CLINICAL AND THERAPEUTIC STUDIES OF HUMAN FILARIASIS

点击翻译按钮获取中文摘要

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.