Posttreatment Reactions After Single-Dose Diethylcarbamazine or Ivermectin in Subjects With Loa loa Infection

Abstract

Background: Severe adverse reactions have been observed in individuals with Loa loa infection treated with either diethylcarbamazine (DEC), the drug of choice for loiasis, or ivermectin (IVM), which is used in mass drug administration programs for control of onchocerciasis and lymphatic filariasis in Africa. In this study, posttreatment clinical and immunologic reactions were compared following single-dose therapy with DEC or IVM to assess whether these reactions have the same underlying pathophysiology.

Methods: Twelve patients with loiasis and microfilarial counts <2000 mf/mL were randomized to receive single-dose DEC (8 mg/kg) or IVM (200 µg/kg). Clinical and laboratory assessments were performed at 4, 8, 24, 48, and 72 hours and 5, 7, 9, and 14 days posttreatment.

Results: Posttreatment adverse events were similar following DEC or IVM, but peaked earlier in subjects who received DEC, consistent with a trend toward more rapid and complete microfilarial clearance in the DEC group. After a transient rise (post-IVM) or fall (post-DEC) in the first 24 hours posttreatment, the eosinophil count rose significantly in both groups, peaking at day 5 in the DEC group and day 9 in the IVM group. Serum interleukin 5 levels and eosinophil activation, as assessed by surface expression of CD69 and serum levels of eosinophil granule proteins, were increased posttreatment in both groups.

Conclusions: Despite differences in eosinophil and lymphocyte counts during the first 24 hours posttreatment, the overall pattern of hematologic and immunologic changes suggest that posttreatment reactions following DEC and IVM share a common pathophysiology.

Clinical trials registration: NCT01593722.

Keywords: Loa loa; diethylcarbamazine; eosinophil; filariasis; ivermectin.

Figure 1.

Time course of posttreatment adverse events (AEs). The histogram shows the total number of AEs recorded for subjects in the diethylcarbamazine (DEC; black bar) and ivermectin (IVM; gray bar) groups for each time point.

Figure 2.

Microfilarial clearance following single-dose administration of diethylcarbamazine (DEC) or ivermectin (IVM). A, The geometric mean microfilariae (MF) count per milliliter of blood is shown over time during the first 14 days post-DEC (black circles, dashed line) or post-IVM (open circles, solid line). Geometric mean of 0 indicates that mf were undetectable in all individuals in the group. B, Individual mf counts at baseline and 14 days posttreatment in both groups. *P < .05 between the 2 groups; Mann-Whitney U test (A) and Wilcoxon signed-rank test (B).

Figure 3.

Hematologic responses following single-dose administration of diethylcarbamazine (DEC) or ivermectin (IVM). Each symbol represents the geometric mean of the absolute cell count expressed as a percentage of baseline for subjects who received DEC (black circles, dashed line) or IVM (open circles, solid line). The gray area indicates below the 100% baseline value. *P < .05 and **P < .01 between the 2 groups; Mann-Whitney U test. Abbreviation: GM%, geometric mean %.

Figure 4.

Eosinophil surface activation marker expression following single-dose administration of diethylcarbamazine (DEC) or ivermectin (IVM). Percentage of CD69⁺ eosinophils at day 0, day 1, and day 3 post-DEC (black circles, dashed line) and post-IVM (open circles, solid line). The gray area shows the range of normal values in >125 healthy subjects (≤2.2%). *P < .05 compared to baseline, Wilcoxon signed-rank test. Abbreviation: ND, not detectable.

Figure 5.

Eosinophil granule protein levels following single-dose administration of diethylcarbamazine (DEC) or ivermectin (IVM). Geometric mean (GM) levels of eosinophil-derived neurotoxin (EDN) and eosinophil peroxidase (EPO) over time posttreatment (A and B, respectively) and EDN and EPO levels in individual subjects at baseline and at 8 hours posttreatment (C and D, respectively) are shown. Subjects who received DEC are indicated by black circles and dashed lines and those who received IVM by open circles and solid lines. *P < .05, Wilcoxon signed-rank test.

Figure 6.

Lymphocyte subset analysis following single-dose administration of diethylcarbamazine (DEC) or ivermectin (IVM). Percentages of baseline CD3⁺CD4⁺, CD3⁺CD4⁺CD25⁺, CD3⁺CD8⁺, and CD3⁺TCRγδ⁺ in peripheral blood measured at day 1 and day 3 posttreatment. Data for individual subjects who received DEC are denoted by black circles and dashed lines and those who received IVM by open circles and solid lines. The gray areas indicate a decrease from baseline values. *P < .05, Wilcoxon signed-rank test.

Figure 7.

Serum mediator levels following single-dose administration of diethylcarbamazine (DEC) or ivermectin (IVM). Heat maps represent the range of net values for the first 7 days posttreatment (from low in blue to high in red) measured for interleukin (IL) 5, IL-9, IL-10, IL-13 (A), monocyte chemotactic protein-1 (MCP-1), eotaxin-1, IL-8, Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) (B), and tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), and IL-17A (C). Subjects have been clustered separately for the 2 treatment groups with subject number shown along the right side of the heat map. A gray square indicates a missing value. Individual values measured at baseline (D0) and at peak are represented below the heat maps for mediators showing a clear expression pattern (DEC group, black circle, IVM group, white circle).