Ottesen, Eric A.

Abstract Onchocerciasis patients treated with diethylcarbamazine often undergo a severe inflammatory response, the Mazzotti reaction. To assess the eosinophil's role in the pathogenesis of the Mazzotti reaction, we obtained serial blood, plasma, and skin biopsy specimens from 21 heavily infected patients and 3 endemic controls, both before and during therapy with diethylcarbamazine. Samples were analyzed for blood eosinophils, plasma levels of eosinophil granule major basic protein (MBP) and eosinophil-derived neurotoxin, eosinophil infiltration and eosinophil and mast cell degranulation in the skin. After the first dose of diethylcarbamazine, blood eosinophils fell from a pre-treatment level of 888 +/- 111 to 203 +/- 42 cells/mm3 at 8 h. This decrease was followed by a marked eosinophilia developing over the remaining 7 days of treatment and 14 days of follow-up. Plasma eosinophil-derived neurotoxin levels increased from 56 +/- 4 ng/ml pretreatment to a peak of 82 +/- 9 ng/ml at 8 h and returned to pretreatment levels by 48 h. Beginning at 12 h, plasma MBP levels increased from 730 +/- 74 ng/ml pretreatment to a peak of 1140 +/- 74 ng/ml after 5 days. Pretreatment skin biopsies stained for MBP by immunofluorescence showed a bright fibrillar pattern in the dermis consistent with chronic eosinophil degranulation; the MBP was localized on elastic tissue fibers. After treatment, skin biopsy specimens showed both the pretreatment fibrillar MBP staining pattern as well as focal eosinophil degranulation. Deposition of MBP around microfilariae in the papillary dermis was visible as early as 1.5 h. The lowest blood eosinophil levels and peak plasma eosinophil-derived neurotoxin levels coincided with the infiltration and degranulation of eosinophils in the skin. Mast cell degranulation in the skin was maximal by the first posttreatment biopsy (1.5 h) coincident with the beginning of eosinophil degranulation. Although the pathogenesis of the Mazzotti reaction is clearly complex, our results indicate that eosinophil degranulation is characteristic of the response and that it occurs with a time course suggestive of a role for the eosinophil in determining the clinical and pathologic manifestations of the reaction.

Abstract Eosinophilia is a common sequela of treatment in patients infected with the parasitic helminth Wuchereria bancrofti. We investigated the relationship between peripheral blood eosinophil levels and serum levels of eosinophil granule major basic protein (MBP) and Charcot-Leyden crystal (CLC) protein in 37 patients with Bancroft’s filariasis who were treated with diethylcarbamazine (DEC). Before treatment with DEC, eosinophil levels and serum levels of CLC protein, but not MBP, were found to be significantly elevated in both filariasis patients and an uninfected endemic control population. After treatment, patients with microfilaremia developed an initial eosinopenia followed by significant increases in their eosinophil levels and serum levels of both MBP and CLC protein, which peaked 1 to 2 wk after initiating treatment. Before treatment, eosinophil levels and serum levels of MBP and CLC protein were unrelated to the number of microfilariae in circulation, but after treatment, the degree of eosinophilia and the elevations in serum MBP and CLC protein were significantly correlated with the patients’ microfilarial worm burdens before treatment. In microfilaremic patients on DEC therapy, there was a statistically significant increase in serum MBP levels concomitant with the initial decrease in eosinophil levels observed on day 1 of therapy in these patients. Patients with filariasis (elephantiasis, hydrocoeles, or filarial fevers) but without microfilaremia, as well as an uninfected endemic control population, showed no change in their eosinophil levels or serum MBP or CLC protein levels during an identical course of DEC therapy. The eosinophilic response resulting from DEC therapy of patients with microfilaremia provides a unique opportunity to study the relationship between eosinophilia, eosinophil function, and possibly eosinophilopoiesis as reflected by the synthesis and/or release of eosinophil proteins in humans exposed to a quantifiable antigenic stimulus.