Doxycycline Reduces Plasma VEGF-C/sVEGFR-3 and Improves Pathology in Lymphatic Filariasis

Abstract

Lymphatic filariasis is a disease of considerable socioeconomic burden in the tropics. Presently used antifilarial drugs are able to strongly reduce transmission and will thus ultimately lower the burden of morbidity associated with the infection, however, a chemotherapeutic principle that directly induces a halt or improvement in the progression of the morbidity in already infected individuals would constitute a major lead. In search of such a more-effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 33 microfilaremic and 18 lymphedema patients took part in a double-blind, placebo-controlled trial of a 6-wk regimen of 200 mg/day doxycycline. Four months after doxycycline treatment, all patients received 150–200 μg/kg ivermectin and 400 mg albendazole. Patients were monitored for Wolbachia and microfilaria loads, antigenemia, filarial dance sign (FDS), dilation of supratesticular lymphatic vessels, and plasma levels of lymphangiogenic factors (vascular endothelial growth factor-C [VEGF-C] and soluble vascular endothelial growth factor receptor-3 [(s)VEGFR-3]). Lymphedema patients were additionally monitored for stage (grade) of lymphedema and the circumferences of affected legs. Wolbachia load, microfilaremia, antigenemia, and frequency of FDS were significantly reduced in microfilaremic patients up to 24 mo in the doxycycline group compared to the placebo group. The mean dilation of supratesticular lymphatic vessels in doxycycline-treated patients was reduced significantly at 24 mo, whereas there was no improvement in the placebo group. Preceding clinical improvement, at 12 mo, the mean plasma levels of VEGF-C and sVEGFR-3 decreased significantly in the doxycycline-treated patients to a level close to that of endemic normal values, whereas there was no significant reduction in the placebo patients. The extent of disease in lymphedema patients significantly improved following doxycycline, with the mean stage of lymphedema in the doxycycline-treated patients being significantly lower compared to placebo patients 12 mo after treatment. The reduction in the stages manifested as better skin texture, a reduction of deep folds, and fewer deep skin folds. In conclusion, a 6-wk regimen of antifilarial treatment with doxycycline against W. bancrofti showed a strong macrofilaricidal activity and reduction in plasma levels of VEGF-C/sVEGFR-3, the latter being associated with amelioration of supratesticular dilated lymphatic vessels and with an improvement of pathology in lymphatic filariasis patients.

Efficacy of 5-week doxycycline treatment on adult Onchocerca volvulus

“…There was also a reduction in the proportion of living female and male worms at this point of time, but the number of extirpated worms was too small to allow the definite conclusion of a macrofilaricidal effect. However, a macrofilaricidal activity of doxycycline was demonstrated against Wuchereria bancrofti (Taylor et al 2005;Debrah et al 2006b), and recently also against O. volvulus, albeit at a higher daily dose of 200 mg/day, also after a longer observation period .…”

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

“…Besides an adulticidal effect, doxycycline has recently been shown to ameliorate pathology in patients with bancroftian filariasis, such as dilation in supratesticular scrotal lymphatic vessels, lymphedema, and hydrocele. 9 This effect was previously unknown and has not been observed after DEC; rather, in contrast, transient hydroceles developed and pre-existing ones increased after DEC. 3 We therefore addressed the following parameters in this trial: 1) long-term antimicrofilarial activity (caused by sterilization of adult female worms); 2) depletion of Wolbachia ; 3) loss of worm nests; 4) reduction of antigen levels; and 5) amelioration of dilated scrotal lymphatic vessels.…”

“…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.…”

“…6,7 In LF, 6-week and 4-week doxycycline treatments (200 mg/day) are effective at reducing Wolbachia single gene copies/Mf by 95%, which leads to sustained reductions of microfilaremia and shows strong macrofilaricidal activity of > 90% with concurrent improvement of LF pathology. 8,9 However, the duration of this treatment is rather long, even for the treatment of individuals or in selected problem areas, making a shorter regimen with doxycycline, likely in combination with "standard" antifilarial drugs, advantageous.…”

Immunology of Lymphatic Filariasis

“…Vascular endothelial growth factor (VEGF) family members have also been implicated in lymphangiogenesis. It was recently shown that lymphaticendothelial specific VEGF-C levels are significantly elevated in individuals with filarial disease (68). The other VEGF family member that has been implicated to play a role in filarial disease is VEGF-A (69).…”