CLINICAL AND THERAPEUTIC STUDIES OF HUMAN FILARIASIS

人类丝虫病的临床和治疗研究

• 批准号: 6288852
• 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/6288852
• 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 pathogenesisOnchocerciasis - 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 posttreatment 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-alpha 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.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 - 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 Chennai, India, 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. The data suggest that both immunologically and clinically there are no obvious differences (save for the presence of microfilaremia) between those who remain microfilaria- free and those who are microfilaremic long term after therapy. Diagnostic techniquesLoa loa- A multiplex PCR-based assessment method, initially using 4 target sequences, was developed for the definitive diagnosis of loiasis. With refinements, 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.Stongyloides stercoralis - A PCR-based diagnostic for the detection of Strongyloides stercoralis in the stool has been established. Therapeutic trials The major advance in the therapeutic approach to the treatment of filarial infections that has come about over the past year is the demonstration of the utility of albendazole for the treatment of DEC-refractory loiasis. - Filarial, loiasis, filariasis, onchocerciasis, strongyloidiasis, albendazole, cytokines - Human Subjects

临床研究和发病机制-由于伊维菌素治疗盘尾丝虫病相关的不良反应(尽管比以前的现有药物二乙氨基马津轻微)可能是严重的、全身性的和虚弱的(几乎总是涉及皮肤)，这种治疗后反应的媒介已经被识别和量化。IL-5和GM-CSF都被发现介导了治疗后出现的嗜酸性粒细胞增多，而IL-6和肿瘤坏死因子-α被认为是治疗后出现的全身不良反应的主要介质。趋化因子RANTES也被确定为正在接受治疗的患者皮肤中的主要嗜酸性粒细胞趋化剂之一，并从这些患者的皮肤活检中获得了一系列的免疫细胞化学分析，以了解皮肤炎症反应的机制。为了确定伊维菌素治疗后的盘尾丝虫病患者的治疗后反应是否与旧药(DEC)治疗后的反应具有相似的病因，加纳最近完成了对接受伊维菌素治疗的盘尾丝虫病患者的仔细临床和实验室研究，并在治疗后反应期间对血液细胞因子水平进行了实验室评估。淋巴丝虫病--库克群岛和印度人口的广泛家庭研究正在评估可能影响暴露于班克罗夫蒂淋巴丝虫病感染的临床结果的因素。虽然这些研究仍在进行中，但已经认识到，在来自印度金奈的40名患有热带肺嗜酸性粒细胞增多症(TPE)的患者中，有两对兄弟受到影响。对这些患者的家系进行了深入的分析，结合对这些家庭的临床和免疫学的人类白细胞抗原研究，继续进行同胞配对分析。评估了维持(三年)微丝蚴血症清除的患者和那些在明确治疗后未能清除的患者之间的临床和免疫学差异。这些数据表明，治疗后长期保持无微丝虫病的患者与长期存在微丝虫病的患者在免疫学和临床上均无明显差异(微丝虫病的存在除外)。诊断技术LOA LOA-一种基于多重聚合酶链式反应的评估方法，最初使用4个靶序列，用于明确诊断血吸虫病。通过改进，使用2个靶序列的系统已被证明是最敏感和特异的。利用该检测系统，我们建立了一种检测感染的方法，灵敏度为100%，特异性为98%。随着最佳灵敏度和特异度的条件现已确定，目前正在通过对在西非收集的全血样本和在NIH转介的患者中进行筛查来建立这种基于PCR的检测方法在活动性感染诊断中的应用。治疗试验过去一年在治疗丝虫感染的治疗方法方面取得的主要进展是证明了阿苯达唑在治疗DEC难治性血吸虫病方面的有效性。-丝虫病、盘尾丝虫病、棘球线虫病、阿苯达唑、细胞因子-人类受试者