Redefining Cerebral Malaria

描述(申请人提供)：“脑型疟疾”是一种临床综合征，由恶性疟原虫寄生虫病患者的抽搐、低血糖或脑膜炎引起的昏迷组成。每年有100万至200万非洲儿童死于脑型疟疾，这一临床病例定义被用来诊断和治疗个别患者，招募多组患者参加研究，以辨别各种关联(与临床和实验室特征、与对严重疾病的抵抗力或易感性有关的遗传特征)，并评估各种预防战略(驱虫蚊帐、间歇性推定疗法、疟疾疫苗候选)的影响。我们基于尸检的研究数据表明，这个标准的临床病例定义有23%的时间是错误的(62)。符合脑型疟疾临床病例定义并死亡的31名患者中，有7名没有脑型疟疾的组织学证据；其他非疟疾死因在尸检中被确定。真正的脑型疟疾患者与昏迷和偶发性寄生虫血症患者区别的唯一临床特征是眼底表现，统称为疟疾视网膜病变。这些数据很耐人寻味，但在考虑脑型疟疾的新定义之前，这些发现必须在非洲疟疾流行病学范围内的多个地点得到证实，而且样本量必须足够大，以评估眼睛发现与脑组织学(在致命病例中)的相关性，并评估在所有符合标准临床定义的病例中“疟疾视网膜病”的预后意义。我们的主要假设是，通过纳入床边眼科检查的结果，脑型疟疾的临床病例定义将得到显著改善。脑部寄生红血球隔离的组织学证据将是诊断的‘金标准’。第二个假设是，脑涂片(像血膜一样准备和染色，因此在非洲大多数地区医院的范围内)可以像脑组织学一样可靠地识别“真正的”脑型疟疾。这些假设将在SMAC(非洲儿童严重疟疾)网络内进行检验，该网络包括东非和西非的五个地点。我们希望能够招募到足够的患者(n=1,964)，在60个月内完成这项研究。符合脑型疟疾临床病例定义的患者将有资格参加。SMAC临床医生将接受直接和间接眼底镜检查方面的培训，如果死亡，将征求家属的同意，通过眶上平板获取脑组织。眼部发现将与脑型疟疾的既定预后因素(所有患者)和脑组织学(在死亡病例中)进行比较。如果这种眼科检查被证明是有用的，脑型疟疾的新定义将极大地提高疟疾治疗、发病机制和预防的关键研究的效率。

DESCRIPTION (provided by applicant): 'Cerebral malaria' is a clinical syndrome consisting of coma not attributable to convulsions, hypoglycemia, or meningitis in patients with P. falciparum parasitemia. The deaths of 1-2 million African children each year are attributed to cerebral malaria, and this clinical case definition is used to diagnose and treat individual patients, to enroll groups of patients in studies to discern various associations (with clinical and laboratory features, with genetic traits associated with resistance or susceptibility to severe disease), and to assess the impact of various prevention strategies (insecticide-treated nets, intermittent presumptive therapy, malaria vaccine candidates). Data from our autopsy-based study suggest that this standard clinical case definition is wrong 23% of the time (62). Seven of 31 patients who met the clinical case definition of cerebral malaria and died had no histological evidence of cerebral malaria; other, non-malarial causes of death were identified at autopsy. The only clinical feature which differentiated the patients with 'true' cerebral malaria from those with coma and incidental parasitemia was ocular fundus findings known collectively as the 'malarial retinopathy'. These data are intriguing, but before a new definition of cerebral malaria can be considered, the findings must be confirmed in multiple sites across the epidemiological spectrum of malaria in Africa, and the sample size must be large enough to evaluate the association of eye findings with cerebral histology (in fatal cases) and to assess the prognostic significance of the 'malarial retinopathy' in all cases satisfying the standard clinical definition. Our primary hypothesis is that the clinical case definition of cerebral malaria would be significantly improved by including the results of a bedside eye examination. Histological evidence of the cerebral sequestration of parasitized red cells will be the 'gold standard' diagnosis. A secondary hypothesis is that 'brain smears' (prepared and stained as thin blood films are, and thus within the scope of most district hospitals in Africa) can identify 'true' cerebral malaria as reliably as brain histology. These hypotheses will be tested within the SMAC (Severe Malaria in African Children) network, which includes five sites in East and West Africa. We expect to be able to enroll enough patients (n=1,964) to complete this study within 60 months. Patients who satisfy the clinical case definition of cerebral malaria will be eligible for enrollment. SMAC clinicians will be trained in direct and indirect opthalmoscopy, and consent to obtain brain tissue via the supra-orbital plate will be sought from family members in the event of a death. Eye findings will be compared to established prognostic factors in cerebral malaria (in all patients) and to brain histology (in fatal cases). If this eye examination does prove useful, a new definition of cerebral malaria would greatly improve the efficiency of pivotal studies of malaria treatment, pathogenesis, and prevention.