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BACKGROUND: Infection with the parasitic filarial nematode Onchocerca volvulus can lead to severe visual impairment and ultimately blindness. Excess mortality has been noted among people with onchocerciasis, but it is not clear whether this effect is entirely due to blindness, or mediated by some more direct effects of the infection. METHODS: We assessed the relations between infection with O volvulus, visual acuity, and host mortality with data obtained by the Onchocerciasis Control Programme in West Africa from 2315 villages in 11 countries. FINDINGS: 297,756 people were eligible for follow-up, and accumulated 2,579449 person-years of follow-up from 1971 through 2001. 24,517 people died during this period; 1283 (5.2%) of these deaths were due to onchocerciasis. Mortality of the human host was significantly and positively associated with increasing microfilarial burden (p<0.00001), but not with blindness after adjustment for microfilarial load and other variables. Overall, after adjustment for microfilarial load and other variables, female individuals had a risk of death about 7.5% lower than males (p<0.00001). Rates of mortality peaked in the mid 1980s but generally decreased thereafter. INTERPRETATION: We have shown a direct relation between O volvulus microfilarial load and host mortality in a comprehensive dataset and in both sexes.

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Most parasites have complex life cycles; and mathematical models can help in targeting interventions and predicting disease-control efforts. For actual applications, quantification and validation of models is a key issue. We illustrate the process of validation by presenting a (re)analysis of fly-feeding experiments carried out by the Onchocerciasis (river blindness) Control Programme (OCP/WHO) in West Africa, with the objective to validate ONCHOSIM, an onchocerciasis transmission model. In these experiments flies were fed on human patients and dissected to count the number of microfilariae they had ingested. To assess microfilarial skin densities, skin snips (biopsies) were taken and examined. Originally, the resulting curve was interpreted as showing saturation and considered the main regulating (density-dependent) mechanism of onchocerciasis transmission in the model. Taking into account measurement errors in the skin microfilarial density of human subjects (on whom the flies were fed) we now conclude that the relationship is essentially linear. This prompts us to requantify ONCHOSIM. Possible alternative density-dependent mechanisms are discussed.

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OBJECTIVE: To elucidate the conditions in which mass treatment with ivermectin reduces the transmission of Onchocerca volvulus sufficiently to eliminate infection from an African community. METHODS: ONCHOSIM, a microsimulation model for onchocerciasis transmission, was used to explore the implications of different treatment intervals, coverage levels and precontrol endemicities for the likelihood of elimination. FINDINGS: Simulations suggested that control strategies based exclusively on ivermectin mass treatments could eliminate onchocerciasis. The duration of treatment required to eliminate infection depended heavily on the treatment programme and precontrol endemicity. In areas with medium to high levels of infection, annual mass treatments with 65% coverage for at least 25 years were necessary. Model predictions suggested that durations exceeding 35 years would be required if there were much heterogeneity in exposure to vector bites and, consequently, wide individual variation in microfilaria counts. If the treatment interval were reduced from 12 to 6 months the time for completion of the programme could be more than halved and elimination could be accomplished in areas of hyperendemicity, provided that the effects of each treatment would be the same as with annual treatments. However, it was doubtful whether high coverage levels could be sustained long enough to achieve worldwide eradication. CONCLUSION: Elimination of onchocerciasis from most endemic foci in Africa appears to be possible. However, the requirements in terms of duration, coverage, and frequency of treatment may be prohibitive in highly endemic areas.

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The standard assay for onchocerciasis diagnosis is microscopical detection of microfilariae in skin snips. Skin snipping is painful, requires appropriate sterilization of equipment, and may fail to diagnose light infections. Two alternatives are a polymerase chain reaction (PCR) test which detects parasite DNA in pieces or scrapings of skin and a test based on allergic reactions to topical application of diethylcarbamazine (DEC). We compared these 2 diagnostics with standard skin snip microscopy in 313 individuals from 2 villages in Guinea, with low prevalence after over 10 years of control by the Onchocerciasis Control Programme. Lower and upper bounds on sensitivities and specificities of these 3 tests were estimated. In addition, these parameters were estimated using 5 different statistical models. Where prevalence was low, PCR and the DEC patch test appeared to be more sensitive than skin snipping which has low sensitivity. As the DEC test is non-invasive, simple and cheap, it may provide a good alternative to skin snipping alone for surveillance in low prevalence areas.

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From 1976 through 1989, weekly aerial spraying operations against blackflies were carried out along the rivers of a wide savanna area of West Africa (approximately 700,000 km(2)) where onchocerciasis was hyperendemic. The level of endemicity began to decrease significantly after 4 years of vector control and became very low in 1989. This situation has been maintained without any vector control activity or chemotherapy, and no incidence of any new cases has been detected. An ophthalmological study carried out in 2000 has confirmed these good results, showing only cicatricial ocular lesions in the examined population. These results led to the conclusion that 14 years of vector control may achieve long-term elimination of onchocerciasis, even in the absence of chemotherapy, provided that the treated areas are not subjected to any contamination by exogenous parasites carried in infected humans or flies.

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The Onchocerciasis Control Programme in West Africa (OCP) has succeeded in eliminating blinding onchocerciasis as a public health problem throughout much of West Africa. The efforts of the OCP are now turning towards surveillance, with the goal of rapidly detecting and controlling outbreaks of infection in the onchocerciasis-free zone. With this goal in mind, cutaneous application of a solution of diethylcarbamazine (the DEC-patch test) was evaluated in 1996-99 as a method to detect patent Onchocerca volvulus infection in children and adolescents, a sentinel population for the detection of recrudescence. In an analysis of 1887 individuals in Côte d'Ivoire and Burkina Faso, the DEC-patch test produced prevalence estimates comparable to those obtained by skin snip. The sensitivity of the DEC-patch assay was marginally greater in children and adolescents than in adults, and was greater in individuals who had received prior Mectizan treatment. These data suggest that the DEC-patch test may be a useful tool for detecting recrudescence of O. volvulus infection in a sentinel population of children and young adults within the onchocerciasis-free zone created by the OCP.

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The classical method of determining the prevalence and intensity of onchocercal infection is by the demonstration and counting of microfilariae in biopsies obtained by skin snipping. Although very specific, this technique is inadequate for detecting early, light or prepatent infections, and is also becoming increasingly unacceptable to the populations investigated. The prolonged clearing effect that Mectizan (ivermectin, MSD) treatment has on skin microfilariae also renders the skin-snip method of diagnosis less appropriate in areas with Mectizan treatment. Given all these factors, the greater challenge in the area of diagnostics for onchocerciasis is to develop a less invasive, adequately sensitive, and equally specific diagnostic test, either to replace or to be an adjunct to the present skin-snip method. This challenge is being addressed, with at least three new diagnostic tests for onchocerciasis under development: an immunological assay, based on a three-antigen cocktail; a PCR-based assay, which may also be used for 'pool screening' of blackflies; and the diethylcarbamazine (DEC) patch test. Of all these tests, the DEC patch test seems to fit best the criteria of an ideal test. The PCR assay would be better than the patch test if the cost of using it could be reduced substantially.

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For many years there was no suitable drug available for the control of onchocerciasis. The advent of Mectizan (ivermectin, MSD; an effective microfilaricide), its registration in October 1987 for the treatment of human onchocerciasis, and its suitability for large-scale application were major break-throughs in the control of human onchocerciasis via chemotherapy. Several studies, both fly-feeding experiments and community trials, have established that Mectizan treatment causes a significant reduction in the transmission of infection. Although long-term treatment in some isolated foci (such as occur in the New World and in some hypo- and meso-endemic areas elsewhere) appears to interrupt transmission, more prolonged treatment is required to prove if transmission can be stopped. Advantage could be taken of the significant impact of Mectizan on transmission by giving treatment while or just before transmission by blackflies is most intense.

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In the extension areas of the Onchocerciasis Control Programme in West Africa, aerial larviciding is supplemented with annual ivermectin treatment, mainly to achieve better control of morbidity. The purpose of this study is to determine whether and to what extent the addition of annual ivermectin treatment permits earlier cessation of vector control than originally recommended. The effectiveness of combined ivermectin distribution and vector control was assessed using an epidemiological model. Model predictions suggest that, dependent on the pre-control endemicity of the area and the proportion of persons treated during each ivermectin round, large-scale annual treatment permits a considerable reduction in the duration of vector control. Taking into account uncertainty about the efficacy of ivermectin, our results indicate that, provided treatment coverage is at least 65% and there is no importation of infection from elsewhere, 12 years of combined control will be sufficient to reduce the risk of recrudescence to below 1% in even the most afflicted areas.

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Ivermectin is an effective drug for the treatment of human onchocerciasis, a disease caused by the parasitic filarial nematode Onchocerca volvulus. When humans are treated, the microfilariae normally found in the skin are rapidly and very nearly completely eliminated. Nonetheless, after a delay, microfilariae gradually reappear in the skin. This study is concerned with the causes of this delay. Hypotheses are tested by comparing the results of model calculations with skin microfilaria counts collected from 114 patients during a trial of five annual treatments in the focus area of Asubende, Ghana. The results obtained strongly suggest that annual treatment with ivermectin causes an irreversible decline in microfilariae production of approximately 30%/treatment. This result has important implications for public health strategies designed to eliminate onchocerciasis as a significant health hazard.

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A previous paper reported that the intake of Onchocerca volvulus microfilariae (mff) by different species of Simulium is essentially proportional to the parasite load in the skin of infected carriers. This paper examines the fate of the ingested mff in susceptible vectors to assess the relationship between parasite intake and infective larval output in blackfly species with and without well-developed cibarial armatures. Analysis is based on data from 3 onchocerciasis endemic areas: Guatemala (S. ochraceum s.l.), West Africa (S. damnosum s.l./S. sirbanum) and the Amazonian focus between South Venezuela and Northern Brazil (S. guianense and S. oyapockense s.l.). The data, which include published and unedited information collected in the field, record experimental studies of parasite uptake by wild flies maintained in captivity until the completion of the extrinsic incubation period. The relationship between L3 output (measured as the mean number of successful larvae/fly or, as the proportion of flies with infective larvae) and average microfilarial intake, was strongly non-linear. This non-linearity was best represented by a sigmoid function in case of armed simuliids (S. ochraceum s.l., S. oyapockense s.l.), or by a hyperbolic expression in that of unarmed flies (S. damnosum s.l., S. guianense). These results are compatible, respectively, with the patterns of 'initial facilitation' and 'limitation' described in culicid vectors of lymphatic filariases. A maximum mean number of 1-3 L3/fly was observed in all 4 vectors. It is concluded that O. volvulus larval development to the infective stage is regulated by density-dependent mechanisms acting at the early phase of microfilarial migration out of the blackfly's bloodmeal. Damage by the bucco-pharyngeal armature may also be density dependent. A hypothesis, based on this density dependence is forwarded to explain initial facilitation, so far only recorded in vectors with well-developed cibarial teeth. Our results provide quantitative support for the conjecture that chemotherapy alone is likely to have a greater impact on reducing onchocerciasis transmission in endemic areas where the main vector has a toothed fore-gut than in foci where the vectors have unarmed cibaria.

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As part of the WHO Onchocerciasis Control Programme in West Africa (OCP), the attack phase of operations in the Niger basin in Guinea began in 1989 with the simultaneous use of ivermectin and vector control. Larvicide applications coupled with annual large-scale ivermectin distribution have greatly reduced blackfly infectivity (by 78.8% for the number of infective larvae per 1000 parous flies). The combination of vector control and ivermectin has permitted excellent control of transmission. In the original OCP area, it took 6-8 years of vector control alone to obtain an equivalent decrease in blackfly infectivity. For the same number of flies caught, transmission was much higher in areas where ivermectin had not been distributed. The combined use of ivermectin and vector control has opened up new prospects for carrying out OCP operations with, notably, the possibility of reducing larviciding operations.

PIP: As part of the World Health Organization Onchocerciasis Control Programme in West Africa (OCP), the attack phase of operations in the Niger basin in Guinea began in 1989 with the simultaneous use of ivermectin and vector control. All the 16 catching points were in holoendemic foci: 8 in the Niger basin in Guinea and 8 in the original OCP area (Mali, Ivory Coast, Ghana, and Burkina Faso). The data were analyzed according to prevalence of microfilariae in the skin and the mean community microfilarial load (CMFL). Between 1990 and 1992 the number of people in the villages treated increased by a factor of 6. In 1992 a total of 91,840 persons were treated in 550 villages. The study covered 10 years, during which 34,492 blackflies were caught at the 8 sites, 87.8% of which were parous. Larvicide applications coupled with annual large-scale ivermectin distribution had greatly reduced blackfly infectivity (by 78.8% for the number of infective larvae per 1000 parous flies; the number infective larvae in the head fell by 75.7% compared with the 1986-87 data before treatment began). After 2 years of large-scale ivermectin treatment, the reduction was 64.6%. In February and March of 1992 a defective larvicide worsened the situation. The average transmission potential during this period in Guinea was 7.3 compared with 93.7 for the original area. For the same number of blackflies caught, transmission in the original area was 5.6 times higher. The combination of vector control and ivermectin permitted excellent control of transmission. In the original OCP area, it took 6-8 years of vector control alone to obtain an equivalent decrease in blackfly infectivity. For the same number of flies caught, transmission was much higher in areas where ivermectin had not been distributed. The combined use of ivermectin and vector control has opened up new prospects for carrying out OCP operations with the possibility of reducing larviciding operations.

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