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We assessed the impact of loiasis and its treatment with ivermectin on hemostasis and inflammation in 38 adults in Cameroon. Participants were divided into four balanced groups based on their Loa loa microfilarial densities. At baseline, eosinophils and platelets increased with microfilarial densities (p<0.001 and p = 0.044, respectively). At day 4 following ivermectin administration, median eosinophils rose from 171/μL to 1,095/μL (p<0.001) and median D-dimers increased from 582 ng/mL to 745 ng/mL (p = 0.024) with a median relative variation of +34.7%. C-reactive protein, fibrinogen, and alpha-1-globulin also increased significantly after treatment. Ivermectin treatment appeared to induce inflammation, coagulation activation and fibrinolysis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lepage et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The standard method to diagnose Loa loa infection and quantify microfilarial density (MFD) is the microscopic examination of calibrated thick blood smears (TBSs). In 1950, it was noticed that successive L. loa MFD samples from a single capillary puncture could exhibit up to 20% variation. Although loiasis treatment allocation is based on MFD to prevent serious adverse events (SAEs), data on this variability are scarce. There are also no guidelines supporting the collection and analysis of one or two TBSs., Methods: We assessed the variability of two successive L. loa MFD samples (MFD 1 and MFD 2 ), collected from 255 patients. We analyzed the influence of sex, age, weight, heart rate, arterial pressure, body temperature, and sampling time on MFD variability, as well the impact of MFD variability on MFD thresholds relevant to loiasis treatment protocols., Results: The MFD 2 was found to have increased in 63% (1145/1826) of TBS pairs and to have decreased in 37% (681/1826) of TBS pairs. The MFD 2 were on average 28% higher than the MFD 1 . These variations drove a total of 333 (17.4%) changes in MFD classes according to loiasis treatment protocol, including 210 (11.3%) class increases. TBSs generated from blood samples from subjects with lower MFD (1-1000 mf/ml) or lower mean arterial pressure (MAP; 55-80 mmHg), or from blood samples collected at an earlier hour time-point (10:00-10:59 a.m.) were more subject to MFD 2 variability in a multivariate analysis. The MFD relative change was not constant over time for a given person., Conclusions: We observed a trend towards an increase in MFD 2 with an important variability between samples that may impact loiasis treatment allocation. We suggest that systematically sampling at least two successive TBSs might allow better MFD assessments to prevent post-treatment SAEs. Further studies are needed to verify this variability in larger samples as well as confirm the potential explanatory variables identified., (© 2024. The Author(s).)

Background: Endemic to Central Africa, loiasis, caused by the vector-borne worm Loa loa, affects approximately 10 million individuals. Clinical manifestations include transient angioedema (Calabar swellings), migration of the adult worm under the eye conjunctiva (eye worm) and less specific general symptoms. Loiasis presents a significant public health challenge because L. loa-infected individuals can develop serious adverse events after taking ivermectin, the drug used to combat onchocerciasis. In this context, alternative interventions and rigorous diagnostic approaches are needed. Diagnosing loiasis is challenging because its main clinical manifestations are sporadic and non-specific. The definitive diagnosis relies on identifying adult worms migrating beneath the conjunctiva, or microfilariae (pre-larvae) in blood smears. However, "occult loiasis" (infection without blood microfilariae) is frequent. Serological rapid antibody diagnostic tests (ARTs) can provide an alternative diagnostic method. We compared a novel ART simultaneously targeting onchocerciasis (IgG4 to Ov-16 and OvOC3261, test line 1) and loiasis (IgG4 to L1-SXP-1, test line 2), called IgG4-SXP-1 biplex test) to the already established Loa-ART (all IgG isotypes to Ll-SXP-1, called pan-IgG-SXP-1 test)., Methodology: Blood samples underwent both ARTs, read qualitatively and semi-quantitatively. Additionally, blood smears, skin snips, Kato-Katz method for soil-transmitted helminthiases identification and eosinophilia measurements were performed. Questionnaires gathered demographic details and loiasis-related signs. ARTs performance was compared using specific loiasis-related signs and microfilaremia as references. Discordances between the two ARTs were investigated using logistic regression models., Principal Findings: Out of 971 participants, 35.4% had L. loa microfilaremia, 71.9% had already experienced loiasis-related signs, 85.1% were positive in the pan-IgG-SXP-1 test and 79.4% were positive in the IgG4-SXP-1 biplex test. In the microfilariae-positive population, the sensitivity of the rapid tests was 87.4% for the pan-IgG-SXP-1 test and 88.6% for the prototype IgG4-SXP-1 biplex test. Sensitivity was similar for both ARTs when using eye worm or Calabar swelling as references, but diagnostic performance varied based on microfilaremia levels and occult loiasis. Overall, IgG4-SXP-1 biplex test demonstrated a sensitivity of 84.1% and specificity of 47.6% for loiasis compared to the pan-IgG-SXP-1 test, leading to a Kappa coefficient estimated at 0.27 ± 0.03 for the qualitative results of the 2 ARTs. In the group that tested positive with the Pan-IgG test but negative with the IgG4-specific test, there was a lower prevalence of STH infection (p = 0.008) and elevated eosinophilia (p<0.001) compared to the general tested population., Conclusion/significance: The sensitivity of each test was good (84-85%) but the diagnostic agreement between the two ARTs was poor, suggesting that IgG and IgG4 antibody responses should be interpreted differently. The assessment of the innovative rapid diagnostic IgG4-SXP-1 biplex test, designed for onchocerciasis and loiasis, shows encouraging sensitivity but underlines the necessity for further in vitro assessment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Campillo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Loa loa filariasis (loiasis) is still considered a relatively benign disease. However, recent epidemiologic data suggest increased mortality and morbidity in L. loa infected individuals. We aimed to examine whether the density of L. loa microfilariae (mfs) in the blood is associated with cardiovascular disease., Methodology: Using a point-of-care device (pOpmètre), we conducted a cross-sectional study to assess arterial stiffness and peripheral arterial disease (PAD) in 991 individuals living in a loiasis-endemic rural area in the Republic of the Congo. Microfilaremic individuals were matched for age, sex and village of residence with 2 amicrofilaremic subjects. We analyzed markers of arterial stiffness (Pulse-Wave Velocity, PWV), PAD (Ankle-Brachial Index, ABI) and cardiovascular health (Pulse Pressure, PP). The analysis considered parasitological results (L. loa microfilarial density [MFD], soil-transmitted helminths infection, asymptomatic malaria and onchocerciasis), sociodemographic characteristics and known cardiovascular risk factors (body mass index, smoking status, creatininemia, blood pressure)., Principal Findings: Among the individuals included in the analysis, 192/982 (19.5%) and 137/976 (14.0%) had a PWV or an ABI considered out of range, respectively. Out of range PWV was associated with younger age, high mean arterial pressure and high L. loa MFD. Compared to amicrofilaremic subjects, those with more than 10,000 mfs/mL were 2.17 times more likely to have an out of range PWV (p = 0.00). Factors significantly associated with PAD were older age, low pulse rate, low body mass index, smoking, and L. loa microfilaremia. Factors significantly associated with an elevation of PP were older age, female sex, high average blood pressure, low pulse rate and L. loa microfilaremia., Conclusion: A potential link between high L. loa microfilaremia and cardiovascular health deterioration is suggested. Further studies are required to confirm and explore this association., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Campillo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Loiasis is endemic in the northern and western part of the Republic of Congo. Between 2004 and 2010, surveys were conducted, using the RAPLOA method, in all departments of the Republic of Congo to assess the distribution of loiasis. Prior to 2004, only two parasitological surveys on loiasis had been conducted in Congo and mainly in the Department of Lékoumou, in the southwestern of the country. In 2019, we conducted a parasitological survey in this same department, more than 30 years after the first surveys., Methods: The study was conducted in 21 villages. Loa loa and Mansonella perstans microfilaremia levels were quantified using 50 µl calibrated blood smears., Results: A total of 2444 individuals were examined. The median age of the screened individuals was 43 (interquartile range: 30-57, range: 18-91) years old. The overall prevalences of L. loa and M. perstans microfilaremia were 20.0% [95% confidence intervals (CI) 18.0-21.6%] and 1.0% (95% CI 0.6-1.4%) respectively. The proportion of individuals with a microfilarial density of L. loa > 8000 mf/ml and > 30,000 mf/ml were 5.1% (95% CI 4.3-6.1%) and 1.1% (95% CI 0.8-1.7%), respectively. The overall community microfilarial load was 3.4 mf/ml., Conclusions: Prevalences and intensities of L. loa infection remained generally stable between the late 1980s and 2019 in the Lékoumou Department. In contrast, parasitological indicators for M. perstans have declined sharply in the intervening years for an unknown reason., (© 2023. The Author(s).)

Background: Case reports have hypothesised that proteinuria, sometimes with glomerulopathy or nephrotic syndromes, might be associated with loiasis. To our knowledge, no study has been done to assess this association. We aimed to investigate the association between Loa loa microfilariae burden and proteinuria., Methods: We did a cross-sectional study between May 16, 2022, and June 11, 2022, to assess the relationship between Loa loa microfilaraemia densities and proteinuria in a rural area of the Republic of Congo. We included all consenting adults living in the target area at study commencement who had L loa microfilarial densities greater than 500 microfilariae per mL during previous screening for a clinical trial in 2019. This study is part of the MorLo project, and used the project's study population of individuals aged 18 years or older who were living near Sibiti. For each microfilaraemic individual, two individuals without L loa microfilarial densities matched on age, sex, and place of residence were included. The association between proteinuria (assessed by dipstick) and L loa microfilarial densities, age, and sex was assessed using an unconstrained ordinal regression model since the parallel-lines assumption was violated for microfilarial densities., Findings: 991 participants were included, of whom 342 (35%) were L loa microfilaraemic. The prevalence of microfilaraemia was 38% (122 of 325) among individuals with trace proteinuria (<300 mg/24 h), 51% (45 of 89) among individuals with light proteinuria (300 mg to 1 g/24 h), and 71% (15 of 21) among individuals with high proteinuria (>1 g/24 h). Individuals with high proteinuria had significantly higher L loa microfilarial densities (p<0·0001): mean microfilariae per mL were 1595 (SD 4960) among individuals with no proteinuria, 2691 (7982) for those with trace proteinuria, 3833 (9878) for those with light proteinuria, and 13 541 (20 118) for those with high proteinuria. Individuals with 5000-14 999 microfilariae per mL and individuals with 15 000 microfilariae per mL or greater were, respectively, 5·39 and 20·49 times more likely to have a high proteinuria than individuals with no microfilaraemia., Interpretation: The risk of proteinuria increases with L loa microfilaraemia. Further studies are needed to identify renal disorders (eg, tubulopathies, glomerulopathies, or nephrotic syndromes) responsible for loiasis-related proteinuria., Funding: European Research Council, MorLo project., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests CB is the recipient of a grant from the Bettencourt-Schueller Foundation (CCU-AH-INSERM-Bettencourt). All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Individuals with high Loa loa microfilarial densities are at risk of developing severe encephalopathy after administration of antiparasitic drugs. Apart from this finding, loiasis is considered benign with no effect on brain function. However, recent epidemiological data suggest an increased mortality and morbidity in L. loa infected individuals, underscoring the importance of studies on the possible neurological morbidity associated with loiasis., Methodology: Using MoCA tests and neurological ultrasounds, we conducted a cross-sectional study to assess cognitive alteration in a population living in a rural area endemic for loiasis in the Republic of Congo. Fifty individuals with high microfilarial densities (MFD) were matched on sex, age and residency with 50 individuals with low MFD and 50 amicrofilaremic subjects. Analyses focused on individuals with MoCA scores indicating an altered cognition (i.e. < 23/30) and on the total MoCA score according to Loa loa MFD, sociodemographic characteristics and neurological ultrasound results., Principal Findings: MoCA scores were very low in the studied population (mean of 15.6/30). Individuals with more than 15,000 microfilariae per milliliter of blood (mean predicted score:14.0/30) are more than twenty times more likely to have an altered cognition, compared to individuals with no microfilaremia (mean predicted score: 16.3/30). Years of schooling were strongly associated with better MoCA results. Extracranial and intracranial atheroma were not associated with L. loa MFD., Conclusion/significance: Loaisis microfilaremia is probably involved in cognitive impairment, especially when the MFD are high. These results highlight the urgent need to better understand loaisis-induced morbidity. Further studies investigating neurological morbidity of loiasis are needed., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Checkouri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background-Rationale: The diagnosis of Loa loa microfilaremia consists in the observation, using a microscope, of microfilariae in a sample of peripheral blood spread on a slide and subsequently stained (the "blood smear technique"). The accurate quantification of Loa loa microfilaremia is important because the choice of the first intention treatment depends on the patient's microfilaremia: severe adverse events can occur in individuals with high microfilarial densities when treated with ivermectin or diethylcarbamazine, the latter drug being the only one which can definitively cure the infection. However, despite the widespread usage of this technique and its role in guiding clinical management of the patient, estimates of its reliability remain scarce., Materials and Methods: We evaluated the reliability (reproducibility and repeatability) of blood smear technique using several sets of 10 L. loo -positive slides, randomly selected, and considered the results with regard to regulatory requirements. The slides had been prepared as part of a clinical trial conducted in Sibiti, Republic of Congo, a region where loiasis is endemic., Results: The estimated and acceptable coefficients of repeatability (NB: the lower, the better) were 13.6% and 16.0%, respectively. The estimated and acceptable coefficients of intermediate reliability (reproducibility) were 15.1% and 22.5%, respectively. The poorest coefficient of intermediate reliability was 19.5% when the tested parameter was related to the technician who performed the readings (10.7% when the reading day was changed). The inter-technician coefficient of variation assessed using 1876 L. loo -positive slides was 13.2%. The coefficient of inter-technician variation considered acceptable was estimated at 18.6%. Discussion-Conclusion. All estimated coefficients of variability were lower than the calculated acceptable coefficients suggesting reliability of the technique, although the lack of laboratory references precludes any conclusion on the quality of this diagnosis. It is imperative to implement a quality system and standardization of procedures for the diagnosis of L. loo microfilaremia, both in endemic countries and in the rest of the world, where the demand for diagnosis has been increasing for years., (Copyright © 2023 SFMTSI.)

Background: The diurnal periodicity of Loa loa microfilaraemia is well known but few studies have documented the short- and long-term stability of microfilarial density. It seems stable over time at the community level, but significant variations have been observed at the individual level., Methods: We assessed the temporal variability of L. loa microfilaraemia at 5-day, 1-month and 16-month intervals and analyzed the influence of sex, age, level of microfilaraemia, temperatures and time of sampling on this variability., Results: At the community level, L. loa microfilaraemia is very stable over time at 5-day, 1-month and 16-month intervals (Pearson correlation coefficients of 0.92, 0.91 and 0.78, respectively, all three with P < 0.001). However, some individuals had significant variations of up to ± 50% of their initial microfilaraemia at 5-day (33.0%), 1-month (36.5%) and 16-month (62.6%) intervals, even in individuals with an initial microfilaraemia density > 20,000 mf/ml (7.7, 23.1 and 41.4%, respectively, for 5 days, 1 month and 16 months). We do not highlight any external factors that have a major impact on this variability., Conclusion: Although at the community level, microfilaria density is very stable, we highlight some individuals with large variations in both the short and long term, which may have an important impact on onchocerciasis control campaigns and longitudinal studies evaluating the impact of an intervention on L. loa microfilaraemia., (© 2023. The Author(s).)

Background: Loa loa microfilariae circulate in the peripheral blood of human hosts following a diurnal periodicity, with maximal microfilaremia levels generally observed between 10:00 am and 3:00 pm. Few studies have assessed factors potentially associated with this periodicity., Methods: Microfilaremia data were collected repeatedly between 9:00 am and 8:00 pm from 13 individuals in the Republic of the Congo. Using local polynomial regression (LOESS), we determined the best models representing the dynamics of microfilaremia over this period. In a second step, using cosinor models, we evaluated the influence of sex, age, and body temperature on the periodicity of L. loa microfilaremia in blood., Results: All subjects reached their maximum microfilaremia between 10:00 am and 4:00 pm. Individual microfilaremia showed different patterns between individuals, and some clearly showed multiple peaks within a day. LOESS provided a good fit to the observed data. Without adjustment, the maximum microfilarial density was reached around 11:00 am. Adjustment revealed three distinct modes of microfilaremia, occurring around 10:00 am, 1:00 pm, and 4:00 pm. Cosinor models also provided good fit to our data. After adjustment on body temperature, the L. loa microfilaremia fluctuation amplitude decreased significantly from 1684.8 to 310.6 microfilariae(mf)/ml and the predicted peak was estimated at 12:02 pm., Conclusions: We characterized the periodicity of L. loa microfilaremia mathematically with two different approaches: cosinor models and LOESS regression. Both models suggest that body temperature plays a role in the variation in microfilaremia within a day. Further studies are needed to identify individual co-factors affecting microfilaremia., (© 2022. The Author(s).)

Background: Albendazole is an orally administered anti-parasitic medication with widespread usage in a variety of both programmatic and clinical contexts. Previous work has shown that the drug's pharmacologically active metabolite, albendazole sulfoxide, is characterised by substantial inter-individual pharmacokinetic variation. This variation might have implications for the efficacy of albendazole treatment, but current understanding of the factors associated with this variation remains incomplete., Methodology/principal Findings: We carried out a systematic review to identify references containing temporally disaggregated data on the plasma concentration of albendazole and/or (its pharmacologically-active metabolite) albendazole sulfoxide following a single oral dose. These data were then integrated into a mathematical modelling framework to infer albendazole sulfoxide pharmacokinetic parameters and relate them to characteristics of the groups being treated. These characteristics included age, weight, sex, dosage, infection status, and whether patients had received a fatty meal prior to treatment or other drugs alongside albendazole. Our results highlight a number of factors systematically associated with albendazole sulfoxide pharmacokinetic variation including age, existing parasitic infection and receipt of a fatty meal. Age was significantly associated with variation in albendazole sulfoxide systemic availability and peak plasma concentration achieved; as well as the clearance rate (related to the half-life) after adjusting for variation in dosage due to differences in body weight between children and adults. Receipt of a fatty meal prior to treatment was associated with increased albendazole sulfoxide systemic availability (and by extension, peak plasma concentration and total albendazole sulfoxide exposure following the dose). Parasitic infection (particularly echinococcosis) was associated with altered pharmacokinetic parameters, with infected populations displaying distinct characteristics to uninfected ones., Conclusions/significance: These results highlight the extensive inter-individual variation that characterises albendazole sulfoxide pharmacokinetics and provide insight into some of the factors associated with this variation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Whittaker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Individuals with high microfilarial densities (MFDs) of Loa loa are at risk of developing serious adverse events (SAEs) after ivermectin treatment. Pretreatment with drugs progressively reducing Loa MFDs below the risk threshold might help prevent these SAEs. We assessed the safety and efficacy of levamisole for this purpose., Methods: A double-blind, randomized, placebo-controlled, MFD-ascending trial was conducted in the Republic of the Congo. Participants were treated in 3 cohorts defined by pretreatment MFD and levamisole dose (cohort 1: 1.0kg and 1.5mg/kg; cohorts 2 and 3: 2.5mg/kg). Safety outcomes were occurrence of SAE and adverse event frequency during the first week. The efficacy outcomes were MFD reduction from baseline and proportions of individuals with at least 40% and 80% MFD reduction at day 2 (D2), D7, and D30., Results: The 2 lowest doses (1.0mg/kg and 1.5mg/kg) caused no SAEs but were ineffective. Compared with placebo, 2.5mg/kg levamisole caused more mild adverse events (10/85 vs. 3/85, P=.018), a higher median reduction from baseline to D2 (-12.9% vs. +15.5%, P<.001), D7 (-4.9% vs. +18.7%, P<.001), and D30 (-0.5% vs. +13.5%, P=.036) and a higher percentage of participants with >40% MFD reduction at D2 (17.5% vs. 1.2%, P<.001), D7 (11.8% vs. 6.3%, P=.269), and D30 (18.5% vs. 9.6%, P=.107)., Conclusions: A single 2.5mg/kg levamisole dose induces a promising transient reduction in Loa loa MFDs and should encourage testing different regimens., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Levamisole was initially prescribed for the treatment of intestinal worms. Because of immunomodulatory properties, levamisole has been used in inflammatory pathologies and in cancers in association with 5-fluorouracil. Levamisole is misused as a cocaine adulterant. Post-marketing reports have implicated levamisole in the occurrence of adverse drug reactions (ADRs) and its use is now limited in Europe and North America. In contrast, all other parts of the World continue to use single-dose levamisole as an anthelmintic. The aim of this study was to identify ADRs reported after levamisole exposure in VigiBase, the World Health Organisation's pharmacovigilance database, and analyse their frequency compared to other drugs and according to levamisole type of use., Methods: All levamisole-related ADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate psychiatric, hepatobiliary, renal, vascular, nervous, blood, skin, cardiac, musculoskeletal and general ADRs associated with levamisole and other drugs exposure. In secondary analyses, we compared the frequency of ADRs between levamisole and mebendazole and between levamisole type of use., Results: Among the 1763 levamisole-related ADRs identified, psychiatric disorders (reporting odds ratio with 95% confidence intervals: 1.4 [1.2-2.6]), hepatobiliary disorders (2.4 [1.9-4.3]), vasculitis (6.5 [4.1-10.6]), encephalopathy (22.5 [17.4-39.9]), neuropathy (4.3 [2.9-7.1]), haematological disorders, mild rashes and musculoskeletal disorders were more frequently reported with levamisole than with other drug. The majority of levamisole-related ADRs occurred when the drug was administrated for a non-anti-infectious indication., Conclusion: The great majority of the levamisole-related ADRs concerned its immunomodulatory indication and multiple-dose regimen. Our results suggest that single-dose treatments for anthelmintic action have a good safety profile., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Between October 2012 and October 2015, we conducted a community trial to assess the impact of semi-annual (twice yearly) community treatment with albendazole on lymphatic filariasis in Seke Pembe, a village in the Republic of the Congo. Semi-annual community treatment with albendazole has been continued in the community since October 2015. We conducted an additional parasitological assessment survey in October 2019, 6 months after the 14th round of semi-annual treatment. Between October 2012 and October 2015, Wuchereria bancrofti antigenemia and microfilaremia rates in the community had decreased from 17.3% to 4.7% and from 5.3% to 0.3%, respectively. In October 2019, the antigenemia rate had decreased further to 2.8% (19 of 687). No microfilariae were found in night blood smears from persons with circulating filarial antigenemia (0 of 16), suggesting that W. bancrofti transmission has been interrupted in Seke Pembe. Semi-annual albendazole treatments also reduced significantly infection rates with soil-transmitted helminths.

Background: Two community trials conducted from 2012 to 2018 in the Republic of Congo and the Democratic Republic of the Congo demonstrated the efficacy of semiannual mass drug administration (MDA) with albendazole (ALB) alone on lymphatic filariasis (LF). However, a high interindividual heterogeneity in the clearance of infection was observed., Methods: We analyzed trial data to assess the effect of individual adherence to ALB MDA on clearance of circulating filarial antigenemia (CFA) and microfilaremia. Community residents were offered a single dose of ALB every 6 months and tested for LF with a rapid test for CFA at baseline and then annually. CFA test results were scored on a semiquantitative scale. At each round, microfilaremia was assessed in CFA-positive individuals. All CFA-positive individuals for whom at least 1 follow-up measure was available were included in the analyses. Parametric survival models were used to assess the influence of treatment adherence on LF infection indicators., Results: Of 2658 individuals enrolled in the trials, 394 and 129 were eligible for analysis of CFA and microfilaremia clearance, respectively. After adjusting for age, sex, and initial CFA score, the predicted mean time for clearing CFA was shorter in persons who had taken 2 doses of ALB per year (3.9 years) than in persons who had taken 1 or 0 dose (4.4 and 5.3 years; P < .001 for both). A similar pattern was observed for microfilaremia clearance., Conclusions: These results demonstrate a clear dose-response relationship for the effect of ALB on clearance of CFA and microfilaremia., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The diagnostic gold standard for onchocerciasis relies on identification and enumeration of (skin-dwelling) Onchocerca volvulus microfilariae (mf) using the skin snip technique (SST). In a recent study, blood-borne Loa loa mf were found by SST in individuals heavily infected with L. loa, and microscopically misidentified as O. volvulus due to their superficially similar morphology. This study investigates the relationship between L. loa microfilarial density (Loa MFD) and the probability of testing SST positive., Methods: A total of 1053 participants from the (onchocerciasis and loiasis coendemic) East Region in Cameroon were tested for (1) Loa MFD in blood samples, (2) O. volvulus presence by SST, and (3) Immunoglobulin (Ig) G4 antibody positivity to Ov16 by rapid diagnostic test (RDT). A Classification and Regression Tree (CART) model was used to perform a supervised classification of SST status and identify a Loa MFD threshold above which it is highly likely to find L. loa mf in skin snips., Results: Of 1011 Ov16-negative individuals, 28 (2.8%) tested SST positive and 150 (14.8%) were L. loa positive. The range of Loa MFD was 0-85 200 mf/mL. The CART model subdivided the sample into 2 Loa MFD classes with a discrimination threshold of 4080 (95% CI, 2180-12 240) mf/mL. The probability of being SST positive exceeded 27% when Loa MFD was >4080 mf/mL., Conclusions: The probability of finding L. loa mf by SST increases significantly with Loa MFD. Skin-snip polymerase chain reaction would be useful when monitoring onchocerciasis prevalence by SST in onchocerciasis-loiasis coendemic areas., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The impact of semiannual mass drug administration (MDA) with albendazole (ALB; 400 mg) alone on lymphatic filariasis (LF) and soil-transmitted helminth (STH) infections was assessed during two trials conducted from 2012 to 2018 in the Republic of Congo and the Democratic Republic of Congo. The collected data were analyzed to evaluate the effect of compliance with ALB treatment on STH infections., Methods: STH infections were diagnosed with duplicate Kato-Katz thick smears and the results are reported as eggs per gram of stool. All subjects with at least two STH infection assessments were included in the analyses. We used parametric survival models to assess the influence of compliance with ALB treatment on the probability of (i) achieving sustained clearance of an STH infection, and (ii) acquiring an STH infection during the follow-up., Results: Out of 2658 subjects included in the trials, data on 202 participants (701 person-years; PY) with hookworm infection, 211 (651 PY) with Ascaris lumbricoides infection and 270 (1013 PY) with Trichuris trichiura infection were available to calculate the probability of achieving sustained clearance of infection. The effect of ALB was dose related for all three STH. For hookworm, the time required for sustained clearance was longer (4.3 years, P < 0.001) for participants who took zero doses per year and shorter (3.4 years, P = 0.112) for participants who took two doses per year compared to those who took one dose per year (3.7 years). For Ascaris, the time required to obtain sustained clearance followed the same pattern: 6.1 years (P < 0.001) and 3.2 years (P = 0.004) vs 3.6 years for, zero, two and one dose per year, respectively. For Trichuris, less time was required for sustained clearance (4.2 years, P < 0.001) for fully compliant participants, i.e. those who took two doses per year, than for those who only took one dose per year (5.0 years). ALB was more effective in achieving sustained clearance of STH infection in subjects with light baseline infection intensities compared to those with higher egg counts., Conclusion: Our results illustrate the importance of MDA compliance at the level of the individual with respect to the STH benefit provided by semiannual ALB MDA, which is used for the elimination of LF in Central Africa.

The standard techniques for diagnosis of human filariasis are the microscopic examination of blood smears or skin biopsies, which are relatively invasive and poorly sensitive at low levels of infection. Recently, filarial DNA has been detected in fecal samples from non-human primates in Central Africa. The aim of this study was to demonstrate proof-of-concept of a non-invasive molecular diagnosis technique for human filariasis by targeting fragments of 12S rDNA, Cox1, ITS1 and LL20-15kDa ladder antigen-gene by conventional PCR in DNA extracted from stool samples of 52 people infected with Mansonella perstans and/or Loa loa. Of these, 10 patients were infected with soil-transmitted helminths (Trichuris trichiura and/or Ascaris lumbricoides), and none were positive for Necator americanus. Interestingly, no filarial gene fragments were detected in the stools of any of the 52 patients. Future studies should evaluate whether a co-infection with soil-transmitted helminths causing gastrointestinal bleeding and likely allowing (micro)filaria exit into the digestive tract, may facilitate the molecular detection of filarial DNA fragments in stool samples., (© M.P.M. Doret et al., published by EDP Sciences, 2021.)

We determined the complete sequence of the mitochondrial DNA (mtDNA) of a parasite discovered between the subcutaneous tissue and the peritoneum of an African nocturnal non-human primate (NHP). The parasite and host sequences were obtained by a combination of Sanger sequencing and nanopore MinION techniques. Analyses of mtDNA gene arrangements and sequences unambiguously showed that the parasite investigated was the pentastomid Armillifer armillatus, also commonly named the tongue worm. The full-length mitochondrial genome of A. armillatus, measuring 16,706 bp in length, contains 13 protein-coding genes, 2 ribosomal RNA genes, and 22 transfer RNA genes, an arrangement identical to that of previously described pentastomid mitochondrial genomes. We describe here the second full mitochondrial genome of A. armillatus to date. To identify the NHP host, maximum likelihood phylogenetic analyses of a 441-bp fragment on the 12S rDNA gene and of a 1,140-bp fragment of the mitochondrial cytochrome b strongly support clustering with the African lorisid Perodicticus potto, a species that has rarely been reported as an intermediate host of this parasite., (© American Society of Parasitologists 2020.)

Background: The World Health Organization now recommends semiannual mass drug administration (MDA) of albendazole with integrated vector management as an option for eliminating lymphatic filariasis (LF) in areas of loiasis-endemic countries where it may not be safe to use diethylcarbamazine or ivermectin in MDA programs. However, the published evidence base to support this policy is thin, and uptake by national programs has been slow., Methodology/principal Findings: We conducted a community trial to assess the impact of semiannual MDA on lymphatic filariasis and soil-transmitted helminth infections (STH) in two villages in the Bandundu province of the Democratic Republic of the Congo with moderately high prevalences for LF and hookworm infections. MDA with albendazole was provided every six months from June 2014 to December 2017 with treatment coverages of the eligible population (all ≥ 2 year of age) that ranged between 56% and 88%. No adverse effects were reported during the trial. Evaluation at 48 months, (i.e. 6 months after the 8th round of MDA), showed that W. bancrofti microfilaremia (Mf) prevalence in the study communities had decreased between 2014 to 2018 from 12% to 0.9% (p<0.001). The prevalence of W. bancrofti antigenemia was also significantly reduced from 31.6% to 8.5% (p<0.001). MDA with albendazole also reduced hookworm, Ascaris lumbricoides and Trichuris trichiura infection prevalences in the community from 58.6% to 21.2% (p<0.001), from 14.0% to 1.6% and 4.1% to 2.9%, respectively. Hookworm and Ascaris infection intensities were reduced by 93% (p = 0.02) and 57% (p = 0.03), respectively. In contrast, Trichuris infection intensity was not significantly reduced by MDA (p = 0.61) over this time period., Conclusion/significance: These results provide strong evidence that semiannual MDA with albendazole alone is a safe and effective strategy for LF elimination in Central Africa. Community MDA also had a major impact on STH infections., Competing Interests: The authors have declared that no competing interests exist.

Background: Onchocerciasis elimination through mass drug administration (MDA) is hampered by coendemicity of Loa loa, as people with high L. loa microfilariae (mf) density can develop serious adverse events (SAEs) after ivermectin treatment. We assessed the geographical overlap of onchocerciasis and loiasis prevalence and estimated the number of coinfected individuals at risk of post-ivermectin SAEs in West and Central Africa from 1995 to 2025., Methods: Focusing on regions with suspected loiasis transmission in 14 countries, we overlaid precontrol maps of loiasis and onchocerciasis prevalence to calculate precontrol prevalence of coinfection by 5 km2 × 5 km2 pixel, distinguishing different categories of L. loa mf intensity. Using statistical and mathematical models, we predicted prevalence of both infections and coinfection for 2015 and 2025, accounting for the impact of MDA with ivermectin., Results: The number of people infected with onchocerciasis was predicted to decline from almost 19 million in 1995 to 4 million in 2025. Of these, 137 000 people were estimated to also have L. loa hypermicrofilaremia (≥20 000 L. loa mf/mL) in 1995, declining to 31 000 in 2025. In 2025, 92.8% of coinfected cases with loiasis hypermicrofilaremia are predicted to live in hypoendemic areas currently not targeted for MDA., Conclusions: Loiasis coinfection is a major concern for onchocerciasis elimination in Africa. We predict that under current strategies, at least 31 000 coinfected people still require treatment for onchocerciasis in 2025 while being at risk of SAEs, justifying continued efforts in research and development for safer drugs and control strategies., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Little information is available on the effect of ivermectin on the third- and fourth-stage larvae of Onchocerca volvulus. To assess a possible prophylactic effect of ivermectin on this parasite, we compared the effects of different ivermectin regimens on the acquisition of onchocercal nodules., Methods: We analyzed data from a controlled randomized clinical trial of ivermectin conducted in the Mbam Valley (Cameroon) between 1994 and 1998 in a cohort of onchocerciasis infected individuals. The number of nodules that appeared between the start and the end of the clinical trial was analyzed, using ANOVA and multivariable Poisson regressions, between four treatment arms: 150 µg/kg annually, 800 µg/kg annually, 150 µg/kg 3-monthly, and 800 µg/kg 3-monthly., Results: The mean number of nodules that appeared during the trial was reduced by 17.7% in subjects treated 3-monthly compared to those treated annually (regardless of the dose). Poisson regression model, adjusting on subject's age and weight, initial number of nodules and intensity of O. volvulus infection in his village of residence, confirmed that the incidence of new nodules was reduced in 3-monthly treatment arms compared to annually treatment arms, and that the dosage of ivermectin does not seem to influence this effect. Furthermore, the number of newly acquired nodules was positively associated with the initial number of nodules. Analysis of disappearance of nodules did not show any significant difference between the treatment groups., Conclusions: To our knowledge, these results suggest for the first time in humans, that ivermectin has a partial prophylactic effect on O. volvulus. Three-monthly treatment seems more effective than annual treatment to prevent the appearance of nodules.

Background: Loiasis is mostly considered a relatively benign infection when compared with other filarial and parasitic diseases, with Calabar swellings and eyeworm being the most common signs. Yet, there are numerous reports in the literature of more serious sequelae. Establishing the relationship between infection and disease is a crucial first step toward estimating the burden of loiasis., Methods: We conducted a systematic review of case reports containing 329 individuals and detailing clinical manifestations of loiasis with a focus on nonclassical, atypical presentations., Results: Results indicate a high proportion (47%) of atypical presentations in the case reports identified, encompassing a wide range of cardiac, respiratory, gastrointestinal, renal, neurological, ophthalmological, and dermatological pathologies. Individuals with high microfilarial densities and residing in an endemic country were at greater risk of suffering from atypical manifestations., Conclusions: Our findings have important implications for understanding the clinical spectrum of conditions associated with Loa loa infection, which extends well beyond the classical eyeworm and Calabar swellings. As case reports may overestimate the true rate of atypical manifestations in endemic populations, large-scale, longitudinal clinico-epidemiological studies will be required to refine our estimates and demonstrate causality between loiasis and the breadth of clinical manifestations reported. Even if the rates of atypical presentations were found to be lower, given that residents of loiasis-endemic areas are both numerous and the group most at risk of severe atypical manifestations, our conclusions support the recognition of loiasis as a significant public health burden across Central Africa., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To provide a systematic review of economic evaluations that has been conducted for onchocerciasis interventions, to summarise current key knowledge and to identify research gaps., Method: A systematic review of the literature was conducted on the 8th of August 2018 using the PubMed (MEDLINE) and ISI Web of Science electronic databases. No date or language stipulations were applied to the searches., Results: We identified 14 primary studies reporting the results of economic evaluations of onchocerciasis interventions, seven of which were cost-effectiveness analyses. The studies identified used a variety of different approaches to estimate the costs of the investigated interventions/programmes. Originally, the studies only quantified the benefits associated with preventing blindness. Gradually, methods improved and also captured onchocerciasis-associated skin disease. Studies found that eliminating onchocerciasis would generate billions in economic benefits. The majority of the cost-effectiveness analyses evaluated annual mass drug administration (MDA). The estimated cost per disability-adjusted life year (DALY) averted of annual MDA varies between US$3 and US$30 (cost year variable)., Conclusions: The cost benefit and cost effectiveness of onchocerciasis interventions have consistently been found to be very favourable. This finding provides strong evidential support for the ongoing efforts to eliminate onchocerciasis from endemic areas. Although these results are very promising, there are several important research gaps that need to be addressed as we move towards the 2020 milestones and beyond., (© 2019 The Authors. Tropical Medicine & International Health published by John Wiley & Sons Ltd.)

Endemic to Central Africa, loiasis - or African eye worm (caused by the filarial nematode Loa loa) - affects more than 10 million people. Despite causing ocular and systemic symptoms, it has typically been considered a benign condition, only of public health relevance because it impedes mass drug administration-based interventions against onchocerciasis and lymphatic filariasis in co-endemic areas. Recent research has challenged this conception, demonstrating excess mortality associated with high levels of infection, implying that loiasis warrants attention as an intrinsic public health problem. This review summarises available information on the key parasitological, entomological, and epidemiological characteristics of the infection and argues for the mobilisation of resources to control the disease, and the development of a mathematical transmission model to guide deployment of interventions., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Mass drug administration (MDA) with ivermectin is the cornerstone of efforts to eliminate human onchocerciasis by 2020 or 2025. The feasibility of elimination crucially depends on the effects of multiple ivermectin doses on Onchocerca volvulus. A single ivermectin (standard) dose clears the skin-dwelling microfilarial progeny of adult worms (macrofilariae) and temporarily impedes the release of such progeny by female macrofilariae, but a macrofilaricidal effect has been deemed minimal. Multiple doses of ivermectin may cumulatively and permanently reduce the fertility and shorten the lifespan of adult females. However, rigorous quantification of these effects necessitates interrogating longitudinal data on macrofilariae with suitably powerful analytical techniques., Methods: Using a novel mathematical modeling approach, we analyzed, at an individual participant level, longitudinal data on viability and fertility of female worms from the single most comprehensive multiple-dose clinical trial of ivermectin, comparing 3-monthly with annual treatments administered for 3 years in Cameroon., Results: Multiple doses of ivermectin have a partial macrofilaricidal and a modest permanent sterilizing effect after 4 or more consecutive treatments, even at routine MDA doses (150 µg/kg) and frequencies (annual). The life expectancy of adult O. volvulus is reduced by approximately 50% and 70% after 3 years of annual or 3-monthly (quarterly) exposures to ivermectin., Conclusions: Our quantification of macrofilaricidal and sterilizing effects of ivermectin should be incorporated into transmission models to inform onchocerciasis elimination efforts in Africa and residual foci in Latin America. It also provides a framework to assess macrofilaricidal candidate drugs currently under development., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Treatment of onchocerciasis using mass ivermectin administration has reduced morbidity and transmission throughout Africa and Central/South America. Mass drug administration is likely to exert selection pressure on parasites, and phenotypic and genetic changes in several Onchocerca volvulus populations from Cameroon and Ghana-exposed to more than a decade of regular ivermectin treatment-have raised concern that sub-optimal responses to ivermectin's anti-fecundity effect are becoming more frequent and may spread., Methodology/principal Findings: Pooled next generation sequencing (Pool-seq) was used to characterise genetic diversity within and between 108 adult female worms differing in ivermectin treatment history and response. Genome-wide analyses revealed genetic variation that significantly differentiated good responder (GR) and sub-optimal responder (SOR) parasites. These variants were not randomly distributed but clustered in ~31 quantitative trait loci (QTLs), with little overlap in putative QTL position and gene content between the two countries. Published candidate ivermectin SOR genes were largely absent in these regions; QTLs differentiating GR and SOR worms were enriched for genes in molecular pathways associated with neurotransmission, development, and stress responses. Finally, single worm genotyping demonstrated that geographic isolation and genetic change over time (in the presence of drug exposure) had a significantly greater role in shaping genetic diversity than the evolution of SOR., Conclusions/significance: This study is one of the first genome-wide association analyses in a parasitic nematode, and provides insight into the genomics of ivermectin response and population structure of O. volvulus. We argue that ivermectin response is a polygenically-determined quantitative trait (QT) whereby identical or related molecular pathways but not necessarily individual genes are likely to determine the extent of ivermectin response in different parasite populations. Furthermore, we propose that genetic drift rather than genetic selection of SOR is the underlying driver of population differentiation, which has significant implications for the emergence and potential spread of SOR within and between these parasite populations.

Background: The standard treatment strategy of mass drug administration with ivermectin plus albendazole for lymphatic filariasis cannot be applied in central Africa, because of the risk of serious adverse events in people with high Loa loa microfilaraemia. Thus, alternative strategies are needed. We investigated one such alternative strategy for mass drug administration for elimination of lymphatic filariasis and soil-transmitted helminth infections in Republic of the Congo., Methods: In 2012, we started a 3 year community trial of biannual mass administration of albendazole in a village in Republic of the Congo. All volunteering inhabitants aged 2 years or older were offered albendazole (400 mg) every 6 months. Infection with Wuchereria bancrofti was diagnosed with a rapid card immunochromatographic test for antigenaemia. People with antigenaemia were tested for microfilaraemia by night blood smears. Individuals were also tested for soil-transmitted helminth infections (ie, hookworm, Ascaris lumbricoides, Trichuris trichiura) with the Kato-Katz method. Assessment surveys were done at 12, 24, and 36 months. The main outcome measure was change in infection rates from baseline to year 3., Findings: Therapeutic coverage was more than 80% in all six rounds of mass administration of albendazole. Between 2012 and 2015, W bancrofti antigenaemia and microfilaraemia rates in the community fell significantly, from 17·3% (95% CI 14·7-20·0) to 4·7% (3·3-6·6; p<0·0001) and from 5·3% (3·9-7·1) to 0·3% (0·1-1·2; p<0·0001), respectively. The geometric mean microfilaria count in microfilaraemic people fell from 199·4 (120·4-330·5) per mL in 2012 to 39·1 (95% CIs not computed) per mL in 2015 (p=0·0095). Hookworm infection was undetectable after 1 year. Between 2012 and 2015, the number of A lumbricoides eggs expelled per g of faeces fell from 9844·6 (8209·0-11 480·0) to 724·4 (340·7-1114·2; p<0·0001), and of T trichiura eggs from 1107·4 (878·5-1336·3) to 366·0 (255·7-476·2; p<0·0001)., Interpretation: Our findings strongly support WHO's provisional strategy of biannual mass administration of albendazole to eliminate lymphatic filariasis in areas where loiasis is co-endemic and ivermectin cannot be safely mass administered., Funding: Bill & Melinda Gates Foundation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)