A Reevaluation of the Tolerability and Effects of Single-Dose Ivermectin Treatment on Onchocerca volvulus Microfilariae in the Skin and Eyes in Eastern Ghana.

Mass administration of ivermectin (IVM) has significantly reduced onchocerciasis prevalence, intensity, and morbidity in most endemic areas. Most IVM clinical trials were performed long ago in persons with high-intensity infections that are uncommon in West Africa today. This cohort treatment study recruited participants from a hypoendemic area in eastern Ghana to reevaluate the efficacy and tolerability of IVM with a special focus on the kinetics of microfilaria (Mf) clearance. Mf in the skin and anterior chambers (AC) were assessed by skin snip and slit lamp examinations at baseline and at 3 and 6 months after treatment with IVM 150 µg/kg. Most participants (184-231, 79.7%) enrolled were treatment-naïve. The baseline geometric mean skin Mf count was 12.67/mg (range 3-86). Although persons with MfAC at baseline (64/231, 27%) had significantly higher skin Mf counts than people without MfAC, 7 of 39 (15%) of persons with skin Mf counts in the range of 3-5 Mf/mg had MfAC. Skin Mf were detected in 14% (31/218) and 45% (96/216) of participants 3 and 6 months after IVM treatment, respectively. MfAC were detected in 12 of 212 (5.7%) study participants at 6 months. 81% (187 of 231) of participants experienced 439 adverse events within 7 days after treatment; all adverse events were mild (96.1%) or moderate. This study has provided new data on the kinetics of Mf in the skin and eyes after IVM treatment of persons with light to moderate intensity Onchocerca volvulus infections that are common in Africa at this time.

Serious Neurological Adverse Events after Ivermectin-Do They Occur beyond the Indication of Onchocerciasis?

Serious neurological adverse events have been reported from large scale community-based ivermectin treatment campaigns against Onchocerciasis volvulus in Africa. The mechanism of these events has been debated in the literature, largely focusing on the role of concomitant infection with Loa loa versus the presence of mdr-1 gene variants in humans allowing ivermectin penetration into the central nervous system. A case series of serious neurological adverse events occurring with the use of ivermectin outside of the onchocerciasis indication has been identified in VigiBase, an international database of suspected adverse drug reactions. Forty-eight cases have been reported from multiple countries in which ivermectin has been prescribed for multiple indications; clinical review excluded 20 cases with more probable explanations or other exclusion criteria. Within the remaining 28 cases, there is supportive evidence for a causative role of ivermectin including presence of the drug in brain tissue in one case and recurrence of symptoms on repeated exposure in three cases. This series suggests that serious neurological adverse events observed with the use of ivermectin in the treatment of onchocerciasis may not be entirely explained by concomitant high burden loiasis infections. By comparison with the extensive post marketing experience with ivermectin in the successful treatment of parasitic infections, the number of reported cases suggests that such events are likely rare. However, elucidation of individual-level risk factors could contribute to therapeutic decisions that can minimize harms. Further investigation into the potential for drug-drug interactions and explorations of polymorphisms in the mdr-1 gene are recommended.

Hierarchical dynamics influence the distribution of immature black flies (Diptera: Simuliidae).

Adult black flies (Simuliidae) are medically important insects and they are the sole vector of Onchocerca volvulus. Immature black flies are major components of aquatic macroinvertebrate assemblages in streams and play a vital role in nutrient dynamics. In this study, we examined effect of hierarchical dynamics (spatio-temporal pattern) on the distribution of immature black flies in South Indian streams. The sampling was done in streams of Western Ghats, South India. A total of 16 species belong to two subgenera: Simulium (10 species) and Gowmphostilbia (6 species) of Simulium were observed. Alpha diversity indices were analyzed, which indicate the abundance and species richness between sampling sites. Non-parametric analysis recognized the key environmental variables including latitude and stream order. Subsequently, the monsoon influences the larval assemblages and its association was high in leaf litter as revealed through statistical analyses. Although the members of the immature black fly assemblage with different environmental factors, they are very closely related to spatial and temporal organization and secondarily with other factors prevailing in streams.

The Onchocerciasis Control Programme in West Africa (OCP).

The Onchocerciasis Control Programme in West Africa (OCP) started operations in 1975. Its main objectives were to eliminate human onchocerciasis, as a disease of public-health importance and an obstacle to socio-economic development, from the Programme area. By the end of 2002, the OCP covered 11 West African countries, and had introduced large-scale Mectizan (ivermectin) distribution to about 10 million people, through the communitydirected treatment approach, with treatment coverages ranging from 51%-81%. Research on large-scale Mectizan use illustrated the importance of evidence-based results, the power of multicountry studies, the need for social science in community-driven endeavours and operations research, and the value of empowering communities as allies in disease control. The generous donation of Mectizan by Merck & Co., Inc., has increased general interest in health-related public-private partnerships and generated the momentum for other donations to tackle other diseases. The vector control on which the OCP was initially based successfully interrupted the transmission of the parasite causing human onchocerciasis, Onchocerca volvulus, in many areas. The introduction of Mectizan led to the decline in anterior-segment lesions in the eye and the arrest of posterior-segment lesions. The drug continues to be highly effective in morbidity control, although recently there have been reports of sub-optimal responses in some adult O. volvulus, albeit in a few, very small and isolated foci.

The Onchocerciasis Elimination Program for the Americas (OEPA).

Human onchocerciasis (river blindness) occurs in 13 foci distributed among six countries in Latin America (Brazil, Colombia, Ecuador, Guatemala, Mexico and Venezuela), where about 500,000 people are considered at risk. An effort to eliminate the disease from the region was launched in response to a specific resolution adopted by the PanAmerican Health Organization (PAHO) in 1991: to eliminate onchocerciasis from the region, as a public-health problem, by 2007. The effort took advantage of the donation of the drug Mectizan (ivermectin) by Merck & Co., Inc. In 1992, the Onchocerciasis Elimination Program for the Americas (OEPA) was launched, with its headquarters in Guatemala, to act as a technical and co-ordinating body of a multinational, multi-agency coalition that includes the endemic countries, PAHO, The Carter Center, Lions Clubs, the United States Centers for Disease Control and Prevention, The Bill and Melinda Gates Foundation, Merck & Co., Inc., and other partners. This public-private partnership facilitated the establishment of programmes for the semi-annual mass administration of Mectizan in the six countries with onchocerciasis. The aims were to (1) provide sustained treatments, with coverage reaching at least 85% of those eligible to receive the drug (in the 1845 endemic communities that are distributed within the 13 regional foci); (2) eliminate new morbidity caused by Onchocerca volvulus infection by 2007; and (3) eliminate transmission of the parasite wherever feasible. Significant progress has already been made in all six countries, each of which has active programmes with treatment coverages exceeding the target of 85%. The progress is being documented in accordance with certification guidelines for onchocerciasis elimination established by the World Health Organization. No new cases of onchocercal blindness are being reported in the region, and ocular disease attributable to O. volvulus has been eliminated from nine of the 13 foci. Treatment is no longer needed in Santa Rosa, Guatemala, where transmission has been eliminated, and will be halted in at least three other foci in 2008, as they confirm the interruption of transmission. Treatment efforts should now be concentrated on the five foci where significant transmission remains: Central (Guatemala), Amazonas/Roraima (Brazil), North-central (Venezuela), North-east (Venezuela) and South (Venezuela). Based upon the experience gained, the well-established operations and the success achieved so far, it seems reasonable to estimate that onchocerciasis could be eliminated from most of the remaining foci in the Americas by 2012. The protocol, criteria and deadline for stopping all onchocerciasis treatment in the region should soon be addressed by OEPA's Program Co-ordinating Committee (PCC), in co-ordination with the PAHO.

Diagnostic value of nodule palpation in onchocerciasis.

Nodule palpation is the major diagnostic tool for determining the prevalence of infection in areas of the African Programme for Onchocerciasis Control (APOC) and is recommended for identifying communities at risk and selecting them for mass drug administration. The diagnostic value of palpation, however, has not been quantified in terms of sensitivity and predictive values. We derive these measures from the probability that a nodule is palpable, which has been estimated by stochastic simulations from an extensive pre-control database. We show that nodule palpation is only reliable in highly endemic areas and that false-positive diagnoses can lead to considerable misclassifications of regions where endemicity is actually low. Its diagnostic precision is poor because of large intra- and inter-individual variability. The findings underline the need for further development of available diagnostics that allow long-term monitoring when endemicity declines.

Susceptibility of Simulium damnosum complex larvae to temephos in the Tukuyu onchocerciasis focus, southwest Tanzania.

Tukuyu onchocerciasis focus was earmarked for vector control using insecticide against larval stages. Susceptibility tests of mature larvae of Simulium damnosum s.l. vectors to temephos insecticide were carried out before and after two years of insecticide treatment of rivers within Tukuyu onchocerciasis focus, south-western Tanzania. The tests were done in 1999/2000 and 2004 using WHO standard methods. Mature larvae were exposed to 9 concentrations of temephos active ingredient, from the weakest 0.00975mg/litre to the strongest of 2.5mg/l. Each test concentration and control was run in duplicates of 25 larvae each, set for three hours in a cool temperature. After incubation, test solution was discarded and larval condition checked. Numbers of larvae in each category were recorded and used to determine mortality rate for each concentration as well as for the LC50 and LC95. A total of 1,666 larvae were tested, 942 during the pre- and 724 post-treatment. Results showed that both pre and post-treatment samples were susceptible, attaining 100% mortality at the diagnostic dose of 1.25mg/l, and LC50 between 0.129-0.34mg/l pre - and 0.144-0.211 mg/l (95% CI, P < 0.05) post- treatment. These values fall within the standard diagnostic dose of < or = 0.4mg/l for susceptible S. damnosum s.l populations. It was concluded that the endemic S. damnosum population was susceptible to temephos before and after two years of intermittent field application. Temephos was thus recommended for continued use in onchocerciasis vector control in the Tukuyu focus, to complement Community Directed Treatment with Ivermectin, but close monitoring of vector susceptibility should be done.

Rapid assessment method for prevalence and intensity of Loa loa infection.

OBJECTIVE: To assess the validity of observations on eye worm and Calabar swellings for the rapid assessment of the prevalence and intensity of loiasis at the community level. METHOD: A total of 12895 individuals over the age of 15 years living in 102 communities in Cameroon and Nigeria took part in the study. A standardized questionnaire was administered to participants from whom finger-prick blood samples were collected and examined for Loa loa microfilariae. Rapid assessments of the prevalence and intensity of loiasis were made on the basis of a history of eye worm or Calabar swellings. FINDINGS: There was a strong correlation between the indices of the rapid assessment procedures and the parasitological indices of L. loa endemicity. The rapid assessment indices were effective in diagnosing high-risk communities (sensitivity 94-100%; specificity 66-92%). The highest sensitivity (100%) and specificity (92%) were obtained with a rapid assessment procedure based on a history of eye worm lasting 1-7 days together with confirmation by the guided recognition of a photograph of adult L. loa in the eye. CONCLUSION: Rapid assessment of the prevalence and intensity of loiasis at the community level can be achieved using a procedure based on the history of eye worm lasting 1-7 days together with confirmation by the guided recognition of a photograph of an adult L. loa in the eye.

Onchocerca volvulus-exposed persons fail to produce interferon-gamma in response to O. volvulus antigen but mount proliferative responses with interleukin-5 and IL-13 production that decrease with increasing microfilarial density.

The cellular immune response to Onchocerca volvulus antigen (OvAg) was studied in 551 persons exposed to O. volvulus transmission in a hyperendemic area of Ghana, West Africa. A whole-blood assay showed that, in response to a soluble O. volvulus extract, cell proliferation, as well as interleukin (IL)-5 and IL-13 concentrations in the supernatants, were high in cultures of blood from microfilaria (mf)-negative persons and significantly decreased with increasing mf counts of the donors. Only background concentrations of interferon (IFN)-gamma were found, and these did not correlate with mf counts. In response to a mitogen, cells from all persons strongly reacted with proliferation and secretion of all 3 cytokines studied. These findings show that the response of human peripheral blood cells to OvAg does not include significant IFN-gamma production; that mf negativity is associated with IL-5 and IL-13 production but not, as previously suggested, with IFN-gamma production; and that IL-5 and IL-13 production decreases with increasing mf density.

Infectivity and transmission dynamics of simulium damnosum s. 1 around Owena dam (Ondo State).

A twelve month study on the infectivity and transmission dynamics of simulium damnosum s.1 around Owena dam was conducted as part of a longitudinal study of onchocerciasis in the community living in the vicinity of the dam. A total of 3,133 flies (49.6% nilliparous, 50.4% parous) were caught during the period of study and dissected. The annual biting rate per year was recorded as 33,663 flies while the parous biting rate was recorded as 16,780 for these flies. 0.4% of the flies were infected with Onchocerca volvulus larvae while 0.3% of these had the infective larvae. However 0.3% of the nulliparous flies were found to be infected with mermithid larvae and 0.5% with trematodes. The biting activity of the fly was observed to be bimodal with a small peak in the morning hours (10.00-11.00 hours) and a more pronounced peak in the evening (16.00-17.00 hours). An annual transmission potential of 109 larvae per man per year was recorded with 64% of the infection being recorded during the early dry season when the parous rate was very high. The implications of these findings to the study area are discussed.

Onchocerciasis in Ecuador: prevalence of infection on the Ecuador-Colombia border in the Province of Esmeraldas

The prevalence of onchocerciasis infection was determined in communities on 7 rivers located in the northern area of the canton San Lorenzo, province of Esmeraldas. Diagnosis of the infection was obtained by skin biopsies and recombinant-antigen based-serology. No evidence of infection was detected in 9 communities studied along the Rio Mataje, which forms the frontier between Ecuador and Colombia, nor in 10 adjacent communities located on 5 interior rivers. Evidence for Onchocerca volvulus infection was found in 4 communities on the Rio Tululvi with the following prevalence: La Boca (3,5 per cent by biopsy and 3,9 per cent by serology), Guayabal (9,1 per cent by both biopsy and serology), La Ceiva (51,5 per cent by biopsy and 53 per cent by serology), and Salidero (4 per cent by biopsy and 7,7 per cent by serology). A few individuals in these communities were seropositive for O. volvulus in the absence of detectable dermal microfilariae: these might harbor very light or prepatent infections. No clinical disease attributable to onchocerciasis was found. The infected communities will be included in the ivermectin-based National Control Program for the disease, with no evidence of the infection having extended north of the Ecuadorian-Colombian border.

Transmission of onchocerca volvulus by simulium damnosum S.L. in four villages in the Gorama Chiefdom; Kono district; Sierra Leone

Quantitative studies on the transmission of onchocerca volvulus; including monthly and annual biting densities; age composition; parity rates; infection and infective rates of the similium damnosum s.l. population; were carried out for a year in a tropical rain-forest zone in Sierra Leone. In all 19;432 s. damnosum s.l. female flies were acught and 8;755 dissected; of which 6.307 were parous. The annual biting rate (ABR) varied between 20;787 and 39;188; 5.4 per cent of all flies were infected with O. volvulus; 3.6 per cent carried infective larvae in the head capsule; with mean of 2.5 per fly. The annual transmission potential (ATP) varied between 1;138 and 2;081. The ATPs for Bunabu; Matama; Kangama and Moimandu villages were 2;081; 1;403; 1;138 and 1;498 respectively; with most of the infection occuring during the months of May and August. The prevalences of skin microfilariae (mf) in Bunabu; Matama; Kangama and Moimandu villages were 79.0 per cent; 51.3 per cent; 78.0 per cent and 80.0 per cent respectively