Neutrophil activation in ivermectin-treated onchocerciasis patients

Abstract

SUMMARY Invermectin is a safe and effective drug for onchocerciasis treatment. In certain individuals, however, therapy is accompanied by adverse reactions. The mechanisms underlying these reactions are not yet known. The aim of the present study was to investigate whether neutrophils are involved in the development of these adverse reactions. Elastase and lactoferrin, two markers for the release of neutrophil azurophilic and specific granule contents respectively, were measured by radioimmunoassays in plasma of onchocerciasis patients with varying degrees of side effects, as well as in control subjects before and 1 and 2 days after ivermectin treatment. A considerable increase of elastase levels after treatment was observed, whereas lactoferrin levels did not change. The percentage of patients with elevated elastase levels was significantly correlated with the degree of side effects. These findings suggest that neutrophil activation may be involved in the development of adverse reactions in these patients.

Immunoepidemiological Profiling of Onchocerciasis Patients Reveals Associations with Microfilaria Loads and Ivermectin Intake on Both Individual and Community Levels

“…Neutrophils have been a rather neglected cell population but numerous pieces of research are beginning to reveal a see-saw relationship between eosinophils and neutrophils during filarial infections. Studies have shown that both eosinophils and neutrophils increased shortly after IVM therapy with the former being strongly associated with MF elimination within the draining lymph nodes [55] , [56] . Our data shows that neutrophils are significantly elevated in a-MF patients even after a lengthy interval of individual IVM therapy but according to our regression analysis it is the presence of MF that is most associated with neutrophil numbers.…”

How do the macrocyclic lactones kill filarial nematode larvae?

“…Perhaps the simplest hypothesis, given the effects of IVM on protein secretion by Mf (Moreno et al 2010), is that the MLs inhibit release of immunomodulatory signals by the parasites and thus allow the innate immune system to recognize and remove them. Ivermectin treatment does cause neutrophil activation and increases in C-reactive protein and IL-6 in onchocerciasis patients and although this was associated with adverse effects of the treatment (Njoo et al 1993; 1994), it could be an important part of the drug’s mode of action. Nematodes release immunomodulatory molecules from a variety of places other than the excretory/secretory pore, including the gut and uterus (Chehayeb et al 2014; Buck et al 2014), however neither of these structures are present in Mf, and the ES pore is likely to be the main, if not only, site of release from this particular stage of the parasite life cycle.…”

Human filarial Wolbachia lipopeptide directly activates human neutrophils in vitro

“…Systemically, neutrophil activation is also observed during the adverse reactions following microfilaricidal treatment of filariasis patients, which correlate with pretreatment mf loads and the presence of liberated Wolbachia DNA or whole bacterial cells in the circulation 16 – 18 . Systemic adverse events and levels of liberated circulating Wolbachia also positively correlate with neutrophilia, circulating levels of pro-inflammatory cytokines, including the neutrophil CXC chemokine IL-8 (CXCL8) and neutrophil-derived molecules, such as calprotectin and calgranulin B 16 – 19 .…”