Redefining Cerebral Malaria

描述（由申请人提供）：“脑疟疾”是恶性疟原虫寄生虫病患者的一种临床综合征，包括昏迷，而不是由于抽搐、低血糖或脑膜炎。每年有100万至200万非洲儿童死于脑型疟疾，这一临床病例定义用于诊断和治疗个别患者，将患者分组纳入研究，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相关的遗传特征），并评估各种预防战略(驱虫蚊帐、间歇性推定治疗、疟疾候选疫苗)。我们基于尸检的研究数据表明，这种标准的临床病例定义在23%的情况下是错误的（62）。31例符合脑型疟疾临床病例定义并死亡的患者中有7例没有脑型疟疾的组织学证据；尸检时确定了其他非疟疾死亡原因。区分“真正的”脑型疟疾患者与昏迷和偶发寄生虫病患者的唯一临床特征是眼底发现，统称为“疟疾视网膜病变”。这些数据令人感兴趣，但在考虑脑疟疾的新定义之前，这些发现必须在非洲疟疾流行病学谱的多个地点得到证实，样本量必须足够大，以评估眼部发现与脑组织学（在致命病例中）的关联，并评估所有符合标准临床定义的病例中“疟疾性视网膜病变”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。寄生红细胞脑隔离的组织学证据将是诊断的“金标准”。第二种假设是，“脑涂片”（像薄血膜一样制备和染色，因此在非洲大多数地区医院的范围内）可以像脑部组织学一样可靠地识别“真正的”脑疟疾。这些假设将在SMAC（非洲儿童严重疟疾）网络内进行测试，该网络包括东非和西非的五个站点。我们希望能够招募足够的患者（n= 1964）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入组。SMAC临床医生将接受直接和间接视镜检查的培训，并且在死亡的情况下，将征求家属同意通过眶上板获取脑组织。将把眼部检查结果与脑疟疾（所有患者）中已确定的预后因素和脑组织学（死亡病例）进行比较。如果这种眼科检查确实证明有用，脑型疟疾的新定义将大大提高疟疾治疗、发病机制和预防关键研究的效率。

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.