Loa loa Microfilarial Periodicity in Ivermectin-Treated Patients: Comparison Between Those Developing and Those Free of Serious Adverse Events

Kamgno, Joseph; Pion, S. D. S.; Mackenzie, Charles D.; Thylefors, B; Boussinesq, Michel

doi:10.4269/ajtmh.2009.09-0356

Cited by 34 publications

(28 citation statements)

References 40 publications

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“…Similar to microscopy, optimum PCR performance requires proper timing of blood collection at mid-day when microfilaremia is greatest; however, a microfilaremia kinetics study by Kamgno et al . suggests that smaller numbers of organisms may be detectable outside the window of peak microfilaremia [23], and a nomogram may be used to extrapolate qPCR results to predict true parasite burden. Another important issue is that the assays in their current form are still not practical for point-of-care use in endemic areas.…”

Section: Discussionmentioning

confidence: 99%

Rapid Molecular Assays for Specific Detection and Quantitation of Loa loa Microfilaremia

2011

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BackgroundAccurate diagnosis of Loa loa infection is essential to the success of mass drug administration efforts to eliminate onchocerciasis and lymphatic filariasis, due to the risk of fatal encephalopathic reactions to ivermectin occurring among highly microfilaremic Loa-infected individuals living in areas co-endemic for multiple filarial species.Methodology/Principal FindingsFrom a pool of over 1,800 L. loa microfilaria (mf) expressed sequence tags, 18 candidate L. loa mf-specific PCR targets were identified. Real-time PCR (qPCR) assays were developed for two targets (LLMF72 and LLMF269). The qPCR assays were highly specific for L. loa compared with related filariae and also highly sensitive, with detection limits of 0.1 pg genomic DNA, or 1% of DNA extracted from normal blood spiked with a single L. loa microfilaria. Using various DNA extraction methods with dried blood spots obtained from Cameroonian subjects with parasitologically proven loiasis, the LLMF72 qPCR assay successfully estimated mf burden in 65 of 68 samples (50–96,000 mf/mL by microscopy), including all 12 samples subjected to a simple 10-minute boiling extraction. Additionally, the assay detected low-level microfilaremia among 5 of 16 samples from patients thought to be amicrofilaremic by microscopy.Conclusions/SignificanceThis novel, rapid, highly sensitive and specific qPCR assay is an important step forward in the laboratory diagnosis of L. loa infection.

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Section: Discussionmentioning

confidence: 99%

Rapid Molecular Assays for Specific Detection and Quantitation of Loa loa Microfilaremia

2011

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“…Although the pathogenesis of the neurologic SAEs is still not well understood (8,15), data clearly demonstrate a relationship between the pretreatment L. loa microfilaria (mf) density (14,16) and the risk of SAEs, with levels of 5,000 mf/ml and 30,000 mf/ml felt to be the most significant thresholds (13), though other factors may also be involved (17)(18)(19). Consequently, some IVM-based MDA programs for onchocerciasis (Ov) have been delayed, and lymphatic filariasis (LF) control programs (using IVM-albendazole) have been put on hold in large parts of Central Africa where L. loa infection is also endemic (20).…”

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Loop-Mediated Isothermal Amplification for Rapid and Semiquantitative Detection of Loa loa Infection

et al. 2014

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cRapid and accurate tests are currently needed to identify individuals with high levels of Loa loa microfilaria (mf), so that these individuals may be excluded from mass ivermectin administration campaigns against onchocerciasis and lymphatic filariasis being conducted in areas where Onchocerca volvulus, Wuchereria bancrofti, and L. loa are coendemic. To address this need, colorimetric loop-mediated isothermal amplification (LAMP) assays targeting the L. loa-specific gene sequences LLMF72 and LLMF342 were developed for the detection and quantification of L. loa microfilaremia. Both LAMP assays were highly specific (100%) for L. loa infection compared to the absence of infection or infection with related filarial pathogens. The LLMF72-based LAMP assay showed greater analytic sensitivity (limit of detection, 0.1 pg/ml of genomic DNA [gDNA] and/or 5 mf/ml) than the LLMF342-based LAMP assay (10 pg/ml of gDNA and/or 50 mf/ml), and its analytic sensitivity was similar to that of LLMF72-based quantitative PCR (qPCR). A high level of correlation was observed between microfilaria counts as determined by LLMF72-based qPCR and time to positivity by the LAMP assay, and performance measures of sensitivity, specificity, and positive and negative predictive values were similar for both assays when applied to field-collected clinical samples. By simply varying the run time, the LAMP assay was able to accurately distinguish individuals at risk for serious adverse events (SAEs) after exposure to ivermectin, using thresholds of >5,000 mf/ml and >30,000 mf/ml as indicators of increasing levels of risk. In summary, LLMF72 LAMP represents a new molecular diagnostic tool that is readily applicable as a point-of-care method for L. loa microfilarial detection and quantification in resource-limited countries where L. loa infection is endemic.

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“…4 For this purpose, the periodicity of L. loa mf was compared in individuals who did and did not develop an SAE. Diurnal periodicity was observed in all subjects, which is inconsistent with the hypothesis that an infection with a simian L. loa was responsible for the SAE cases.…”

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“…Diurnal periodicity was observed in all subjects, which is inconsistent with the hypothesis that an infection with a simian L. loa was responsible for the SAE cases. 4 The role of a genetic mutation in a P-glycoprotein gene called mdr-1 (ABCB1) that enhances the permeability of the blood-brain barrier to ivermectin was also assessed in individuals who had experienced an SAE. 5 No association between this mutation and the occurrence of SAEs was shown.…”

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Absence of an Association Between Plasmodium falciparum Infection and Post-Ivermectin Loa-Related Non-Neurologic Serious Adverse Events

Domgue¹,

Pion

Gounoue

et al. 2014

The American Journal of Tropical Medicine and Hygiene

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Abstract. Although ivermectin treatment can induce serious adverse events (SAEs) in individuals harboring high Loa loa microfilaremia (mf), not all patients with high mf levels develop such reactions, suggesting that cofactors may be involved. A study was conducted in Cameroon to investigate the possible role of Plasmodium coinfection at the time of ivermectin treatment in the development of SAEs. Before their first ivermectin treatment, thick smears were obtained from 4,175 individuals to determine the burden of Plasmodium sp., L. loa, and Mansonella perstans. After treatment, 18 (4.3 per 1,000) patients developed a non-neurologic SAE. Logistic regression analysis, adjusting for age, sex, P. falciparum infection, and M. perstans infection intensities, confirmed that L. loa mf was the main risk factor for SAEs. We found no evidence that coinfection with P. falciparum at the time of ivermectin treatment was associated with the occurrence of Loa-related SAEs in this population.

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Loa loa Microfilarial Periodicity in Ivermectin-Treated Patients: Comparison Between Those Developing and Those Free of Serious Adverse Events

Cited by 34 publications

References 40 publications

Rapid Molecular Assays for Specific Detection and Quantitation of Loa loa Microfilaremia

Rapid Molecular Assays for Specific Detection and Quantitation of Loa loa Microfilaremia

Loop-Mediated Isothermal Amplification for Rapid and Semiquantitative Detection of Loa loa Infection

Absence of an Association Between Plasmodium falciparum Infection and Post-Ivermectin Loa-Related Non-Neurologic Serious Adverse Events

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