CLINICAL AND THERAPEUTIC STUDIES OF HUMAN FILARIASIS

人类丝虫病的临床和治疗研究

• 批准号: 6098938
• 负责人: Thomas B Nutman
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6098938
• 关键词: anthelmintics; clinical research; clinical trials; disease /disorder classification; enzyme linked immunosorbent assay; epidemiology; filariasis; human subject; human therapy evaluation; immunity; onchocerciasis; parasitic disease chemotherapy; parasitic disease diagnosis; parasitic diseases; pathologic process; polymerase chain reaction

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.

盘尾丝虫病的临床研究和发病机制- 因为与治疗相关的不良反应 用伊维菌素治疗盘尾丝虫病（尽管比用 先前可用的药物，乙胺嗪）可能是严重的， 全身性和衰弱（几乎总是涉及皮肤）， 这种治疗后反应的介质已经被鉴定， 量化。已经发现IL-5和GM-CSF两者都介导细胞凋亡。 治疗后观察到嗜酸性粒细胞增多，IL-6和TNF-α已被 是全身不良反应的主要介质 看治疗后。趋化因子RANTES也被 被鉴定为一种主要的嗜酸性粒细胞化学引诱剂， 接受治疗的患者的皮肤，以及一系列皮肤活检， 用于免疫细胞化学分析 了解皮肤炎症反应的机制 见过为了确定治疗后反应是否 以下伊维菌素治疗的患者与盘尾丝虫病共享一个 与使用旧药物治疗后的患者的病因相似 (DEC)，对盘尾丝虫病进行了仔细的临床和实验室研究 最近在加纳完成了一项对接受伊维菌素治疗的患者的 和实验室评估血液细胞因子水平在 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，莫凯）的全部人口 在最初研究班氏丝虫病17年后， 能够对自然历史进行重要的观察 临床丝虫病，这是知之甚少，因为它的长期 慢性病程“暴露但未感染”的存在 （pupelimmune）个体被证实，因为大多数人 在1974年被归类为这样的人仍然完全没有感染， 继续暴露于感染。可能影响 暴露于W. bancrofti感染正在 通过在库克群岛和 印第安人。虽然这些研究仍在进行中，但它 已经认识到，在马德拉斯的40名患者中， 热带肺嗜酸性粒细胞增多症（TPE）综合征有两种 受影响的兄弟深入分析了 这些患者，结合临床，免疫HLA 对这些家庭的研究，同胞对分析仍在继续。临床和 维持（三个）的患者之间的免疫学差异 微丝蚴血症者和未能清除微丝蚴血症者 经过明确的治疗后，已被评估。虽然 研究仍在进行中，初步分析表明，无论 免疫学？背叛？它允许持久的 尽管治疗，寄生虫仍然存在。因此，免疫学和 临床上没有明显的差异（除了存在 微丝蚴血症），在那些保持微丝蚴自由和 微丝蚴血症者治疗后长期存活者。诊断 技术Loa loa-一种基于多重PCR的评估方法， 最初使用4个靶序列，开发用于确定 诊断Loxia。经过改进，现在系统使用2个目标 序列已被证明是最敏感和特异的。 使用这种基于PCR和ELISA的检测系统，我们 开发了一种检测感染的方法， 敏感性和98%特异性。在最优条件下 灵敏度和特异性现在已经设定，这种 目前，基于PCR的检测方法在诊断活动性感染中的应用尚不多见。 通过筛选收集的全血样本， 西非和转诊至NIH的患者中。治疗 在治疗方面有四个主要的进展， 治疗丝虫病的方法 关于过去一年。这些是：1）伊维菌素的效用， 与DEC联合用于以社区为基础的淋巴 丝虫病; 2）7天/月的杀灭巨丝虫效果的证据 施用DEC治疗淋巴丝虫病; 3） 阿苯达唑治疗洛可可及其在由于 极端数量的循环微丝蚴， 其他治疗方案的候选人; 4） 阿苯达唑用于治疗DEC难治性癫痫。