。然而，这一定义包括患有严重非疟疾和同时伴有寄生虫病的个体，因此在疫苗试验中可能缺乏特异性。虽然没有针对严重疟疾的“金标准”个体检测，但可以使用逻辑模型在儿童群体中估计疟疾归因分数（MAFs），我们使用逻辑模型来检验各种病例定义作为试验终点的适用性。在横断面调查中，共从健康儿童和肯尼亚地区医院收治的1 361名患有严重疾病的儿童身上采集了4 583份血液样本。在患有严重疾病和每微升血液中寄生虫超过2,500的2岁以下儿童中，中度和低传播地区的maf高于85%，但在高传播地区仅为61%。HIV和营养不良与maf降低无关，但胃肠炎伴严重脱水（定义为皮肤肿胀减少）、下呼吸道感染（临床医生的最终诊断）、脑膜炎（脑脊液[CSF]检查）和菌血症与maf降低相关。不排除这些条件时，总MAF为85%(95%可信区间[CI] 83.8% ~ 86.1%)，排除后为89% (95% CI 88.4% ~ 90.2%)，当阈值为2500只/μl时，总MAF为95% （95% CI 94.0% ~ 95.5%）。应用阈值和排除标准将敏感性降低至80% （95% CI 77%-83%）。通过应用寄生虫密度阈值和排除患有脑膜炎、下呼吸道感染（临床医生诊断）、菌血症和严重脱水的肠胃炎的儿童，但没有排除感染艾滋病毒或营养不良的儿童，可以提高严重疟疾病例定义的特异性。公认的严重疟疾的定义适用于临床目的，但是Philip Bejon及其同事指出，通过寄生虫密度阈值和排除患有某些疾病的儿童，可以改善临床试验中严重疟疾的特异性。疟疾每年造成一百多万人死亡，其中大多数是非洲的儿童。直到几年前，对疟疾的研究还不够，但现在许多研究人员都活跃在这个领域。医生称一些疟疾病例“很严重”。严重的儿童疟疾很难精确诊断。目前诊断严重疟疾的方案非常敏感：也就是说，几乎所有患有严重疟疾的儿童都将被正确诊断为严重疟疾。然而，议定书并不是很具体：许多没有严重疟疾的儿童，其症状是由其他疾病引起的，将被定义为患有严重疟疾。对于患病儿童的临床护理来说，这一定义是可以接受的，因为它确保将抗疟疾药物提供给所有可能从中受益的人，以及一些不需要这些药物的额外儿童。然而，这个定义对于研究目的并不是特别有用。在进行旨在预防疟疾病例的临床试验时，重要的是评估所测试的干预措施是否实际有效。因此，这类研究需要一种更具体的方法来计算人群中的疟疾病例数。目前诊断严重疟疾的定义包括可在床边或通过实验室调查观察到的一系列体征和症状，以及在患者血液中检测到疟疾寄生虫。然而，在许多疟疾流行地区，很大一部分人口携带没有疾病迹象的疟疾寄生虫；与此同时，疟疾的体征和症状与其他疾病相同。这里的研究人员想弄清楚他们是否可以开发出一种可用于研究的严重疟疾的准确“病例定义”。在这项研究中，研究了两组儿童：第一组是肯尼亚基利菲区医院儿童病房的1422名儿童，第二组是周围社区的4583名儿童。采集血样是为了查明儿童血液中疟原虫的普遍程度，还收集了入院儿童的标准临床和实验室数据。然后，研究人员用计算机比较了这些数据，并试图找出，通过将某些具有特殊体征、症状或观察结果的儿童排除在严重疟疾的诊断之外，他们是否能够提高定义的准确性。基本上，对于每一组患者，作者计算了“疟疾归因分数”，即可能由疟疾引起疾病的被研究个体的比例。研究人员发现，在疟疾低传播和中度传播的地区，可归因于疟疾的个体比例很高——接近85%。在疟疾传播率高的地区，这一比例要低得多，但可以通过只纳入血液中寄生虫比例高的儿童来改善这一比例。重要的是，研究人员还能够通过排除被诊断患有肠胃炎、下呼吸道感染、脑膜炎和血液中细菌感染的个体，提高对可能由疟疾引起的疾病的儿童的识别。如果所有这些人都被排除在外——所以只有那些血液中每微升寄生虫超过2500个的人才被认为患有严重疟疾——“疟疾归因率”上升到95%。这些发现不应直接用于改变对患有严重疟疾症状和体征的儿童的临床护理，而应用于临床试验，为该试验制定疟疾的“病例定义”。这种能力将帮助研究人员更准确地发现在他们的试验中测试的干预措施是否真的有助于预防疟疾病例。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0040251访问这些网站。世界卫生组织全球疟疾方案详细介绍了该组织在防治疟疾方面的活动，并提供了一些有用的资源；美国疾病控制和预防中心提供了许多疟疾资源，包括插图在内的关于疟疾的一般信息可从“Medline Plus”百科全书中获得
Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%). The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition. The accepted definition of severe malaria is appropriate for clinical purposes, but Philip Bejon and colleagues show its specificity in clinical trials may be improved by a parasite density threshold and by excluding children with certain conditions. Malaria is responsible for over a million deaths every year, and most of those who die are children in Africa. Until a few years ago, not enough research was being done on malaria, but now many researchers are active in this field. Doctors describe some cases of malaria as being “severe.” Severe malaria in children is very hard to diagnose precisely. Current protocols for diagnosing severe malaria are very sensitive: that is, virtually all children who do have severe malaria will be correctly diagnosed as such. However, the protocols are not very specific: many children who do not have severe malaria, but whose symptoms are instead caused by other diseases, will be defined as suffering from severe malaria. This definition is acceptable for the clinical care of sick children, because it ensures that antimalarial drugs are given to all who might benefit from them, plus some additional children for whom those drugs are not required. However, this definition is not particularly useful for research purposes. When conducting a clinical trial aimed at preventing cases of malaria, it is important to evaluate whether the intervention being tested actually works. Therefore, a more specific method of calculating the number of malaria cases within a population is needed for this type of research. The current definition for diagnosing severe malaria includes a set of signs and symptoms that may be observed at the bedside or as a result of laboratory investigation, along with the detection of malaria parasites in the patient's blood. However, in many malarious areas, a large proportion of the population carries malaria parasites without signs of disease; at the same time, the signs and symptoms of malaria are shared with other diseases. The investigators here wanted to find out whether they could develop an accurate “case definition” of severe malaria that can be used in research. In this study, two groups of children were studied: first, 1,422 children admitted to the children's wards of the Kilifi District Hospital in Kenya, and second, 4,583 children from the surrounding community. Blood samples were taken in order to find out how common malaria parasites were in the children's blood, and standard clinical and laboratory data were also collected from the children admitted to the hospital. The researchers then compared these data using a computer and tried to find out whether, by excluding certain children who had particular signs, symptoms, or observations, from the diagnosis of severe malaria, they were able to improve the accuracy of their definition. Essentially, for each patient group, the authors calculated “malaria-attributable fractions,” i.e., the proportion of individuals studied whose disease was likely caused by malaria. The researchers found that in areas with low and moderate transmission of malaria, the proportion of individuals whose disease could be attributed to malaria was high—nearly 85%. In areas with a high transmission rate of malaria, this fraction was much lower, but could be improved by including only children with a high proportion of parasites in their blood. Importantly, the researchers were also able to increase the recognition of children with disease likely caused by malaria by excluding individuals who had also been diagnosed with gastroenteritis, lower respiratory tract infections, meningitis, and bacterial infection in the blood. If all of these individuals were excluded—so only individuals with more than 2,500 parasites per microliter in their blood were regarded as having severe malaria—the “malaria-attributable fraction” rose to 95%. These findings should not be directly used to change the clinical care of children with the signs and symptoms of severe malaria, but rather can be used within a clinical trial to create a “case definition” of malaria particular to that trial. This ability will help researchers more accurately find out whether the intervention being tested in their trial really does help to prevent cases of malaria or not. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040251. The World Health Organization Global Malaria Programme details the organization's activities in fighting malaria, and provides a number of helpful resources; a factsheet on children and malaria is also available The US Centers for Disease Control and Prevention provides many malaria resources General information about malaria, including illustrations, is available from the“Medline Plus” encyclopedia
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影响因子：
6.4
作者：
Mwangi, TW;Ross, A;Marsh, K
通讯作者：
Marsh, K
影响因子：
2
作者：
SMITH, T;SCHELLENBERG, JA;HAYES, R
通讯作者：
HAYES, R
影响因子：
3.6
作者：
WRIGHT, PW;AVERY, WG;MCLARTY, JW
通讯作者：
MCLARTY, JW
影响因子：
168.9
作者：
Berkley, JA;Mwangi, I;Newton, CRJC
通讯作者：
Newton, CRJC
影响因子：
158.5
作者：
Berkley, JA;Lowe, BS;Scott, JAG
通讯作者：
Scott, JAG