Doxycycline improves filarial lymphedema independent of active filarial infection: a randomized controlled trial

Sabine Mand, Alexander Yaw Debrah, Ute Klarmann, Linda Batsa, Yeboah Marfo-Debrekyei, Alexander Kwarteng, Sabine Specht, Aurea Belda-Domene, Rolf Fimmers, Mark Taylor, Ohene Adjei, Achim Hoerauf, Sabine Mand, Alexander Yaw Debrah, Ute Klarmann, Linda Batsa, Yeboah Marfo-Debrekyei, Alexander Kwarteng, Sabine Specht, Aurea Belda-Domene, Rolf Fimmers, Mark Taylor, Ohene Adjei, Achim Hoerauf

Abstract

Background: The aim of this study was to determine whether improvement of filarial lymphedema (LE) by doxycycline is restricted to patients with ongoing infection (positive for circulating filarial antigen [CFA]), or whether the majority of CFA-negative patients with LE would also show a reduction in LE severity.

Methods: One hundred sixty-two Ghanaian participants with LE stage 1-5 (Dreyer) were randomized blockwise into 2 groups (CFA positive or negative) and allocated to 3 treatment arms of 6 weeks: (1) amoxicillin (1000 mg/d), (2) doxycycline (200 mg/d), or (3) placebo matching doxycycline. All groups received standard hygiene morbidity management. The primary outcome was reduction of LE stages. Secondary outcomes included frequency of acute attacks and ultrasonographic assessment of skin thickness at the ankles. Parameters were assessed before treatment and after 3, 12, and 24 months.

Results: Doxycycline-treated patients with LE stage 2-3 showed significant reductions in LE severity after 12 and 24 months, regardless of CFA status. Improvement was observed in 43.9% of doxycycline-treated patients, compared with only 3.2% and 5.6% in the amoxicillin and placebo arms, respectively. Skin thickness was correlated with LE stage improvement. Both doxycycline and amoxicillin were able to reduce acute dermatolymphangioadenitis attacks.

Conclusions: Doxycycline treatment improves mild to moderate LE independent of ongoing infection. This finding expands the benefits of doxycycline to the entire population of patients suffering from LE. Patients with LE stage 1-3 should benefit from a 6-week course of doxycycline every other year or yearly, which should be considered as an improved tool to manage morbidity in filarial LE. Clinical Trials Registration. ISRCTN 90861344.

Figures

Figure 1.
Figure 1.
Participant flow. Flow chart of all assessed volunteers (circulating filarial antigen positive and negative). Abbreviations: CFA, circulating filarial antigen; USG, ultrasonography.
Figure 2.
Figure 2.
Lymphedema (LE) staging. Differences in LE severity at 12 and 24 months compared with pretreatment severity is shown for each treatment group, according to per-protocol analysis. A, Box plots for all patients. B, C, Differences for the circulating filarial antigen (CFA)–positive (B) and CFA-negative (C) subgroups. For all figure parts, 0 denotes no change in LE stage, changes to <0 denote a decrease to lower LE stages, and changes to >0 denote an increase to higher LE stages. Abbreviation: LE, lymphedema.
Figure 3.
Figure 3.
Kaplan-Meier curves showing occurrence of acute attacks after treatment end for each treatment arm. Arrows denote follow-up time points. The following significant differences between the 3 treatment arms were detected at 3 months: amoxicillin versus doxycycline (P = .018) and amoxicillin versus placebo (P = .007); at 12 months: doxycycline versus placebo (P = .012) and amoxicillin versus placebo (P = .007); and at 24 months: doxycycline versus placebo (P = .007).
Figure 4.
Figure 4.
Reduction in skin thickness at the ankles, as analyzed by ultrasound. Box plots show differences in skin thickness at the ankles at 24 months compared to pretreatment (P = .001 for overall difference between the 3 treatment arms; Kruskal-Wallis test).

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