Reduction in Levels of Plasma Vascular Endothelial Growth Factor-A and Improvement in Hydrocele Patients by Targeting Endosymbiotic Wolbachia sp. in Wuchereria bancrofti with Doxycycline

Abstract

The treatment for hydrocele is expensive, invasive surgery-hydrocelectomy. A drug that could prevent or improve this condition could replace or supplement hydrocelectomy. In Ghana, 42 hydrocele patients participated in a double-blind, placebo-controlled trial of a six-week regimen of doxycycline, 200 mg/day. Four months after doxycycline treatment, patients received 150 mug/kg of ivermectin and 400 mg of albendazole, which is used for mass chemotherapy in this area. Patients were monitored for levels of Wolbachia sp., microfilaremia, antigenemia, plasma levels of vascular endothelial growth factor-A (VEGF-A) and stage/size of the hydrocele. Wolbachia sp. loads/microfilaria, microfilaremia, and antigenemia were significantly reduced in the doxycycline-treated patients compared with the placebo group. The mean plasma levels of VEGF-A were decreased significantly in the doxycycline-treated patients who had active infection. This finding preceded the reduction of the stage of hydrocele. A six-week regimen of doxycycline treatment against filariasis showed amelioration of pathologic conditions of hydrocele patients with active infection.

Macrofilaricidal Activity and Amelioration of Lymphatic Pathology in Bancroftian Filariasis after 3 Weeks of Doxycycline Followed by Single-Dose Diethylcarbamazine

“…From previously published studies, the results for the 4-month follow-up are not surprising, because we showed that Mf levels decrease according to Mf half-life without DEC or ivermectin intervention, 11 and significant and apparent reductions in worm nests and vessel dilation are more easily seen 12 months after the study start, when the adult worms have died and their antigens, such as CFA, have been cleared. 8,9,17 Because the 10-day doxycycline group did have a 90% reduction in Wolbachia that resulted in loss of worm nests and FDS 7 days after DEC administration, treatment times between 10 and 21 days should be tested to determine the shortest regimen that will result in the macrofilaricidal effects and reverse early pathology.…”

“…Although it requires a longer treatment time than currently used drugs, the advantage of anti-wolbachial treatment is that it has shown higher macrofilaricidal activity than DEC (ivermectin is not macrofilaricidal on its own) and that it leads to a reduction of lymph vessel dilation as well as to an improvement of lymphedema stages 9,15,16 and also hydrocele. 17 Because the treatment time (4 weeks) with just doxycycline needed to achieve a macrofilaricidal effect is long, the macrofilaricidal efficacy of doxycycline treatment before DEC treatment was tested. Two time courses (10 and 21 days) of doxycycline were included in the study design to determine whether the combination treatment would allow for a shorter doxycycline treatment.…”

“…The combination of doxycycline and DEC, in contrast to DEC alone, also reverses dilation of lymph vessels and thus improves lymphatic pathology, similar to what was observed for the combination of doxycycline and ivermectin/albendazole in earlier studies. 9,17 It may be this ameliorating effect on pathology that makes the use of doxycycline preferable for the treatment of individuals by doctors, who are charged with selecting a treatment that improves their patients' disease conditions.…”

Immunology of Lymphatic Filariasis

“…The other VEGF family member that has been implicated to play a role in filarial disease is VEGF-A (69). Elevated levels of VEGF-A and endothelin-1 have been observed in the serum of filarial-infected individuals and more specifically, VEGF-A has been implicated to play a role in the development of hydrocele due to its ability to induce increased vascular density, enhance leucocyte adhesion and promote lymphangiogenesis (70). Thus, excess secretion of pro-inflammatory cytokines and angiogenic factors like VEGF-A could result in extravasation and accumulation of fluids, plasma, and lymph from the blood and lymphatic vessels into the scrotum resulting in the formation of hydrocele.…”

Filarial hydrocele: a neglected condition of a neglected tropical disease

“…Further, some patients with filarial hydrocele (diagnosed by ultrasonography) do not have detectable microfilaria and circulating filarial antigens (Og4C3) in their blood [42][43][44]. This apparent discrepancy in ultrasonographic and biochemical/microbiological markers has been explained as resulting from the fact that ultrasonography is more sensitive in the diagnosis of filariasis than detection of either microfilaria or the circulating filarial antigen in the blood, especially when the microfilaria density is low [42,45].…”