The filarial parasite, Mansonella perstans (Mp), is endemic in central and West Africa with a geographic distribution that overlaps those of Wuchereria bancrofti (Wb), Loa loa, and Onchocerca volvulus. Despite microfilarial prevalences as high as 100% in some regions, little is known about the clinical manifestations of Mp infection. During an ultrasound survey of men coinfected with Mp and Wb in Sabougou, Mali, a surprisingly high prevalence of hydrocele was noted. Since Mp adults are generally found in serosal cavities, this raised the possibility that Mp infection was contributing to this pathology. To further investigate this association, ultrasound examinations were performed in 32 men with Mp monoinfection from the same villages as the original study and 23 normal controls living in Bamako. The prevalence of hydrocele (> 5 ml) was 5/32 (16%) as compared to 35/63 (56%) in men coinfected with Wb and Mp and 0/23 (0%) in normal controls. Other abnormal findings included lymphatic dilatation in 31/32 (97%), and testicular and/or scrotal calcifications in 8/32 (25%), as compared to 57/63 (90%) and 16/63 (25%) in coinfected patients. Although mild lymphatic dilatation was also noted in 13/23 (56%) of the normal controls, scrotal calcifications were not seen in this group. Interestingly, Mp microfilariae were detected in the hydrocele fluid of 2/15 patients with Mp infection who underwent hydrocelectomy and from whom fluid was examined at the time of the surgery. These findings suggest a heretofore unrecognized association between Mp infection and intra- and extra-testicular pathology. ? ? The clinical and immunologic contributions of Mp infection are unknown, in part, because of the lack of response of Mp to standard antifilarial therapies. The recent discovery of bacterial endosymbionts (Wolbachia) in most filarial species, including Mp (Keiser et al. 2008 Mol Biochem Parasitol), provides new therapeutic options for reducing microfilaremia. In an open label, randomized trial, subjects with Mp microfilaremia with and without concomitant Wb infection were recruited from 4 villages in Mali and received doxycycline (200 mg daily for 6 weeks; n=106) or no treatment (n=110). At 6 months, Wb coinfected subjects were randomized further to receive a single dose of albendazole (400 mg) and ivermectin (150 g/kg) or no treatment. Subjects were monitored daily during treatment for adverse events. The effects of drug treatment on Mp and Wb microfilarial levels were assessed at 6 and 12 months following the initiation of doxycycline therapy. Doxycycline was safe and effective at reducing Mp microfilaremia at 6 and 12 months. Furthermore, at 12 months, 67/69 doxycycline-treated subjects had no detectable Mp microfilariae/60 l blood as compared to 10/63 untreated subjects. Single dose albendazole and ivermectin provided no additional benefit to doxycycline in reducing Mp microfilaremia 6 months following their use. These results are consistent with previous findings that Mp harbors the intracellular endosymbiont, Wolbachia, and provide the first example of effective therapy for Mp infection. ? ? In Mali, infection with Wuchereria bancrofti and/or Mansonella perstans exists in several regions highly endemic for malaria, and co-infection is common. Pre-existing filarial infection and the resultant bias toward a modulated Type 1 immune response could alter the response to incoming malarial parasites, clearance of which is thought to depend on robust IFN and TNF responses. In turn, this could affect the clinical manifestations and outcome of malaria infection. To determine the effect of filarial infection on the prevalence and severity of malaria infection, 41 filaria-positive (FP) and 42 filaria-negative (FN) children and young adults (1-20 years of age) matched for age, gender and HbS/HbC status were followed weekly through the malaria transmission season (July-December 2007). Anthelmintic treatment was administered to diminish the potential confounding effect of geohelminth infection. Clinical malaria was defined as signs and symptoms consistent with malaria infection in the presence of parasitemia. Baseline parameters were comparable between the groups. There were no differences between the FP and FN subjects with respect to the incidence of malaria, the incidence of fever at presentation with malaria or the time to first malaria episode. However, parasitemia at the time of the first malaria episode was significantly higher in the FN group (926 parasites/mm3 vs. 353 parasites/ mm3 in the FP group, p=0.04). These findings suggest that filarial infection does not influence susceptibility to malaria infection but may lower the threshold for developing symptomatic infection. Analysis of symptom scores and cytokines during clinical malaria episodes is currently underway and should help elucidate the role of immune effectors in this process. ? ? To examine the chronic effects of pre-existent filarial infection on the immune response to malaria, filaria antigen- specific and malaria antigen-specific cytokine responses were examined in 20 FN and 19 FP individuals prior to the malaria transmission season. Of note, the Fil+ group mounted a markedly diminished IL-12p70, IFN- and IP10 response following MalAg stimulation compared to the Fil- group but a significantly higher IL-10 response. Whereas, anti-TGF- had little effect, anti-IL10 antibodies induced a significant reversal of the MalAg specific downregulation of IL-12p70, IFN- , and IP10. Blocking both IL-10 and TGF- together was no different than with IL-10 blockade alone. Taken together these data demonstrate that filarial infections clearly modulate the Pf-specific IL-12p70-IFN- axis known to be pivotal for resistance to malarial parasites and do so in an IL10-dependent manner. Whether this Pf-specific Type 1 modulation extends to the level of CD4+ T cell frequencies of effector or regulatory cells is currently being evaluated in the same population. ? ? Albendazole and ivermectin are currently used in combination for annual mass treatment of Wuchereria bancrofti (Wb) infection in Africa. Although the drugs have been donated, the cost of such programs is very high and has proven to be a major impediment to the success of programs in countries with limited financial resources. Data from albendazole treatment of other filarial infections and one study comparing single to multi-dose DEC/albendazole in Wb infection suggest that increased dose and/or frequency of albendazole dosing may be more effective in maintaining microfilarial clearance. Furthermore, the optimal dose of ivermectin for suppression of Wb microfilaremia is greater than that being used in the mass treatment program. To determine the effect of increased dose and frequency of albendazole/ivermectin (A/I) treatment on microfilarial clearance, 42 Wb microfilaremic residents of an endemic area in Mali, were randomized to receive two doses of standard annual A/I therapy (400 mg/150 mcg/kg; n=22) or four doses of biannual increased dose A/I therapy (800 mg/400 mcg/kg; n=20). Six months after the first dose of therapy, microfilarial clearance rates were comparable (16/22 (80%) in the annual standard dose group and 13/20 (65%) in the biannual high dose group). The one year evalaution is currently underway.
