SEVERE MALARIA IN AFRICAN CHILDREN: A CLINICAL NETWORK

疟疾仍然是撒哈拉以南非洲的一个主要祸害，每年造成1至200万儿童死亡。我们对疾病发病机制的理解取得了重大进展，同时出现了杀死疟疾寄生虫速度比目前首选药物奎宁快两倍的药物，但严重疟疾的死亡率并没有改变。15-40%患有脑型疟疾、疟疾相关酸中毒和/或严重贫血的儿童将死亡，其中一半死亡发生在抵达医院后的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，形成了一个临床试验网络（SMAC）。我们自己试图证明有希望的干预措施对疟疾死亡率有任何影响，我们个人对此感到沮丧，我们决定，我们的基本目标是降低非洲儿童与严重疟疾有关的死亡率，最好通过开展基于死亡率的多中心研究来实现。这种方法是必要的，因为在任何一个部位的结局死亡都没有替代标记物。我们建议评估疟疾合并酸中毒儿童的液体复苏，以及戊氧弗林（PTX）作为脑型疟疾儿童的辅助治疗。这两种方法都需要在大规模临床试验之前进行试点研究（1年）。我们的网络也很好地定位于评估“疾病关联”，这可能阐明发病过程或揭示潜在的新靶点。因为它很容易评估，因为有可能的生物学和寄生虫学意义，我们想确定在儿童恶性疟原虫感染的预测价值的门框内DiQment。这项研究将成为一项正在进行的网络活动的一部分，利用前瞻性收集并存档在数据库中的标准化信息描述每个站点的疟疾经验。统计和行政“核心”将促进网络的工作。数据将在每个场址输入，并传送到一个中央设施（在五个场址之一）进行分析。每年将举行一次SMAC会议，会议之间的间隔将通过频繁的地点访问来打断，以便年轻的研究人员能够标准化他们的观察并体验其他环境。这种在严重儿童疟疾中开展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揭示出与特定干预相关的死亡率甚至很小的下降。鉴于疟疾造成的巨大伤亡，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.