SEVERE MALARIA IN AFRICAN CHILDREN: A CLINICAL NETWORK

疟疾仍然是撒哈拉以南非洲的一大祸害，每年造成1-2百万儿童死亡。我们对疾病发病机制的理解已经取得了重大进展，沿着的是杀死疟原虫速度快两倍的药物的出现--奎宁，目前的首选药物--但严重疟疾的死亡率没有改变。患有脑型疟疾、疟疾相关酸中毒和/或严重贫血的儿童中有15-40%会死亡，其中一半的死亡发生在到达医院后12小时内。五个在非洲儿童严重疟疾方面经验丰富的临床中心联合起来，组成了一个临床试验网络（SMAC）。我们个人对自己试图证明有希望的干预措施对疟疾死亡率的影响感到沮丧，我们决定，我们的根本目标是降低非洲儿童与严重疟疾相关的死亡率，最好是通过进行基于死亡率的多中心研究来实现。这种方法是必要的，因为 没有结果的替代标志物 任何一个地点的死亡都是罕见的。我们建议对患有疟疾并发酸中毒的儿童进行液体复苏，并对患有脑型疟疾的儿童进行戊四氮（PTX）作为辅助治疗。这两种方法都需要在更大规模的临床试验之前进行初步研究（1年）。我们的网络也很适合评估“疾病关联”，这可能会阐明发病过程或揭示潜在的新靶点。因为它是简单的评估，因为有合理的生物学和寄生虫学的影响，我们想确定白细胞内DiQment在儿童恶性疟原虫感染的预测价值。这项研究将是一项正在进行的网络活动的一部分，利用预先收集并存档在数据库中的标准化信息，描述每个地点的疟疾经验。统计和行政“核心”将促进网络的工作。将在每个研究中心输入数据，并传输至中心机构（5个研究中心之一）进行分析。每年将举行一次SMAC会议，会议之间的间隔将被频繁的研究中心之间的访问所打断，以便年轻的研究人员可以标准化他们的观察并体验其他环境。这种在重症儿童疟疾中进行多中心试验的能力以前是不存在的。一个大群体的统计能力可以发现与特定干预相关的死亡率即使很小的下降。考虑到疟疾造成的巨大死亡人数，这可能意味着整个撒哈拉以南非洲地区的死亡率大幅下降。

Malaria remains a major scourge in sub-Saharan Africa, killing 1-2 million children each year. Major advances in our understanding of disease pathogenesis have occurred, along with the emergence of drugs which kill the malaria parasite twice as rapidly quinine, the current drug of choice--- but the mortality rate for severe malaria has not changed. Between 15-40% of children with cerebral malaria, malaria-associated acidosis and/or severe anemia will die, and half of those deaths occur within 12 hours of arriving at a hospital. Five clinical centers with much experience of severe malaria in African children have joined together to form a clinical trials network (SMAC). Individually frustrated by our own attempts to demonstrate any impact of promising interventions on malaria mortality, we have decided that our fundamental goal, to lower the death rate associated with severe malaria in African children, would be best realized by conducting mortality-based multi-center studies. This approach is necessary because there are no surrogate markers for outcome deaths in any one site are rare We are proposing to evaluate fluid resuscitation in children with malaria complicated by acidosis, and pentoxifvrnne (PTX) as adjunct therapy in children with cerebral malaria. Both of these require pilot studies (1 year) prior to the larger clinical trials. Our network is also well-positioned to evaluate "disease associations" which may illuminate pathogenetic processes or reveal potential new targets. Because it is simple to assess and because there are plausible biological and parasitological implications, we would like to determine the predictive value of intraleukocvtic DiQment in children with P. falciparum infections. This study will be part of an ongoing network activity, describing the malaria experience in each site using standardized information collected prospectively and archived in a database. The statistical and administrative "cores" will facilitate the efforts of the network. Data will be entered at each site and transmitted to a central facility (at one of the five sites) for analysis. There will be an annual SMAC meeting, and the intervals between meetings will be punctuated by frequent visits between sites so that young investigators can standardize their observations and experience other settings. This capacity to conduct multi-center trials in severe pediatric malaria has not existed before. The statistical power of a large group can unearth even a small decrease in mortality associated with a particular intervention. Given the enormous toll of malaria, this could re resent a significant decline in the death rate across sub-Saharan Africa.