Exploring factors associated with Trichuris trichiura infection in school children in a high-transmission setting in Kenya.

Objectives: Kenya has implemented a national school-based deworming program, which has led to substantial decline in the prevalence of soil-transmitted helminths (STHs), although some pockets of infections remain. To effectively design an STH control program that leads to significant reductions of Trichuris trichiura, there is a need to understand the drivers of persistent infection despite ongoing treatment programs. Methods: This study was conducted between July and September 2019 at the south coast of Kenya, using a two-stage sampling design. First, a school-based cross-sectional survey was conducted in 2265 randomly selected school children from selected schools in areas known to be endemic for T. trichiura. After this, we conducted a nested case-control study wherein all children positive for T. trichiura (142) were matched to 148 negative controls based on age and village. A household survey was then conducted with all household members of cases and controls. In addition, a subsample of 116 children found to be infected with T. trichiura were followed up to assess the efficacy of albendazole at day 21 post-treatment. The predictors of presence of T. trichiura were investigated through multilevel logistic regression, considering clustering of infection. Results: Overall, 34.4% of the children were infected with at least one STH species; T. trichiura was the most common (28.3%), 89.1% of those with T. trichiura had light-intensity infections. The prevalence of T. trichiura was significantly higher in male children and was positively associated with younger age and number of people infected with T. trichiura in a household. The parasitological cure rate and egg reduction rate of T. trichiura were 35% and 51%, respectively. Other STHs identified were hookworm (9.6%) and Ascaris lumbricoides (5.7%). Conclusions: T. trichiura remains a significant public health challenge in the study area with albendazole treatment efficacy against the parasite, remaining lower than the World Health Organization-recommended thresholds. Because of the observed focal transmission of T. trichiura in the current area, control efforts tailored to local conditions and targeting lower implementation units should be used to achieve optimal results on transmission.

Clinical Presentation of American Tegumentary Leishmaniasis in a Leishmania (Viannia) braziliensis Endemic Hotspot: A 35-Year History.

American tegumentary leishmaniasis (ATL) is a neglected tropical disease affecting the skin and mucosa. American tegumentary leishmaniasis due to Leishmania (Viannia) braziliensis is endemic in Argentina, where the Department of Oran is a hyperendemic focus. All cases of ATL with laboratory confirmation evaluated at a referral center in Oran city between 1985 and 2019 were analyzed retrospectively. Information from cases included clinical form, lesion size and number, time of evolution, and anatomical location; sex, age, and geographic origin were also studied. The temporal distribution of cases was analyzed. A total of 3,573 cases were included in the analysis. The ratio of males to females was 3:1 and the median age was 33 years old. Eighty-seven percent of cases were from Oran city and its surroundings, highlighting the hyperendemic nature of the area. Regarding clinical forms, 92.5% of cases were cutaneous and 7.5% were mucosal, with a median evolution time until clinical evaluation of 30 days and 7 months, respectively. Single cutaneous lesions were more frequent, localized mainly on the exposed areas in the upper and lower limbs. Secondary events were observed and described in 140 (4%) cases, with a median interval of 3.8 years for the appearance of recurrent mucosal disease in previously cutaneous forms. This is the largest case series of ATL due to L. (V.) braziliensis. The most classic presentation is of adult males with single cutaneous ulcers in exposed body areas, with < 10% of cases with mucosal complications. This comprehensive clinical characterization serves as a basis for future studies of the care and control of this neglected tropical disease.

An adaptive phase II/III safety and efficacy randomized controlled trial of single day or three-day fixed-dose albendazole-ivermectin co-formulation versus albendazole for the treatment of Trichuris trichiura and other STH infections. ALIVE trial protocol.

Background: Soil-transmitted helminths (STH) are targeted for control through mass drug-administration campaigns to prevent morbidity affecting at-risk groups in endemic regions. Although broadly successful, the use of albendazole and mebendazole achieved variable progress, with deficiencies against Trichuris trichiura and a predictable low efficacy against Strongyloides stercoralis. Novel drug combinations offer a potential solution, providing they can be delivered safely and maintain efficacy against all STH species. Here we present the protocol of a clinical trial to evaluate a fixed-dose combination (FDC) tablet containing albendazole and ivermectin that will be compared against albendazole against STH . Methods: An adaptive phase II/III randomized controlled trial will be undertaken in STH endemic sites in Ethiopia, Kenya and Mozambique to evaluate an oral FDC of 400 mg albendazole and either 9- or 18 mg ivermectin. FDC will be administered as a single dose or single doses over three-consecutive days and assessed against a single dose of 400 mg albendazole. In the phase II trial, 126 T. trichiura-infected children weighting 15 to 45 kg will be treated in a dose-escalation manner to determine safety objectives. In the phase III trial, 1097 participants aged 5 to 18 years old infected with T. trichiura, hookworm and S. stercoralis will be recruited to determine safety and efficacy. The trial will be open-label with blinded outcome assessors. Cure rate measured 21-days after-treatment in duplicate Kato-Katz is the primary efficacy outcome. Secondary objectives include efficacy evaluation by quantitative polymerase chain reaction (PCR) as an outcome measurement, description of pharmacokinetic parameters, palatability and acceptability evaluations, and monitoring of anthelmintic resistance. Conclusions: This trial with registrational goals seeks to evaluate an innovative fixed-dose combination of albendazole and ivermectin co-formulated tablets, with the goal of providing an anthelmintic regimen with improved efficacy and spectrum of coverage against STH. ClinicalTrials.gov registration: NCT05124691 (18/11/2021).

Pharmacokinetic Characterization and Comparative Bioavailability of an Innovative Orodispersible Fixed-Dose Combination of Ivermectin and Albendazole: A Single Dose, Open Label, Sequence Randomized, Crossover Clinical Trial in Healthy Volunteers.

Soil-transmitted helminths are intestinal worm diseases transmitted through the soil. Available treatments are albendazole and/or ivermectin. The co-administration of existing drugs is an appropriate strategy. A fixed-dose combination adds practical advantages mainly considering mass drug administration. The aim is to characterize pharmacokinetics and to evaluate the comparative bioavailability of an innovative fixed-dose combination of ivermectin/albendazole 18/400 mg compared with the marketed references. Seventy-eight healthy volunteers were included in this laboratory-blinded, randomized, three-treatment, three-period crossover study. Each subject received a single dose of ivermectin/albendazole 18/400 mg (1 tablet); ivermectin 3 mg (6 tablets); and albendazole 400 mg (1 tablet). Serial blood samples for the pharmacokinetic analysis were obtained pre-dose and up to 72 h post-dose. Plasma concentrations of ivermectin H2B1a, ivermectin H2B1b, albendazole, and albendazole sulfoxide were analyzed by LC-MS/MS. Pharmacokinetic parameters were estimated by a non-compartmental analysis and bioavailability compared through a bioequivalence analysis. Safety and tolerability were assessed throughout the study. Main pharmacokinetic parameters of the fixed combination were estimated for both, ivermectin [Cmax (mean, confidence interval): 86.40 (30.42-39.23) ng/ml; AUC0-72 (mean, CI): 1,040 (530-1,678) ng·h/mL; tmax (median, min., and max.); 4.50 (2.50-5.50)] and albendazole [Cmax (mean, CI): 22.27 (1.89-111.78) ng/ml; AUC0-72 (mean, CI): 94.65 (11.65-507.78) ng·h/mL; tmax (median, min., and max.): 2.50 (1.00-12.00) h]. The 90% confidence interval of the geometric mean ratios demonstrated the bioequivalence in the case of ivermectin (Cmax: 110.68%-120.49%; AUC0-72: 110.46%-119.60%) but not in the case of albendazole (Cmax: 53.10%-70.34%; AUC0-72: 61.13%-76.54%). The pharmacokinetic profile of a new fixed-dose combination of ivermectin and albendazole was characterized. The bioequivalence versus the reference ivermectin was demonstrated, though bioequivalence versus albendazole was not shown. The three medications analyzed were well tolerated. The results allow the advancement to the next phase of the clinical program to demonstrate efficacy and safety in patients affected by soil-transmitted helminths. Clinical Trial Registration: https://www.clinicaltrialsregister.eu/ctr-search/search/, identifier Nr. 2020-003438-19.

Ivermectin and albendazole coadministration: opportunities for strongyloidiasis control.

In 2020, WHO recognised the importance of strongyloidiasis alongside soil-transmitted helminths (STH) in their 2021-30 roadmap, which aspires to target Strongyloides stercoralis with preventive chemotherapy by use of ivermectin. Combination treatment with both albendazole, the primary drug used to treat STH, and ivermectin, would improve the efficiency of mass drug administration targeting both STH and S stercoralis. In this Personal View, we discuss the challenges and opportunities towards the development of an efficient control programme for strongyloidiasis, particularly if it is to run concurrently with STH control. We argue the need to define the prevalence threshold to implement preventive chemotherapy for S stercoralis, the target populations and optimal dosing schedules, and discuss the added benefits of a fixed-dose coformulation of ivermectin and albendazole. Implementation of an efficient control programme will require improvements to current diagnostics, and validation of new diagnostics, to target and monitor S stercoralis infections, and consideration of the challenges of multispecies diagnostics for S stercoralis and STH control. Finally, the evolution of ivermectin resistance represents a credible risk to control S stercoralis; we argue that genome-wide approaches, together with improved genome resources, are needed to characterise and prevent the emergence of resistance. Overcoming these challenges will help to reduce strongyloidiasis burden and enhance the feasibility of controlling it worldwide.

Mapping the global distribution of Strongyloides stercoralis and hookworms by ecological niche modeling.

BACKGROUND: The WHO has established a control strategy for Strongyloides stercoralis in school-aged children as well as targets and to maintain control programs for Ascaris lumbricoides, Trichuris trichiura and hookworms. For an efficient development of control programs, it is necessary to know the target countries around the world, as well as the areas within each country where efforts should be focused. Therefore, maps that provide information on the areas at risk for soil-transmitted helminth (STH) infections on a national and sub-national scale would allow for a better allocation of resources. METHODS: We used the ecological niche models MaxEnt and Kuenm R library to estimate the global distribution of S. stercoralis and hookworms. We used occurrence points of both species extracted from surveys of two literature reviews and from the Global Atlas of Helminth Infection database, together with 14 raster maps of environmental variables. RESULTS: We obtained two raster maps with the presence probability of S. stercoralis and hookworm infections at a global level and then estimated the global population at risk to be 2.6 and 3.4 billion, respectively. The population at risk was also estimated at the country level using estimations for areas as small as 25 km2. A relationship was found between the probability of the presence of S. stercoralis and its prevalence, and a raster map was generated. Annual precipitation, annual temperature, soil carbon content and land cover were the main associated environmental variables. The ecological niches of Strongyloides stercoralis and hookworms had an overlap of 68%. CONCLUSIONS: Here we provide information that can be used for developing more efficient and integrated control strategies for S. stercoralis and hookworm infections. This information can be annexed to the study of other risk factors or even other diseases to assess the health status of a community. GRAPHICAL ABSTARCT.

Leishmaniasis tegumentaria y flebótomos en la localidad de Colonia Santa Rosa del norte de Argentina / Tegumentary leishmaniasis and sandflies in Colonia Santa Rosa locality in northern Argentina

Resumen La leishmaniasis tegumentaria (LT) es causada por parásitos del género Leishmania y transmitida por especies de flebótomos, insectos pertenecientes al orden Diptera, familia Psychodidae. El objetivo de este trabajo fue analizar la presencia de casos de LT y su variación temporal entre 1985 y 2019, las formas clínicas, la ubicación de las lesiones en los pacientes y la presencia de flebótomos en la localidad de Colonia Santa Rosa, del norte de Argentina. Los pacientes se diagnosticaron mediante frotis e intradermorreacción de Montenegro. Se colocaron trampas CDC en 14 sitios en el horario de 19 a 7. Se diagnosticaron 120 casos de LT y la prevalencia global fue del 0,75% (^16.000 habitantes). Los pacientes presentaron formas cutáneas simples y múltiples (88,79%) y mucocutáneas (10,83%). Las lesiones cutáneas fueron más frecuentes en extremidades inferiores. Del total de flebótomos, Nyssomyia neivai fue la especie predominante (95%), y, en menor proporción, estuvieron presentes Migonemyia migonei (1,9%), complejo cortelezzii (1,3%) y Evandromyia sallesi (0,09%). La persistente ocurrencia de casos y la presencia de flebótomos en la citada localidad nos sugiere la transmisión endémica en la zona. Esto senala la necesidad de planificar medidas preventivas y de control de la LT en el norte de Argentina.

Abstract Tegumentary leishmaniasis (TL) is caused by parasites of the genus Leishmania and transmitted by the sandfly species, insects belonging to the order Diptera, family Psychodidae. Historically, the most endemic area of TL in Argentina has been the northern region. The aim of this work was to analyze the presence and temporal variation of TL cases reported between 1985 and 2019 in Colonia Santa Rosa locality, northern Argentina. Furthermore, its clinical forms were characterized and sandflies were captured. Patients were diagnosed by smear and the Montenegro skin test. For sampling, CDC light traps were placed at 14 sites from 7pm to 7am. The correlation between vegetation cover and sandfly abundance was also studied. One hundred and twenty TL cases were diagnosed and the overall prevalence was 0.75% (M6 000 inhabitants). Patients presented simple and multiple cutaneous leishmaniasis (88.79%) and the mucocutaneous form (10.83%). Skin lesions were more frequent on the lower extremities (46.73%). Of the total number of sandflies, Nyssomyia neivai (95%) was the predominant species followed by Migonemyia migonei (1.9%), cortelezzii complex (1.3%) and Evandromyia sallesi (0.09%). The persistent occurrence of cases and the presence of sandflies in the locality suggest the existence of endemic transmission in the area. This highlights the need to design prevention and control measures for TL in northern Argentina.

Correction: Lack of efficacy of standard doses of ivermectin in severe COVID-19 patients.

[This corrects the article DOI: 10.1371/journal.pone.0242184.].

Safety and Efficacy of a MEURI Program for the Use of High Dose Ivermectin in COVID-19 Patients.

Background: In the absence of antiviral alternatives, interventions under research for COVID-19 might be offered following guidelines from WHO for monitored emergency use of unregistered and experimental interventions (MEURI). Ivermectin is among several drugs explored for its role against SARS-CoV-2, with a well-known safety profile but conflicting data regarding clinical utility for COVID-19. The aim of this report is to inform on the results of a MEURI Program of high-dose ivermectin in COVID-19 carried out by the Ministry of Health of the Province of La Pampa, Argentina. Methods: COVID-19 subjects, within 5 days of symptoms onset were invited to participate in the program, which consisted in the administration of ivermectin 0.6 mg/kg/day for 5 days plus standard of care. Active pharmacosurveillance was performed for 21 days, and hepatic laboratory assessments were performed in a subset of patients. Frequency of Intensive Care Unit (ICU) admission and COVID-19-related mortality of subjects in the ivermectin intention to treat group were compared with that observed in inhabitants of the same province during the same period not participating in the program. Results: From 21,232 subjects with COVID-19, 3,266 were offered and agreed to participate in the ivermectin program and 17,966 did not and were considered as controls. A total of 567 participants reported 819 adverse events (AEs); 3.13% discontinued ivermectin due to adverse events. ICU admission was significantly lower in the ivermectin group compared to controls among participants ≥40 year-old (1.2 vs. 2.0%, odds ratio 0.608; p = 0.024). Similarly, mortality was lower in the ivermectin group in the full group analysis (1.5 vs. 2.1%, odds ratio 0.720; p = 0.029), as well as in subjects ≥ 40 year- old (2.7 vs. 4.1%, odds ratio 0.655; p = 0.005). Conclusions: This report highlights the safety and possible efficacy of high dose ivermectin as a potentially useful intervention deserving public health-based consideration for COVID-19 patients.

Diptera (Insecta: Pterygota) larvae as predators of Strongyloides stercoralis causing false negative stool cultures.

A stool sample of a five-year-old boy with suspected STH infection arrived at the Laboratory of the Instituto de Investigaciones de Enfermedades Tropicales (IIET), National University of Salta in Oran, province of Salta, Argentina in 2017. Three Harada Mori were prepared, of which only one showed the presence of S. stercoralis. In the other two, the presence of an unknown larva was observed, which was later identified as an insect larva of the Diptera order. PCR analysis of the liquid medium of Harada Mori and Diptera larvae revealed presence of S. stercoralis DNA. These results, added to the predatory characteristics of the dipteran larvae, indicate that the S. stercoralis larvae were prey for these organisms, resulting in a negative diagnosis for S. stercoralis in the Harada Mori.

Strongyloides stercoralis and Trypanosoma cruzi coinfections in a highly endemic area in Argentina.

BACKGROUND: Strongyloidiasis and Chagas disease are endemic in northern Argentina. In this study we evaluate the association between S. stercoralis and T. cruzi infections in villages with diverse prevalence levels for these parasites. Further understanding in the relationship between these Neglected Tropical Diseases of South America is relevant for the design of integrated control measures as well as exploring potential biologic interactions. METHODOLOGY: Community based cross-sectional studies were carried in different villages of the Chaco and Yungas regions in Argentina. Individuals were diagnosed by serology for S. stercoralis and T. cruzi. The association between S. stercoralis and T. cruzi, and between anemia and the two parasites was evaluated using two approaches: marginal (Ma) and multilevel regression (Mu). RESULTS: A total of 706 individuals from six villages of northern Argentina were included. A total of 37% were positive for S. stercoralis, 14% were positive for T. cruzi and 5% were positive for both. No association was found between infection with S. stercoralis and T. cruzi in any of the models, but we found a negative correlation between the prevalence of these species in the different villages (r = -0.91). Adults (> 15 years) presented association with S. stercoralis (Ma OR = 2.72; Mu OR = 2.84) and T. cruzi (Ma OR = 5.12; Mu OR = 5.48). Also, 12% and 2% of the variance of infection with S. stercoralis and T. cruzi, respectively, could be explained by differences among villages. On the other hand, anemia was associated with infection with S. stercoralis (Ma OR = 1.73; Mu OR = 1.78) and was more prevalent in adults (Ma OR = 2.59; Mu OR = 2.69). CONCLUSION: We found that coinfection between S. stercoralis and T. cruzi is not more frequent than chance in endemic areas. However, the high prevalence for both parasites, raises the need for an integrated strategy for the control of STH and Chagas disease.

[Tegumentary leishmaniasis and sandflies in Colonia Santa Rosa locality in northern Argentina]. / Leishmaniasis tegumentaria y flebótomos en la localidad de Colonia Santa Rosa del norte de Argentina.

Tegumentary leishmaniasis (TL) is caused by parasites of the genus Leishmania and transmitted by the sandfly species, insects belonging to the order Diptera, family Psychodidae. Historically, the most endemic area of TL in Argentina has been the northern region. The aim of this work was to analyze the presence and temporal variation of TL cases reported between 1985 and 2019 in Colonia Santa Rosa locality, northern Argentina. Furthermore, its clinical forms were characterized and sandflies were captured. Patients were diagnosed by smear and the Montenegro skin test. For sampling, CDC light traps were placed at 14 sites from 7pm to 7am. The correlation between vegetation cover and sandfly abundance was also studied. One hundred and twenty TL cases were diagnosed and the overall prevalence was 0.75% (≈16 000 inhabitants). Patients presented simple and multiple cutaneous leishmaniasis (88.79%) and the mucocutaneous form (10.83%). Skin lesions were more frequent on the lower extremities (46.73%). Of the total number of sandflies, Nyssomyia neivai (95%) was the predominant species followed by Migonemyia migonei (1.9%), cortelezzii complex (1.3%) and Evandromyia sallesi (0.09%). The persistent occurrence of cases and the presence of sandflies in the locality suggest the existence of endemic transmission in the area. This highlights the need to design prevention and control measures for TL in northern Argentina.

Scope and limitations of a multiplex conventional PCR for the diagnosis of S. stercoralis and hookworms.

OBJECTIVES: Describe the diagnostic characteristics of a conventional multiplex PCR for the diagnosis of S. stercoralis, N. americanus and Ancylostomas spp. METHODS: Fecal samples were collected from a cross-sectional study in Orán department, Salta province, Argentina. The stool samples were analyzed using concentration-sedimentation, Harada Mori, McMaster, and Baermann techniques. DNA was extracted from 50 mg fecal sample using the FastPrep® Spin Kit for Soil. Three pairs of primers were used for the amplification of three products of 101, 330, and 577 base pairs (bp) for S. stercoralis, N. americanus and Ancylostoma spp, respectively. The sensitivity and analytical specificity of multiplex PCR were evaluated, as well as the sensitivity and diagnostic specificity, using a composite standard and Bayesian approach. RESULTS AND CONCLUSIONS: Multiplex PCR did not present cross-reaction with other intestinal parasites, and the detection limit for multiplex PCR was between 2 and 20 pg of genomic DNA. In addition it presented a diagnostic sensitivity of 97.4% for S. stercoralis and 90.3% for hookworms with a specificity of 100% and 87.6%, respectively. PCR identified a higher proportion (p <0.01) of coinfections (15.3%) than microscopic techniques (3.5%). Also, multiplex PCR showed that there was a positive association between S. stercoralis and hookworms (odds ratio = 2.12). However, this association was due to N. americanus (odds ratio= 3.22), since no association was observed between S. stercoralis and Ancylostoma spp. Neither was an association observed between the two species of hookworms.

Effect of Ivermectin and Atorvastatin on Nuclear Localization of Importin Alpha and Drug Target Expression Profiling in Host Cells from Nasopharyngeal Swabs of SARS-CoV-2- Positive Patients.

Nuclear transport and vesicle trafficking are key cellular functions involved in the pathogenesis of RNA viruses. Among other pleiotropic effects on virus-infected host cells, ivermectin (IVM) inhibits nuclear transport mechanisms mediated by importins and atorvastatin (ATV) affects actin cytoskeleton-dependent trafficking controlled by Rho GTPases signaling. In this work, we first analyzed the response to infection in nasopharyngeal swabs from SARS-CoV-2-positive and -negative patients by assessing the gene expression of the respective host cell drug targets importins and Rho GTPases. COVID-19 patients showed alterations in KPNA3, KPNA5, KPNA7, KPNB1, RHOA, and CDC42 expression compared with non-COVID-19 patients. An in vitro model of infection with Poly(I:C), a synthetic analog of viral double-stranded RNA, triggered NF-κB activation, an effect that was halted by IVM and ATV treatment. Importin and Rho GTPases gene expression was also impaired by these drugs. Furthermore, through confocal microscopy, we analyzed the effects of IVM and ATV on nuclear to cytoplasmic importin α distribution, alone or in combination. Results showed a significant inhibition of importin α nuclear accumulation under IVM and ATV treatments. These findings confirm transcriptional alterations in importins and Rho GTPases upon SARS-CoV-2 infection and point to IVM and ATV as valid drugs to impair nuclear localization of importin α when used at clinically-relevant concentrations.

Clinical diagnosis of COVID-19. A multivariate logistic regression analysis of symptoms of COVID-19 at presentation.

INTRODUCTION: The objective of this cross-sectional study was to describe the main symptoms associated with COVID-19, and their diagnostic characteristics, to aid in the clinical diagnosis. METHODS: An analysis of all patients diagnosed by RT-PCR for SARS-CoV-2 between April and May 2020 in Argentina was conducted. The data includes clinical and demographic information from all subjects at the time of presentation (n=67318, where 12% were positive for SARS-CoV-2). The study population was divided into four age groups: pediatric (0-17 years), young adults (18-44 years), adults (45-64 years), and elderly (65-103 years). Multivariate logistic regression was used to measure the association of all symptoms and to create a diagnostic model based on symptoms. RESULTS: Symptoms associated with COVID-19 were anosmia, dysgeusia, headache, low-grade fever, odynophagia, and malaise. However, the presentation of these symptoms was different between the different age groups. In turn, at the time of presentation, the symptoms associated with respiratory problems (chest pain, abdominal pain, and dyspnea) had a negative association with COVID-19 or did not present statistical relevance. On the other hand, the model based on 16 symptoms, age and sex, presented a sensitivity of 80% and a specificity of 46%. CONCLUSIONS: There were significant differences between the different age groups. Additionally, there were interactions between different symptoms that were highly associated with COVID-19. Finally, our findings showed that a regression model based on multiple factors (age, sex, interaction between symptoms) can be used as an accessory diagnostic method or a rapid screening of suspected COVID-19 cases.

Corrigendum to Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial [EClinicalMedicine 37 (2021) 100,959]".

[This corrects the article DOI: 10.1016/j.eclinm.2021.100959.].

Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial.

BACKGROUND: There are limited antiviral options for the treatment of patients with COVID-19. Ivermectin (IVM), a macrocyclic lactone with a wide anti-parasitary spectrum, has shown potent activity against SARS-CoV-2 in vitro. This study aimed at assessing the antiviral effect of IVM on viral load of respiratory secretions and its relationship with drug concentrations in plasma. METHODS: Proof-of-concept, pilot, randomized, controlled, outcome-assessor blinded trial to evaluate antiviral activity of high-dose IVM in 45 COVID-19 hospitalized patients randomized in a 2:1 ratio to standard of care plus oral IVM at 0·6 mg/kg/day for 5 days versus standard of care in 4 hospitals in Argentina. Eligible patients were adults with RT-PCR confirmed SARS-CoV-2 infection within 5 days of symptoms onset. The primary endpoint was the difference in viral load in respiratory secretions between baseline and day-5, by quantitative RT-PCR. Concentrations of IVM in plasma were measured. Study registered at ClinicalTrials.gov: NCT04381884. FINDINGS: 45 participants were recruited (30 to IVM and 15 controls) between May 18 and September 9, 2020. There was no difference in viral load reduction between groups but a significant difference was found in patients with higher median plasma IVM levels (72% IQR 59-77) versus untreated controls (42% IQR 31-73) (p = 0·004). Mean ivermectin plasma concentration levels correlated with viral decay rate (r: 0·47, p = 0·02). Adverse events were similar between groups. No differences in clinical evolution at day-7 and day-30 between groups were observed. INTERPRETATION: A concentration dependent antiviral activity of oral high-dose IVM was identified at a dosing regimen that was well tolerated. Large trials with clinical endpoints are necessary to determine the clinical utility of IVM in COVID-19. FUNDING: This work was supported by grant IP-COVID-19-625, Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación, Argentina and Laboratorio ELEA/Phoenix, Argentina.

Efficacy and Safety of Albendazole and High-Dose Ivermectin Coadministration in School-Aged Children Infected With Trichuris trichiura in Honduras: A Randomized Controlled Trial.

BACKGROUND: The efficacy of currently available anthelminthics against Trichuris trichiura infections is significatively lower than for other soil-transmitted helminths. The combination of ivermectin (IVM) and albendazole (ALB) has shown significant improvements in efficacy. METHODS: Safety and efficacy randomized controlled clinical trial comparing 3 experimental regimens against ALB monotherapy for the treatment of T. trichiura infections in northern Honduras. Infected children were randomized to 4 treatment arms: arm 1, single-dose ALB (400 mg); arm 2, single-dose ALB (400 mg) plus IVM (600 µg/kg); arm 3, ALB (400 mg) for 3 consecutive days; or arm 4, ALB (400 mg) plus IVM (600 µg/kg) for 3 consecutive days. Efficacy was measured based on the egg reduction and cure rates, both assessed 14-21 days after treatment, using the Kato-Katz method. Safety was evaluated by analyzing the frequency and severity of adverse events. RESULTS: Of 176 children randomized to 1 of the 4 treatment arms, 117 completed treatment and follow-up. The egg reduction rates for arms 1, 2, 3, and 4 were 47.7%, 96.7%, 72.1%, and 100%, respectively; with P values <.001 for comparisons between IVM groups and ALB-only arms. The cure rates were 4.2%, 88.6%, 33.3%, and 100%, respectively. A total of 48 adverse events (85.4% mild) were reported in 36 children. CONCLUSIONS: The combined use of ALB and high-dose IVM is a highly effective and well tolerated treatment for the treatment of T. trichiura infections, offering significantly improved treatment for the control of this infection. CLINICAL TRIALS REGISTRATION: NCT04041453.

Performance evaluation of Baermann techniques: The quest for developing a microscopy reference standard for the diagnosis of Strongyloides stercoralis.

BACKGROUND: Soil-transmitted helminths (STH) are common in low and middle income countries where there is lack of access to clean water and sanitation. Effective diagnosis and treatment are essential for the control of STH infections. However, among STH parasites, Strongyloides stercoralis is the most neglected species, both in diagnostics and control strategies. Diagnostic methods cover different approaches, each with different sensitivities and specificities, such as serology, molecular techniques and microscopy based techniques. Of the later, the Baermann technique is the most commonly used procedure. In the literature, several ways have been described to perform the Baermann method, which illustrates the overall lack of a '(gold) reference standard' method for the diagnosis of S. stercoralis infection. In this study we have evaluated the performance of three Baermann techniques in order to improve the reference standard for the microscopic diagnosis of S. stercoralis infection thereby facilitating individual case detection, mapping of the disease and proper evaluation of treatment responses. METHODS/PRINCIPAL FINDINGS: A community based cross sectional study was conducted at Zenzelima, Bahir Dar Zuria Ethiopia. A total of 437 stool samples were collected and analyzed by the following procedures: conventional Baermann (CB), modified Baermann (MB), and modified Baermann with charcoal pre-incubation (MBCI). The diagnostic sensitivity and Negative Predictive Value (NPV) of each technique was calculated using the combination of all the three techniques as a composite reference standard. Our result indicated that larvae of S. stercoralis were detected in 151 (34.6%) stool samples. The prevalence of S. stercoralis infection based on the three diagnostic methods was 9.6%, 8.0%, and 31.3% by CB, MB, and MBCI respectively. The sensitivity and NPV for CB, MB, and MBCI were 26.7% and 70.8%, 22.1% and 69.6%, and 87.0% and 93.2%, respectively. The MBCI showed significant difference (P- value = <0.001) in the sensitivity and NPV values when compared with CB and MB values. The agreement between CB, MB, and MBCI with the composite reference standard was 31.8%, 26.7%, 89.6%, respectively. CONCLUSION/SIGNIFICANCE: Our results suggest the superior performance of MBCI. It is relatively easy to implement, simple to perform and comparatively cheaper. The CB is by far the commonly used method in routine diagnostic although this technique significantly underestimates the true burden of the disease and thereby contributing to the exclusion of S. stercoralis from the control strategies. Therefore, MBCI is recommended as a routine microscopy-based diagnostic test for S. stercoralis infection, particularly in settings where molecular procedures are not available.

Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model.

Recently published data indicates that high ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray administration may contribute to attaining high drug concentrations in nasopharyngeal tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performances of a novel IVM spray formulation were assessed in a pig model. Piglets received IVM either orally (0.2 mg/kg) or by one or two nasal spray doses. The overall safety, and histopathology of the IVM-spray application site tissues, were assessed. The IVM concentration profiles measured in plasma and respiratory tract tissues after the nasal spray were compared with those achieved after the oral administration. Animals tolerated well the nasal spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in nasopharyngeal and lung tissues. The nasal/oral IVM concentration ratios in nasopharyngeal and lung tissues markedly increased by repeating (12 h apart) the spray application. The fast attainment of high and persistent IVM concentrations in nasopharyngeal tissue is the main advantage of the nasal over the oral route. These original results support the undertaking of future clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the prevention and/or treatment of COVID-19.