CLINICAL AND THERAPEUTIC STUDIES OF HUMAN FILARIASIS

盘尾丝虫病的临床研究及发病机制 因为与治疗有关的不良反应 使用伊维菌素的盘尾丝虫病(尽管比使用伊维菌素的 以前可获得的药物二乙胺嘧啶)可能是严重的， 系统性的，衰弱的(几乎总是涉及皮肤)， 已经确定了这种治疗后反应的介体，并 量化的。IL-5和GM-CSF都被发现介导了 治疗后出现嗜酸性粒细胞增多，IL-6和肿瘤坏死因子-α 被牵连为全身不良反应的主要媒介 在治疗后看到的。趋化因子RANTES也一直是 被鉴定为嗜酸性粒细胞趋化因子之一 正在接受治疗的患者的皮肤，以及连续的皮肤活检 从这些患者身上获得用于免疫细胞化学分析的 了解皮肤炎症反应的机制 看到了。为了确定后处理反应是否 伊维菌素治疗盘尾丝虫病的疗效观察 与使用旧药治疗的患者的病因相似 (12月)，对盘尾丝虫病进行了仔细的临床和实验室研究 接受伊维菌素治疗的患者最近在加纳完成了 以及血液细胞因子水平的实验室评估 治疗后反应。淋巴丝虫病-通过重新评估 一个太平洋岛屿(库克群岛的莫克岛)的全部人口都是地方病 在最初研究班克罗夫斯坦丝虫病17年后，它已经 有可能对自然历史进行重要的观察 临床丝虫病，由于其漫长的历史而鲜为人知 慢性病程。“暴露而不感染”的存在 (假定免疫)个人被确认，因为大多数人 在1974年被归类为此类感染时，尽管 持续暴露在感染中。可能的影响因素 暴露于班氏假单胞菌感染的临床结果是 由库克群岛和澳大利亚的广泛家庭研究评估 印第安人。虽然这些研究仍在进行中，但它已经 已经认识到在来自马德拉斯的40名患有 热带肺嗜酸性粒细胞增多症(TPE)综合征有两种 一对受影响的兄弟。对家谱的深入分析 这些患者，结合临床，免疫学的人类白细胞抗原 对这些家族的研究，同胞配对分析仍在继续。临床和临床 维持(持续三年)患者之间的免疫学差异 几年)清除微丝虫病和未能清除微丝虫病的人 已经对最终的治疗进行了评估。尽管 研究仍在进行中，初步分析表明，无论 免疫学？缺陷？这允许持久化 尽管接受了治疗，寄生虫仍然存在。因此，无论是在免疫学上还是在 临床上没有明显的差异(除了 微丝虫病)，在那些保持微丝虫病的人和 那些长期治疗后出现微丝衰者。诊断性 技术LOA-一种基于多重PCR的评估方法， 最初使用了4个靶点序列，被开发为最终的 血吸虫病的诊断。经过改进，现在的系统使用2个目标 序列已被证明是最敏感和最特异的。 使用这个基于聚合酶链式反应和酶联免疫吸附检测系统，我们有 开发了一种100%检测感染的方法 敏感度和98%特异度。具有最优的条件 现在已经确定了灵敏度和特异度，这种方法的实用性 目前，以聚合酶链式反应为基础的检测方法在活动性感染诊断中的应用 是通过对收集的全血样本进行筛查而建立的 西非和其他转诊至美国国立卫生研究院的患者。治疗性的 试验在治疗方面取得了四个主要进展 治疗丝虫感染的方法已经到来 在过去的一年里。这些是：1)伊维菌素在 联合DEC用于淋巴系统的社区治疗 丝虫病；2)证明7天/月的大杀丝虫病效果 DEC治疗淋巴丝虫病3)疗效观察 阿苯达唑治疗血吸虫病及其在因 循环微丝虫的极端数量，不会是 其他治疗方案的候选方案；4) 阿苯达唑治疗DEC难治性血吸虫病。

Clinical studies and pathogenesis Onchocerciasis - Because the adverse reactions associated with treatment of onchocerciasis with ivermectin (although milder than with the previous available drug, diethycarbamazine) can be severe, systemic, and debilitating (and almost always involve the skin), the mediators of this post treatment reaction have been identified and quantified. Both IL-5 and GM-CSF have been found to mediate the post-treatment eosinophilia seen, and IL-6 and TNF-a have been implicated as the major mediators of the systemic adverse reactions seen post-treatment. The chemokine, RANTES, has also been identified as one of the major eosinophil chemoattractants in the skin of patients undergoing treatment, and serial skin biopsies have been obtained from these patients for immunocytochemical analysis to understand the mechanism of the skin inflammatory response seen. In order to determine whether the posttreatment reactions following ivermectin therapy of patients with onchocerciasis share a similar etiology with those following treatment with the older drug (DEC), a careful clinical and laboratory study of onchocerciasis patients receiving ivermectin has recently been completed in Ghana and the laboratory evaluation of blood cytokine levels during the posttreatment reactions. Lymphatic filariasis - By re-evaluating the entire population of a Pacific island (Mauke, Cook Islands) endemic for bancroftian filariasis 17 years after initially studying it, it has been possible to make important observations on the natural history of clinical filariasis which is poorly understood because of its long chronic course. The existence of "exposed but not infected" (putatively immune) individuals was confirmed, as most of those categorized as such in 1974 remained entirely infection free despite continued exposure to infection. Possible factors affecting the clinical outcome of exposure to W. bancrofti infection are being evaluated by extensive family studies in both the Cook Islands and Indian populations. While these studies are still ongoing, already it has been recognized that among 40 patients from Madras with the tropical pulmonary eosinophilia (TPE) syndrome there are two pairs of affected brothers. Intense analysis of the family trees of these patients, in conjunction with clinical, immunological HLA studies of these families, sib pair analysis continues. The clinical and immunological differences between patients who maintain (for three years) clearance of microfilaremia and those who fail to do so following definitive treatment has been assessed. Although the studies are still ongoing, preliminary analyses suggest that whatever immunological ?defect? that allows for the persistence of the parasite remains despite therapy. Thus, both immunologically and clinically there are no obvious differences (save for the presence of microfilaremia), between those who remain microfilaria free and those who microfilaremic long term after therapy. Diagnostic techniques Loa loa- A multiplex PCR-based assessment method, initially using 4 target sequences, was developed for the definitive diagnosis of loiasis. With refinements, now a system using 2 target sequences has been shown to be the most sensitive and specific. Using this system of PCR and ELISA-based detection, we have developed a method for detection of infection that is 100% sensitive and 98% specific. With the conditions for optimal sensitivity and specificity having now been set, the utility of such a PCR-based assay in the diagnosis of active infection is currently being established by screening whole blood samples collected in West Africa and among patients referred to the NIH. Therapeutic trials There have been four major advances in the therapeutic approaches to the treatment of filarial infections that have come about over the past year. These are: 1) the utility of ivermectin in combination with DEC for community-based therapy for lymphatic filariasis; 2) the proof of the macrofilaricidal effects of 7 day/month administration of DEC for lymphatic filariasis; 3) the efficacy of albendazole for loiasis and its utility in patients who, because of extreme numbers of circulating microfilariae, would not be candidates for other therapeutic regimens; 4) the utility of albendazole for the treatment of DEC-refractory loiasis.