Controlled human hookworm infection remodels plasmacytoid dendritic cells and regulatory T cells towards profiles seen in natural infections in endemic areas.

Hookworm infection remains a significant public health concern, particularly in low- and middle-income countries, where mass drug administration has not stopped reinfection. Developing a vaccine is crucial to complement current control measures, which necessitates a thorough understanding of host immune responses. By leveraging controlled human infection models and high-dimensional immunophenotyping, here we investigated the immune remodeling following infection with 50 Necator americanus L3 hookworm larvae in four naïve volunteers over two years of follow-up and compared the profiles with naturally infected populations in endemic areas. Increased plasmacytoid dendritic cell frequency and diminished responsiveness to Toll-like receptor 7/8 ligand were observed in both controlled and natural infection settings. Despite the increased CD45RA+ regulatory T cell (Tregs) frequencies in both settings, markers of Tregs function, including inducible T-cell costimulatory (ICOS), tumor necrosis factor receptor 2 (TNFR2), and latency-associated peptide (LAP), as well as in vitro Tregs suppressive capacity were higher in natural infections. Taken together, this study provides unique insights into the immunological trajectories following a first-in-life hookworm infection compared to natural infections.

Public engagement for the conduct of a controlled human infection study testing vaccines against Necator americanus (hookworm) in areas of active hookworm transmission in Brazil.

Controlled Human Infection Models (CHIS) involve administering human pathogens to healthy participants in controlled medical settings, which can elicit complex bioethical issues. Understanding how the community perceives such studies can significantly increase the participant's sense of cooperation and increases the researcher's and the participant's transparency. The current study describes the development of an educational intervention to achieve these ends as it aims to (1) analyze perceptions of the Controlled Human Infection Studies (CHIS), and (2) evaluate the participants' comprehension of the CHIS. METHODS: This is a qualitative action research that includes the development of an educational intervention with residents of a rural area in Minas Gerais, Brazil, where there is continuous natural transmission of the human pathogen Necator americanus ("hookworm"). In this area, it is intended to carry out a proposed phase 3 vaccine clinical trial in the future to test the efficacy of hookworm vaccines using controlled human infection. Two data collection strategies were used: an educational intervention and a focus group. RESULTS: The participants' perceptions showed distinct perspectives on CHIS. On one side, they recognized that the investigation is essential for the community, but on the other side, they thought that there would be resistance to its conduct by fear of infection. The idea that the study would generate a benefit for the greater good, contributing to the prevention of hookworm infection, was clearly stated. The participants perceived that the study offered concrete risks that could be reduced by constant monitoring by the researchers. They also mentioned the importance of access to information and the positive influence those who express interest in participating in the study can exert in the community. In relation to comprehension the participants memorized the information, mobilized it to explain everyday situations and created strategies to disseminate the study and engage the community in its development. By repeating and making sense of the information, the participant not only assimilates the knowledge transmitted, but also creates new knowledge. CONCLUSION: We concluded that an educational process of discussion and dialogue around participants' perceptions about the CHIS, promotes understanding and allows ways to disseminate information about the research to be collectively created.

The effect of novel aromatic heterocycle substituted aminamidine derivatives on Necator americanus.

BACKGROUND: The efficacy of current drugs against hookworms at a single dose is highly variable across regions, age groups and infection intensity. Extensive and repeated use of these drugs also leads to potential drug resistance. Therefore, novel drugs are required for sustained disease control. OBJECTIVES: Novel aromatic heterocycle substituted aminamidine derivatives (AADs) were synthesized based on tribendimine (TBD), and their in vivo potency against Necator americanus was tested. METHODS: The efficacy of the AADs was tested in male hamsters. Oral and IV pharmacokinetic parameters were determined in male Sprague-Dawley rats. The proteomic profiles of N. americanus samples treated with AADs were compared using tandem mass tag-based quantitative proteomic analyses. RESULTS: Most AADs exhibited better anthelmintic activity than TBD at a single oral dose. Compound 3c exhibited improved solubility (>50×), and the curative dose was as low as 25 mg/kg. Similar to TBD, 3c was rapidly metabolized after oral administration and transformed into p-(1-dimethylamino ethylimino)aniline (dADT), an active metabolite against intestinal nematodes. dADT from 3c had better pharmacokinetic profiles than that from TBD and achieved an oral bioavailability of 99.5%. Compound 3c possessed rapid anthelmintic activity, clearing all worms within 24 h after an oral dose of 50 mg/kg. Quantitative proteomic analysis indicated that it might be related to ATP metabolism and cuticle protein synthesis. CONCLUSIONS: Compound 3c is a novel and promising compound against N. americanus in vivo.

Modulation of intestinal epithelial permeability by chronic small intestinal helminth infections.

Increased permeability of the intestinal epithelial layer is linked to the pathogenesis and perpetuation of a wide range of intestinal and extra-intestinal diseases. Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed as a treatment for many of the same diseases. Helminths induce immunoregulatory changes in their host which could decrease epithelial permeability, which is highlighted as a potential mechanism through which helminths treat disease. Despite this, the influence of a chronic helminth infection on epithelial permeability remains unclear. This study uses the chronically infecting intestinal helminth Heligmosomoides polygyrus to reveal alterations in the expression of intestinal tight junction proteins and epithelial permeability during the infection course. In the acute infection phase (1 week postinfection), an increase in intestinal epithelial permeability is observed. Consistent with this finding, jejunal claudin-2 is upregulated and tricellulin is downregulated. By contrast, in the chronic infection phase (6 weeks postinfection), colonic claudin-1 is upregulated and epithelial permeability decreases. Importantly, this study also investigates changes in epithelial permeability in a small human cohort experimentally challenged with the human hookworm, Necator americanus. It demonstrates a trend toward small intestinal permeability increasing in the acute infection phase (8 weeks postinfection), and colonic and whole gut permeability decreasing in the chronic infection phase (24 weeks postinfection), suggesting a conserved epithelial response between humans and mice. In summary, our findings demonstrate dynamic changes in epithelial permeability during a chronic helminth infection and provide another plausible mechanism by which chronic helminth infections could be utilized to treat disease.

Safety and immunogenicity of the co-administered Na-APR-1 and Na-GST-1 hookworm vaccines in school-aged children in Gabon: a randomised, controlled, observer-blind, phase 1, dose-escalation trial.

BACKGROUND: A human hookworm vaccine is being developed to protect children against iron deficiency and anaemia associated with chronic infection with hookworms. Necator americanus aspartic protease-1 (Na-APR-1) and N americanus glutathione S-transferase-1 (Na-GST-1) are components of the blood digestion pathway critical to hookworm survival in the host. Recombinant Na-GST-1 and catalytically inactive Na-APR-1 (Na-APR-1[M74]) adsorbed to Alhydrogel were safe and immunogenic when delivered separately or co-administered to adults in phase 1 trials in non-endemic and endemic areas. We aimed to investigate the safety and immunogenicity of these antigens in healthy children in a hookworm-endemic area. METHODS: This was a randomised, controlled, observer-blind, phase 1, dose-escalation trial, conducted in a clinical research centre, in 60 children aged six to ten years in Lambaréné, a hookworm-endemic region of Gabon. Healthy children (determined by clinical examination and safety laboratory testing) were randomised 4:1 to receive co-administered Na-GST-1 on Alhydrogel plus Na-APR-1(M74) on Alhydrogel and glucopyranosyl lipid A in aqueous formulation (GLA-AF), or co-administered ENGERIX-B hepatitis B vaccine (HBV) and saline placebo, injected into the deltoid of each arm. Allocation to vaccine groups was observer-masked. In each vaccine group, children were randomised 1:1 to receive intramuscular injections into each deltoid on two vaccine schedules, one at months 0, 2, and 4 or at months 0, 2, and 6. 10 µg, 30 µg, and 100 µg of each antigen were administered in the first, second, and third cohorts, respectively. The intention-to-treat population was used for safety analyses; while for immunogenicity analyses, the per-protocol population was used (children who received all scheduled vaccinations). The primary outcome was to evaluate the vaccines' safety and reactogenicity in healthy children aged between six and ten years. The secondary outcome was to measure antigen-specific serum IgG antibody levels at pre-vaccination and post-vaccination timepoints by qualified ELISAs. The trial is registered with ClinicalTrials.gov, NCT02839161, and is completed. FINDINGS: Between Jan 23 and Oct 3, 2017, 137 children were screened, of whom 76 were eligible for this trial. 60 children were recruited, and allocated to either 10 µg of the co-administered antigens (n=8 for each injection schedule), 30 µg (n=8 for each schedule), 100 µg (n=8 for each schedule), or HBV and placebo (n=6 for each schedule) in three sequential cohorts. Co-administration of the vaccines was well tolerated; the most frequent solicited adverse events were mild-to-moderate injection-site pain, observed in up to 12 (75%) of 16 participants per vaccine group, and mild headache (12 [25%] of 48) and fever (11 [23%] of 48). No vaccine-related serious adverse events were observed. Significant anti-Na-APR-1(M74) and anti-Na-GST-1 IgG levels were induced in a dose-dependent manner, with peaks seen 14 days after the third vaccinations, regardless of dose (for Na-APR-1[M74], geometric mean levels [GML]=2295·97 arbitrary units [AU] and 726·89 AU, while for Na-GST-1, GMLs=331·2 AU and 21·4 AU for the month 0, 2, and 6 and month 0, 2, and 4 schedules, respectively). The month 0, 2, and 6 schedule induced significantly higher IgG responses to both antigens (p=0·01 and p=0·04 for Na-APR-1[M74] and Na-GST-1, respectively). INTERPRETATION: Co-administration of recombinant Na-APR-1(M74) and Na-GST-1 to school-aged Gabonese children was well tolerated and induced significant IgG responses. These results justify further evaluation of this antigen combination in proof-of-concept controlled-infection and efficacy studies in hookworm-endemic areas. FUNDING: European Union Seventh Framework Programme.

Geohelmintiasis, estado nutricional y antropometría de niños de 3 a 6 años del Centro Escolar de la ciudad de Guayaquil, Ecuador / Geohelminthiasis, nutritional status and anthropometry of children from 3 to 6 years old from the School Center of the city of Guayaquil, Ecuador

Las geohelmintiasis son nematodos que afectan al hombre a través de la ingesta de huevos parasitarios, afectando el estado nutricional antropométrico de la población infantil, motivo por el cual se planteó como objetivo determinar incidencia de las helmintiasis transmitidas por el suelo en el estado nutricional antropométrico de niños de 3 a 6 años en un centro escolar Guayaquil en Ecuador, durante el último semestre del 2018. Se aplicó la metodología descriptiva de corte transversal; donde se incluyeron 92 preescolares de 3 a 6 años. A cada niño(a) se le hizo su estudio antropométrico nutricional, unido a un estudio coprológico realizado a 45 niños. Se obtuvo el Índice de Masa Corporal (IMC) con el cual se determinó el estado nutricional (IMC/Edad/Sexo), usando los percentiles del Ministerio de Salud Pública de Ecuador. Se revisaron los IMC de los 35 niños que presentaron geohelminiasis quienes evidenciaron una ligera disminución en la ganancia de los valores de las variables antropométricas. Se encontró predominio del sexo femenino (54,35%), la edad fue 3,78 años, peso: 15,21 Kg y talla: 100,23 cm2, el IMC fue 16,62 Kg/cm2, sin diferencias entre el sexo; la especie de mayor ocurrencia fue la Trichuris. trichiura 43,47% (niñas 10/23) y 66,67% (niños 8/12). Se concluye que 29,34% de los preescolares estudiados están malnutridos, presentan geohelmintiasis, por ello es recomendable realizar intervenciones dirigidas a representantes, estudiantes y docentes, para atender paralelamente geohelmintiasis y nutrición para garantizar la calidad de vida(AU)

Geohelminthiasis are nematodes that affect man through the ingestion of parasitic eggs, affecting the anthropometric nutritional status of the infant population, which is why the objective was to determine the incidence of soil-transmitted helminthiasis in the anthropometric nutritional status in children aged 3 to 6 years of a school in Ecuador, during the last semester of 2018. A cross-sectional descriptive methodology was applied; where 92 preschoolers from 3 to 6 years old were included. Each child was given his or her nutritional anthropometric study, together with a coprological study of 45 children. There was obtained the Body Mass Index (BMI) with which there decided the nutritional state (BMI / Age / Sex), using the centiles of the Department of Public health of Ecuador. The BMI of the 35 children with geohelminiasis were reviewed and showed a slight decrease in the gain of anthropometric variables. The prevalence of female sex was found (54,35%), the age was 3,78 years, weight: 15,21 Kg and height: 100,23 cm2, the BMI was 16,62 Kg/cm2, with no differences between sex; the species of greatest occurrence was Trichuris trichiura 43,47% (girls 10/23) and 66,67% (boys 8/12). It is concluded that 29.34% of the preschools studied are malnourished, have geohelminthiasis, so it is advisable to make interventions aimed at representatives, students and teachers, to attend parallel geohelminthiasis and nutrition to ensure quality of life(AU)

Diferencias morfológicas relevantes para la identificación específica de larvas de uncinarias y Strongyloides stercoralis / Relevant morphological differences for the specific identification of larvae of hookworms and Strongyloides stercoralis

Objetivos: Describir las características morfológicas diferenciales más relevantes de los estadios larvarios de uncinarias (Ancylostoma duodenale y Necator americanus), y S. stercoralis, para su identificación específica en laboratorio clínico convencional. Material y métodos: Estudio observacional durante julio del 2015 a agosto del 2016. Se realizaron cultivos en placa de agar de muestras fecales positivas por microscopía a larvas de nematodos o huevos de uncinaria. Las larvas desarrolladas en cultivo fueron descritas morfológicamente mediante claves, se identificaron las características morfológicas diferenciales más relevantes y se ilustraron mediante microfotografías. Resultados: Las características morfológicas más relevantes para la diferenciación específica fueron la longitud de la cavidad bucal y la prominencia del poro genital en el estadio rabditiforme; y la forma del cuerpo, el extremo terminal de la cola y el diámetro del extremo anterior del intestino en relación al esófago en el estadio filariforme. Conclusiones: Las uncinarias A. duodenale y N. americanus, y S. stercoralis pueden identificarse específicamente por microscopía óptica mediante el análisis morfológico de sus estadíos larvarios desarrollados en cultivo. Debido al requerimiento de equipos e insumos de uso común en laboratorio de microbiología, se recomienda esta metodología para uso en laboratorios clínicos convencionales. (AU)

Objectives: To determine the most relevant morphologic differences of larval stages of hookworms (Ancylostoma duodenale y Necator americanus) and S. stercoralis for their specific identification in a conventional laboratory. Methods: An observational study was carried-out between July and August 2016. Positive fecal samples at microscopy to nematode larvae or to eggs of hookworms were cultured in agar plate. Larvae that developed in culture were described morphologically using passwords. We identified the most relevant differential morphologic features and illustrated them using microphotography. Results: The most relevant morphologic features that allow differentiating these nematodes were the longitude of the oral cavity and the prominence of the genital primordium for the rabditiform larva; the shape of the body, the terminal end of the tail and the diameter of the anterior extreme of the intestine in relation to the esophagus for the filariform larvae. Conclusions: Hookworms and S. stercoralis can be specifically identified by optic microscopic examination of their larval stages developed in culture. We recommend this methodology for conventional microbiology laboratories due to the requirement of simple equipment. (AU)

Ancilostomíase / Ancylostomiasis

A ancilostomíase é uma doença parasitária causada pelos helmintos Ancylostoma duodenale e Necator americanus, com importante.

La uncinaria americana-stile / The uncinaria american-stile

En nuestros estudios previos expusimos nuestras dudas y vacilaciones en la clasificación de ese verme intestinal Uncinaria Americana-Stiles. Hicimos la enumeración de las demás especies conocidas como anemiantes o patógenas de los mamíferos: U. trigonocéfala, U. stenocéfala, U. ceinua, etc; y dedujimos la semejanza que existía entre nuestra especia y la U. estenocéfala. Posteriormente identificamos el anquilostomo nuestro con el de Stiles, y en este trabajo resumimos sus caracteres específicos y hábitat, comparados con los del U. duodenalis, Dubini, con sus respectivas láminas. Puede decirse que la U. americana es la que por si sola causa las anemias de Venezuela. En la colección del Hospital Vargas se encuentra cerca de cincuenta mil parásitos expulsados por los enfermos y mezclados a ellos se ha encontrado 32 ejemplares de la U. duodenal

Uncinariasis: Hallazgo incidental durante CPRE / Uncinariasis: Incidental find during ERCP

Se presentan tres casos de uncinariasis como hallazgo incidental durante un procedimiento de CPRE, Colangio Pancreatografía Retrógrada Endoscópica. Los pacientes no presentaban síntomas debidos a su parasitosis. La CPRE se llevó a cabo por ictericia obstructiva, encontrando coledocolitiasis en dos de los pacientes. Se revisa la epidemiología, ciclo de vida, patofisiología y tratamiento de la uncinariasis. No debemos olvidarnos que vivimos en un clima tropical propicio al desarrollo de diferentes enfermedades parasitarias que requieren un diagnóstico y tratamiento oportuno

Hookworm infection and anemia in adult women in rural Chiapas, Mexico

OBJECTIVE: To describe associations between anemia and hookworm (Necator americanus) infection in hospitalized women in rural Chiapas, Mexico. MATERIAL AND METHODS: We retrospectively reviewed the hospital records of 68 anemic women (defined as having a hemoglobin level <10mg/dl) or with intestinal parasitism, identified through hospital discharge and transfusion records for the calendar year 1999. The medical charts of 86 cases were located, 18 of which were not confirmed as anemia cases. The hospital is located in Altamirano, Chiapas. Characteristics of subjects were compared using Student's t-test (for continuous variables) and the chi2 test (for categorical variables). A p-value <0.01 was used for statistical significance. Chart review and data analysis took place during the year 2000. RESULTS: Fifty percent of women who had stool examinations were infected with N. americanus. Necator often coexisted with other potential causes of anemia, such as pregnancy and hemorrhage. Hemoglobin levels in hookworm-infected women (mean 4.1 g/dl) were significantly lower than in uninfected women (mean 7.0 gm/dl), and Necator prevalence was significantly higher in the anemic women (50 percent) than in the overall hospital population (1.9 percent). CONCLUSIONS: Anemic women should be offered stool testing where Necator is present, and should be considered for antihelminthic treatment even if pregnant. Further investigation is recommended among women in Chiapas, and probably elsewhere in Mexico

Revisión de Tema: Nemátodos intestinales de importancia médica en Colombia ¿un problema resuelto? / intestinal nematodes of medical importance in Colombia: a solved problem?

Las enteroparasitosis, en general, constituyen un gran problema de salud pública en el mundo. De éstas, las nematodosis figuran entre las más destacadas en Colombia. Debido a que estos parásitos pueden ingresar al organismo por vía oral o por la piel, los hábitos higiénico-sanitarios deficientes, entre ellos el fecalismo, facilitan su transmisión y conservación.Entre las nematodosis más prevalentes en nuestro país tenemos aquéllas causadas por Ascaris lumbricoides, Trichuris trichiura (tricocéfalo), uncinarias (Necator americanus y Ancylostoma duodenale) y Strongyloides stercoralis. Cuando la carga de dichos parásitos es considerablemente alta o se acompaña de alteraciones en las defensas del hospedero, se pueden producir complicaciones que comprometen seriamente la salud del paciente.En la actualidad se sabe que el control farmacológico de estas nematodosis es efectivo y seguro. No obstante, sin autocuidado y mantenimiento sostenible de buenas condiciones higiénico-sanitarias, no es posible su erradicación.Por lo anterior, esta revisión dirigida al personal de la salud, especialmente a los médicos generales, discutirá los aspectos más relevantes de estas nematodosis y de sus complicaciones, haciendo énfasis en su biología, fisiopatología, manifestaciones clínicas, diagnóstico, tratamiento y algunos datos epidemiológicos.

Abstract Intestinal parasites, in general, constitute a great worldwide, public health problem. Of them, nematodes are among the most outstanding in Colombia. Because these parasites can enter into the organism either by ingestion or through the skin, faulty hygienic-sanitary habits facilitate their transmission and conservation. Among nematodosis the more frequent in Colombia are those caused by Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), hookworms (Necator americanus and Ancylostoma duodenale) and Strongyloides stercoralis. When the burden of these parasites is considerably high and/or is accompanied by alterations in host defenses, complications can take place that seriously affect health. Presently it is known that pharmacological control of these nematodosis is effective and safe. Nevertheless, without selfcare, and maintenance of good hygienic-sanitary conditions, their eradication will not be feasible. This review of outstanding aspects of nematodosis, with emphasis on their biology, physiopathology, clinical manifestations, diagnosis, treatment, and some epidemiologic data, intends to update physicians as a basis for adequate management of this problem.

Relaciones entre las prevalencias de las geohelmintiasis humanas en Venezuela / Relationship between prevalences of geohelminthic infections in human, Venezuela

By means of Kato-Katz technique 113,254 coprological samples of the human population belonging to 100 counties from Venezuela were analyzed. It was determined the following prevalences: ascaris lumbricoides 26,8 percent, trichuris trichiura 32,7 percent and hookworm 5,6 percent. It was found a strong correlation between a. lumbricoides and t. trichiura infection (p<0,001), a significant correlation between t. trichiura and hookworn (p<0,5) and no correlation between a. lumbricoides and hookworm

Hallazgo de ancylostoma duodenale en la localidad de Pororó, Paraguay

a) Se realizó un trabajo de prevalencia de parásitosintestinales, en la localidad de Pororó. Se encotro que el 93 porciento de la población estudiada estabaparasitada, 61 prciento poseían dos o más parásitos.Entre los principales parásitos intestinales encontrados están: blastocystis hominis 71,3 porciento, uncinaria 52,8 poriento y giardialamblia 19,7 porcientoTambién se realizó el cultivo de las heces por método de Harada-Mori, se encontro: necator americanusen el 68porciento de las muestras, ancylostomaduodenaleen el 36 porciento y strongyloides stercoralis en el4 porciento las cifras de ancylostoma duodenale son superior

Prevalencia de las especies de ancilostomideos en los adoberos de Moche, Trujillo, 1992 / Prevalency of the species of ancilostomideos in the adoberos of Moche, Trujillo, 1992

Se determinó la prevalencia de las especies de Ancilostomideos y sus factores epidemiológicos condicionantes en 71 adoberos de Moche, Trujillo-Perú, empleando la técnica de Teleman para la identificación de los huevecillos y que se cultivaron por el método de Harada-Mori para tipificar las larvas y se recolectaron parásitos adultos post ingestión de 400 mg de albendazole. Se encontró 13 (18.3 por ciento) adoberos infectados por ancilostomídeos; en 11 (84.6 por ciento) se recolectaron larvas, de las cuales 11 fueron Ancylostoma duodenal y en 6 casos se capturaron parásitos adultos de A. duodenale. De los infestados, el 53.8 por ciento pertenecía a la segunda década de la vida; el 92.3 por ciento procedía de la costa y sierra, domiciliando el 69.2 por ciento en el área rural; consumiendo agua no potable y creciendo de letrinas el 76.9 por ciento y de desagüe el 100 por ciento. Todos laboraban en área rural, no usaban calzado ni guantes, descasaban, comían y defecaban en el área de trabajo. El 84.6 por ciento de los infectados era analfabeto o tenían educación primaria, habiendo laborado en otras adoberías en el 53.8 por ciento de los casos y laboraban como adoberos de 1 a 5 años en el 53.8 por ciento de los casos. Concluimos que existe una prevalencia alta de ancilostomídeos, ancylostoma duodenale y Necator americanus, entre los adoberos de Moche-Trujillo.

Comparacion de varias tecnicas coproparasitologicas para el diagnostico de geohelmintiasis intestinales / Comparison of several coproparasitological techniques for diagnosis of soil-transmitted intestinal helminthiasis

Se procesan "a ciegas" 511 muestras de heces por las tecnicas de Kato-Katz, Willis, Ritchie y directo. Al comparar los resultados obtenidos en el diagnostico de Trichuris trichiura, Necator americanus y Ascaris lumbricoides, vimos que la de Kato-Katz fue mas sensible, revelando el mayor numero de casos, siguiendole en orden sucesivo, el Willis, el Ritchie, y el examen directo. Si se tiene en cuenta que el metodo de Kato-Katz es ademas cuantitativo, podemos recomendar-lo como tecnica de eleccion para el diagnostico de las geohelmintiasis intestinales.