Adverse reactions after community treatment of onchocerciasis with ivermectin in Guatemala.

Male and female residents on a Guatemalan coffee plantation where Onchocerca volvulus infections were hyperendemic were offered oral ivermectin (100-200 micrograms/kg) as part of a community-wide treatment programme for onchocerciasis. Forty-five persons were treated and then questioned daily for 28 d about changes in their health. Those with complaints were monitored until all signs and symptoms had resolved. Sixty-seven percent complained of some adverse event after treatment; 60% developed observable adverse reactions attributed clinically to ivermectin. No reaction was life-threatening; the most common were oedema (53%) and fever (47%). Expulsion of intestinal helminths was reported by 38%. Almost all reactions began 24-48 h after treatment; their mean duration was 5 d, despite treatment with acetaminophen and antihistamines. Three patients had oedematous changes lasting over 2 weeks. Incidence, but not severity, of reactions was related to the pretreatment density of microfilariae in skin.

Guatemalan human onchocerciasis. II. Evidence for IgG3 involvement in acquired immunity to Onchocerca volvulus and identification of possible immune-associated antigens.

Ag-specific isotypic differences in immune response to Onchocerca volvulus Ag were assessed for 778 long term residents of endemic Guatemalan areas by quantitative ELISA with 5-min incubation steps and immunoblot. The study population was separated into five groups based on clinical status: N+F+, N+F-, N-F+, N-F-H+, and N-F-H-, where N = O. volvulus adults (nodule), F = microfiladermia, and H = history of O. volvulus infection. A subset of 44 individuals with high exposure to onchocerciasis from the N-F-H- group were critically evaluated and designated as "putatively immune." IgG1 reactivity to O. volvulus Ag was elevated in the majority of infected persons, but not in putatively immune individuals. Specific IgG3 levels, however, were equally elevated in all groups. The majority of N+F- persons also had elevated IgG1 levels, but they were lower than those found in F+ persons. IgG3 reactivities to a group of antigens at 20 kDa (GP20) were seen in many uninfected persons and some N+F- persons. In contrast, most F+ persons, react to this Ag with IgG1 and not IgG3. A mangabey inoculated with the infectious larval stage of O. volvulus (L3), but showed no signs of infection, began to recognize GP20 at 2 wk postinoculation. Early recognition of GP20 was possibly elicited by the larval stage. Purified nodule Ag from N+F+ individuals contained GP20, however, identical nodule Ag prepared from N+F- individuals did not. These data suggest that GP20 Ag may be common to both uterine microfilaria and the infectious larval stages. The fact that GP20 is predominantly recognized by IgG3 in putatively immune persons and some N+F- persons suggests that this increased IgG3 activity may be important in acquired immunity to onchocerciasis.

Guatemalan human onchocerciasis. I. Systematic analysis of patient populations, nodular antigens, and specific isotypic reactions.

The population from five Guatemalan plantations in areas endemic for onchocerciasis was surveyed, and 1032 individuals were recruited to participate in our study. From physical examination, past clinical history (5 to 8 yr), laboratory evidence and sample availability, a group of 778 long term residents with confirmed disease status were selected for detailed examination. We were able to identify 268 long term residents of endemic areas who had never been infected, 44 of these are from hyper- and mesoendemic areas. The 44 uninfected individuals from the hyper- and mesoendemic areas, because of their considerable exposure to this disease, were classified as "putatively immune." Intact nodules containing adult worms of Onchocerca volvulus were homogenized in the presence of protease inhibitors and fractionated into particulate and aqueous isotonic soluble antigens. Systematic analysis of these Ag fractions showed considerable amounts of Ig, presumably associated with Ag in the form of immune complexes. Individual specific antibody reactions from all 778 patients to nodule Ag were examined. Reactions to O. volvulus antigens by antibodies from patients with confirmed parasitic infections were almost exclusively restricted to IgG1 and IgG4 isotypes. Antigenic activity appeared to be primarily associated with low molecular mass (14 to 29 kDa) components. Some competitive blocking of antibody activities of other isotypes by IgG1 was observed, most notable was that of IgG3 and IgA. IgG4 and IgM activities were not significantly blocked.

Experimental Onchocerca volvulus infections in mangabey monkeys (Cercocebus atys) compared to infections in humans and chimpanzees (Pan troglodytes).

Three chimpanzees, three mangabey monkeys (Cercocebus atys), and 14 patas monkeys (Erythrocebus patas) were inoculated with L3 Onchocerca volvulus of Guatemalan origin. One chimpanzee and two mangabey monkeys developed antibody activity to at least three different antigens. Both mangabey monkeys recognized a 20 kDa antigen 3.5-5 months post-inoculation, and the monkeys and the chimpanzee developed antibody activity to 14 and 22 kDa antigens 7.5-13 months post-inoculation. One mangabey monkey and the chimpanzee became microfilaria-positive in skin snips at 16 and 21 months post-inoculation, respectively. Antibody activity to the 20 kDa antigen in the mangabey monkeys is noteworthy because of the prominence of this antigen among putatively immune persons living in onchocerciasis-endemic areas. The two mangabey monkeys responded parasitologically in a manner comparable to immune humans. No microfilariae were detected in one monkey and only scant numbers of microfilariae were observed in the second. The mangabey monkey may be a good animal model for the study of onchocerciasis.

Dynamics of microfilariae of Onchocerca volvulus over the first 72 hours after treatment with ivermectin.

Changes in microfilaria (mf) densities in skin, blood and urine were followed over 72 hours in 8 Guatemalan patients who received invermectin (150 mcg/kg po in a single dose). After an initial increase at 6 hours, the significance of which is not clear, mf densities in skin snips decreased rapidly to reach 13% of their pre-treatment level by 48 hours and then fell much more slowly over the next 24-hour period. The fall in mf concentrations is thought to be mainly a result of movement away from the subepidermal layer. In contrast to what happens after DEC, it was not accompanied by any marked wave of microfilaraemia or microfilaruria, nor by the appearance of a papular rash, although brawny oedema of the skin sometimes developed. Reactions that occurred after ivermectin could not be correlated with the initial density of microfiladermia. It is hypothesized that the movement of mfs may be 1) into the deeper layers of the dermal collagen, 2) the subcutaneous fat, or 3) the lymphatic system.