Efficacy of a single dose versus a multiple dose regimen of Mebendazole against hookworm infections among school children: a randomized open-label trial.

BACKGROUND: Despite the existence of a population-based control program using single dose albendazole or mebendazole as a preventive chemotherapy, hookworm transmission remains high. It causes a negative impact on the growth and school performance of children. In connection to this preventive chemotherapy, different studies produced conflicting results. This study aimed at evaluating the efficacy of single (500 mg) versus multiple doses (100 mg twice a day during three consecutive days) of mebendazole against hookworm infections among school-aged children. METHODS: This randomized open-label clinical trial took place among school-aged children (6-14 years old) in Burie and Debre Elias towns, Northwest Ethiopia. Using simple randomization, eligible hookworm-positive children were allocated (1:1) to either a single or multiple dose treatment arms. Stool samples were collected and processed using McMaster method at baseline and follow-up period (14-21 days after treatment). Only laboratory technicians were blinded. The cure and egg reduction rates were the primary and secondary therapeutic outcome measures against hookworm infections, respectively. An independent t-test was used to compare group means, and logistic regression was used to calculate odds ratio (OR). P-value < 0.05 at 95% CI was considered statistically significant. RESULT: One hundred eight children, 54 in each treatment arm had completed baseline data and received allocated treatment. One hundred three children had completed follow-up data records and included for the final efficacy analysis. Cure rate against hookworm was significantly higher in the multiple dose (96.1%) than in the single dose (30.8%) with OR = 55.125; 95% CI: 11.92-254.9; P < 0.001. The egg reduction rate in the multiple dose treatment arm (99.5%) was also significantly higher than in the single dose arm (68.9%) with difference t (101) =5.38; 95% CI 230.95-505.36; P < 0.001. CONCLUSION: The single dose regimen of mebendazole for the treatment of hookworm infections showed poor cure and egg reduction rates, while the multiple doses revealed satisfactory. Although multiple dose regimen administration is a bit more complex than the single dose, we strongly encourage replacing it with multiple dose regimen during deworming programs in hookworm endemic areas. TRIAL REGISTRATION: This trial is retrospectively registered in www.pactr.org, number PACTR201911466695052 on November 26, 2019.

The role of carbon dioxide in nematode behaviour and physiology.

Carbon dioxide (CO2) is an important sensory cue for many animals, including both parasitic and free-living nematodes. Many nematodes show context-dependent, experience-dependent and/or life-stage-dependent behavioural responses to CO2, suggesting that CO2 plays crucial roles throughout the nematode life cycle in multiple ethological contexts. Nematodes also show a wide range of physiological responses to CO2. Here, we review the diverse responses of parasitic and free-living nematodes to CO2. We also discuss the molecular, cellular and neural circuit mechanisms that mediate CO2 detection in nematodes, and that drive context-dependent and experience-dependent responses of nematodes to CO2.

Revisiting the Ancylostoma Caninum Secretome Provides New Information on Hookworm-Host Interactions.

Hookworm infection is a major tropical parasitic disease affecting almost 500 million people worldwide. These soil-transmitted helminths can survive for many years in the intestine of the host, where they feed on blood, causing iron deficiency anemia and other complications. These parasites release a variety of molecules known as excretory/secretory products (ESPs) that are involved in many different biological processes that govern parasite survival. Using a combination of separation techniques such as SDS-PAGE and OFFGEL electrophoresis, in combination with state-of-the-art mass spectrometry we have reanalyzed the dog hookworm, Ancylostoma caninum, ESPs (AcESP). We identified 315 proteins present in the AcESP, compared with just 105 identified in previous studies. The most highly represented family of proteins is the SCP/TAPs (110 of the 315 proteins), and the most abundant constituents of AcESP are homologues of the tissue inhibitors of metalloproteases (TIMP) family. Interestingly, we identified new homologs of well-known vaccine candidates and immunomodulatory proteins. This study provides novel information about the proteins secreted by A. caninum, and constitutes a comprehensive dataset to study the proteins involved in host-hookworm interactions.

Ascaris and hookworm transmission in preschool children in rural Panama: role of subsistence agricultural activities.

This longitudinal study explored whether aspects of subsistence agriculture were associated with presence and intensity of Ascaris and hookworm in preschool children in rural Panama. Questionnaires were used to collect data on household socio-demographics, child exposure to agriculture and household agricultural practices. Stool samples were collected from children (6 months-5 years) at 3 time points, with albendazole administered after each to clear infections, resulting in 1 baseline and 2 reinfection measures. A novel Agricultural Activity Index (AAI) was developed using principal components analysis to measure the intensity of household agricultural practices. Zero-inflated negative binomial regression models revealed baseline hookworm egg counts were higher if children went to the agricultural plot and if the plot was smaller. Baseline and reinfection Ascaris egg counts were higher if children went to the plot and households had higher AAI, and higher at baseline if the plot was smaller. Caregiver time in the plot was negatively associated with baseline Ascaris egg counts, but positively associated with baseline hookworm and Ascaris reinfection egg counts. Children who spent more time playing around the home were less likely to be infected with Ascaris at baseline. We conclude that preschool child exposure to subsistence agriculture increased Ascaris and hookworm intensity.

Ivermectin treatment of free-ranging endangered Australian sea lion (Neophoca cinerea) pups: effect on hookworm and lice infection status, haematological parameters, growth, and survival.

A placebo-controlled study was used to investigate the effectiveness of ivermectin to treat hookworm (Uncinaria sanguinis) and lice (Antarctophthirus microchir) infections in free-ranging Australian sea lion (Neophoca cinerea) pups and to test the hypotheses that these parasitic infections cause anaemia, systemic inflammatory responses, and reduced growth, and contribute towards decreased pup survival. Ivermectin was identified as an effective and safe anthelmintic in this species. Pups administered ivermectin had significantly higher erythrocyte counts and significantly lower eosinophil counts compared to controls at 1-2 months post-treatment, confirming that U. sanguinis and/or A. microchir are causatively associated with disease and demonstrating the positive effect of ivermectin treatment on clinical health parameters. Higher growth rates were not seen in ivermectin-treated pups and, unexpectedly, relatively older pups treated with ivermectin demonstrated significantly reduced growth rates when compared to matched saline-control pups. Differences in survival were not identified between treatment groups; however, this was attributed to the unexpectedly low mortality rate of recruited pups, likely due to the unintended recruitment bias towards pups >1-2 months of age for which mortality due to hookworm infection is less likely. This finding highlights the logistical and practical challenges associated with treating pups of this species shortly after birth at a remote colony. This study informs the assessment of the use of anthelmintics as a tool for the conservation management of free-ranging wildlife and outlines essential steps to further the development of strategies to ensure the effective conservation of the Australian sea lion and its parasitic fauna.

Immunology of experimental and natural human hookworm infection.

Human hookworm infection is one amongst the most prevalent of the neglected tropical diseases. An informative experimental animal model, that is, one that parallels a human infection, is not available for the study of human hookworm infection. Much of our current understanding of the human immune response during hookworm infection relies on the studies from experimental infection of hookworm-naïve individuals or the natural infections from individuals residing in hookworm-endemic areas. The experimental human infections tend to be acute, dose-controlled infections, often with a low larval inoculum so that they are well tolerated by human volunteers. Natural hookworm infections usually occur in areas where hookworm transmission is constant and infection is chronic. In cases where there has been drug administration in an endemic area, re-infection often occurs quickly even amongst those who were treated. Hence, although many of the characteristics of experimental and natural hookworm infection differ, both models have elements in common: mainly an intense Th2 response with the production of total and specific IgE as well as elevated levels of eosinophilia, IL-5, IL-10 and TNF. While hookworm infection affects millions of individuals worldwide, much of the human immunology of this infection still needs to be studied and understood.

Molecular mechanisms of hookworm disease: stealth, virulence, and vaccines.

Hookworms produce a vast repertoire of structurally and functionally diverse molecules that mediate their long-term survival and pathogenesis within a human host. Many of these molecules are secreted by the parasite, after which they interact with critical components of host biology, including processes that are key to host survival. The most important of these interactions is the hookworm's interruption of nutrient acquisition by the host through its ingestion and digestion of host blood. This results in iron deficiency and eventually the microcytic hypochromic anemia or iron deficiency anemia that is the clinical hallmark of hookworm infection. Other molecular mechanisms of hookworm infection cause a systematic suppression of the host immune response to both the parasite and to bystander antigens (eg, vaccines or allergens). This is achieved by a series of molecules that assist the parasite in the stealthy evasion of the host immune response. This review will summarize the current knowledge of the molecular mechanisms used by hookworms to survive for extended periods in the human host (up to 7 years or longer) and examine the pivotal contributions of these molecular mechanisms to chronic hookworm parasitism and host clinical outcomes.

Effect of sanitation on soil-transmitted helminth infection: systematic review and meta-analysis.

BACKGROUND: In countries of high endemicity of the soil-transmitted helminth parasites Ascaris lumbricoides, Trichuris trichiura, and hookworm, preventive chemotherapy (i.e., repeated administration of anthelmintic drugs to at-risk populations) is the main strategy to control morbidity. However, rapid reinfection of humans occurs after successful deworming, and therefore effective preventive measures are required to achieve public health goals with optimal efficiency and sustainability. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis to assess the effect of sanitation (i.e., access and use of facilities for the safe disposal of human urine and feces) on infection with soil-transmitted helminths. PubMed, Embase, ISI Web of Science, and the World Health Organization Library Database were searched without language restrictions and year of publication (search performed until December 31, 2010). Bibliographies of identified articles were hand-searched. All types of studies reporting data on sanitation availability (i.e., having access at own household or living in close proximity to sanitation facility), or usage, and soil-transmitted helminth infections at the individual level were considered. Reported odds ratios (ORs) of the protective effect of sanitation on soil-transmitted helminth infections were extracted from the papers or calculated from reported numbers. The quality of published studies was assessed with a panel of criteria developed by the authors. Random effects meta-analyses were used to account for observed heterogeneity. Thirty-six publications, consisting of 39 datasets, met our inclusion criteria. Availability of sanitation facilities was associated with significant protection against infection with soil-transmitted helminths (OR  =  0.46 to 0.58). Regarding the use of sanitation, ORs of 0.54 (95% confidence interval [CI] 0.28-1.02), 0.63 (95% CI 0.37-1.05), and 0.78 (95% CI 0.60-1.00) were determined for T. trichiura, hookworm, and A. lumbricoides, respectively. The overall ORs, combining sanitation availability and use, were 0.51 (95% CI 0.44-0.61) for the three soil-transmitted helminths combined, 0.54 (95% CI 0.43-0.69) for A. lumbricoides, 0.58 (95% CI 0.45-0.75) for T. trichiura, and 0.60 (95% CI 0.48-0.75) for hookworm. CONCLUSIONS: Despite a number of limitations (e.g., most studies used a cross-sectional design and were of low quality, with potential biases and considerable heterogeneity), our results reveal that sanitation is associated with a reduced risk of transmission of helminthiases to humans. Access to improved sanitation should be prioritized alongside preventive chemotherapy and health education to achieve a durable reduction of the burden of helminthiases.

Rates and intensity of re-infection with human helminths after treatment and the influence of individual, household, and environmental factors in a Brazilian community.

This study quantifies the rate and intensity of re-infection with human hookworm and Schistosoma mansoni infection 12 months following successful treatment, and investigates the influence of socio-economic, geographical and environmental factors. A longitudinal study of 642 individuals aged over 5 years was conducted in Minas Gerais State, Brazil from June 2004 to March 2006. Risk factors were assessed using interval censored regression for the rate and negative binomial regression for intensity. The crude rate and intensity of hookworm re-infection was 0·21 per year (95% confidence interval (CI) 0·15-0·29) and 70·9 epg (95% CI 47·2-106·6). For S. mansoni the rate was 0·06 per year (95% CI 0·03-0·10) and intensity 6·51 epg (95% CI 3·82-11·11). Rate and intensity of re-infection with hookworm were highest among males and positively associated with previous infection status, absence of a toilet and house structure. Rate and intensity of S. mansoni re-infection were associated with previous infection status as well as geographical, environmental and socio-economic factors. The implications of findings for the design of anti-helminth vaccine trials are discussed.

Environmental characteristics around the household and their association with hookworm infection in rural communities from Bahir Dar, Amhara Region, Ethiopia.

Soil-Transmitted Helminths (STH) are highly prevalent Neglected Tropical Disease in Ethiopia, an estimated 26 million are infected. Geographic Information Systems and Remote Sensing (RS) technologies assist data mapping and analysis, and the prediction of the spatial distribution of infection in relation to environmental variables. The influence of socioeconomic, environmental and soil characteristics on hookworm infection at the individual and household level is explored in order to identify spatial patterns of infection in rural villages from Zenzelema (Amhara region). Inhabitants greater than 5 years old were recruited in order to assess the presence of STH. Socioeconomic and hookworm infection variables at the household level and environmental variables and soil characteristics using RS were obtained. The dominant STH found was hookworm. Individuals which practiced open defecation and those without electricity had a significant higher number of hookworm eggs in their stool. Additionally, adults showed statistically higher hookworm egg counts than children. Nonetheless, the probability of hookworm infection was not determined by socioeconomic conditions but by environmental characteristics surrounding the households, including a combination of vigorous vegetation and bare soil, high temperatures, and compacted soils (high bulk density) with more acidic pH, given a pH of 6.0 is optimal for hatching of hookworm eggs. The identification of high-risk environmental areas provides a useful tool for planning, targeting and monitoring of control measures, including not only children but also adults when hookworm is concerned.

[Investigation on human hookworm infections in Anhui Province from 2014 to 2015].

OBJECTIVE: To understand the current status and changing tendency of human hookworm infections in Anhui Province. METHODS: According to the unified national survey scheme, a total of 48 survey sites were sampled from 16 counties (cities) in 4 ecological regions of Anhui Province using a stratified cluster random sampling method from 2014 to 2015. The hookworm eggs were detected in the fecal samples from permanent residents at ages of over one year living in the survey sites using a modified Kato-Katz thick smear method, and the subjects'health knowledge and behaviors were investigated using questionnaire survey. RESULTS: A total of 12 300 persons were examined in the 48 survey sites from 4 ecological regions of Anhui Province between 2014 and 2015, and 259 subjects were identified with hookworm infections, with a mean prevalence of 2.11%. Among the four ecological regions, the North China Plain had the highest prevalence of human hookworm infections (3.02%) and in all survey sites, Linquan County had the highest prevalence (7.03%). Ancylostoma duodenale was the predominant hookworm species identified (62.16%), and 65.64% had mild infections. The prevalence of human hookworm infections was significantly greater in women than in men (χ2 = 4.16, P < 0.05), and showed a tendency towards a rise with ages (χ2trend = 113.36, P < 0.01). In addition, the prevalence of human hookworm infections varied in occupations (χ2 = 159.41, P < 0.01) and education levels (χ2 = 34.95, P < 0.01). Questionnaire survey showed low prevalence of human hookworm infections in subjects knowing the question"how hookworm infection occurs"and denying"using fresh stools for fertilization"(χ2 = 15.05, P < 0.01; χ2 = 4.19, P < 0.05). CONCLUSIONS: The prevalence of human hookworm infections has greatly decreased in Anhui Province; however, the prevalence remains relatively high in some regions and populations. The North China Plain should be regarded as the key area for hookworm disease prevention and control, and housewives and populations with advanced ages and low educational levels are key targeted populations in Anhui Province.

Host Population Expansion and the Genetic Architecture of the Pinniped Hookworm Uncinaria lucasi.

The long-term fidelity of pinniped hosts to their natal rookery site suggests the genetic architecture of their Uncinaria spp. hookworms should be strongly structured by host breeding biology. However, historical events affecting host populations may also shape parasite genetic structure. Sequences of the mitochondrial cytochrome c oxidase 1 (COI) gene of 86 Uncinaria lucasi individuals were obtained to assess genetic variation and structure of nematodes from 2 host species (68 hookworms from northern fur seals; 18 hookworms from Steller sea lions) and rookeries from 3 widely separated geographic regions: the western Bering Sea and Sea of Okhotsk, eastern Bering Sea, and the eastern Pacific Ocean. High COI haplotype (h = 0.96-0.98) and nucleotide (π = 0.014) diversity was found. The haplotype network showed a star-shaped pattern with a large number of haplotypes separated by few substitutions. The network did not show separation of U. lucasi by geographic region or host species. Fst values between U. lucasi individuals representing geographic regions showed no differentiation, consistent with the absence of genetic structure. At face value, this lack of genetic structure in U. lucasi suggests high gene flow but could also be explained by recent (post-glacial) population expansions of northern fur seals and their hookworms.

Parasite associations predict infection risk: incorporating co-infections in predictive models for neglected tropical diseases.

BACKGROUND: Schistosomiasis and infection by soil-transmitted helminths are some of the world's most prevalent neglected tropical diseases. Infection by more than one parasite (co-infection) is common and can contribute to clinical morbidity in children. Geostatistical analyses of parasite infection data are key for developing mass drug administration strategies, yet most methods ignore co-infections when estimating risk. Infection status for multiple parasites can act as a useful proxy for data-poor individual-level or environmental risk factors while avoiding regression dilution bias. Conditional random fields (CRF) is a multivariate graphical network method that opens new doors in parasite risk mapping by (i) predicting co-infections with high accuracy; (ii) isolating associations among parasites; and (iii) quantifying how these associations change across landscapes. METHODS: We built a spatial CRF to estimate infection risks for Ascaris lumbricoides, Trichuris trichiura, hookworms (Ancylostoma duodenale and Necator americanus) and Schistosoma mansoni using data from a national survey of Rwandan schoolchildren. We used an ensemble learning approach to generate spatial predictions by simulating from the CRF's posterior distribution with a multivariate boosted regression tree that captured non-linear relationships between predictors and covariance in infection risks. This CRF ensemble was compared against single parasite gradient boosted machines to assess each model's performance and prediction uncertainty. RESULTS: Parasite co-infections were common, with 19.57% of children infected with at least two parasites. The CRF ensemble achieved higher predictive power than single-parasite models by improving estimates of co-infection prevalence at the individual level and classifying schools into World Health Organization treatment categories with greater accuracy. The CRF uncovered important environmental and demographic predictors of parasite infection probabilities. Yet even after capturing demographic and environmental risk factors, the presences or absences of other parasites were strong predictors of individual-level infection risk. Spatial predictions delineated high-risk regions in need of anthelminthic treatment interventions, including areas with higher than expected co-infection prevalence. CONCLUSIONS: Monitoring studies routinely screen for multiple parasites, yet statistical models generally ignore this multivariate data when assessing risk factors and designing treatment guidelines. Multivariate approaches can be instrumental in the global effort to reduce and eventually eliminate neglected helminth infections in developing countries.

Prevalence and associated factors of intestinal parasitic infections among patients attending Shahura Health Center, Northwest Ethiopia.

OBJECTIVE: Parasitic infections are the commonest infections affecting 3.5 billion people leading 450 million illnesses. Parasites are major public health problems in developing countries. This study was aimed to assess the prevalence and associated factors of parasitic infections among patients. A cross sectional study was conducted on 364 patients, attending Shahura Health Center, Northwest Ethiopia. Stool specimens were collected and examined using formol-ether concentration technique. Socio-demographic data collected using questionnaire. Binary and multivariable logistic regression analyses were conducted to calculate the strength of association between variables. RESULT: The overall prevalence of intestinal parasitosis was 56.9%. The most prevalent parasite was Entamoeba histolytica/dispar 32.4% followed by Hookworm species 11.8% and Giardia lamblia 7.4% singly or mixed with other parasites. Furthermore, double and triple parasitic infections were observed in 3% and 1.4% patients respectively. Being male in gender (P = 0.049), age group interval between 1 and 20 years of old (P = 0.012), having stomach pain (P = 0.032) and having diarrhea (P = 0.007) were found to be significantly associated with parasitic infection. In conclusion, prevalence of parasitic infection in the area is high. Therefore, ensuring provision of clean potable water and minimizing the contamination of vegetables are recommended.

Epidemiology and morbidity of hookworm-related cutaneous larva migrans (HrCLM): Results of a cohort study over a period of six months in a resource-poor community in Manaus, Brazil.

BACKGROUND: Hookworm-related cutaneous larva migrans (HrCLM) is a neglected parasitic skin disease, widespread in resource-poor communities in tropical and subtropical countries. Incidence and risk factors have never been investigated in a cohort study. METHODOLOGY/PRINCIPAL FINDINGS: To understand the seasonal epidemiology of HrCLM, an open cohort of 476 children in a resource-poor community in Manaus, Brazil was examined for HrCLM monthly over a period of 6 months. Monthly prevalence and intensity of infection were correlated with the amount of monthly precipitation. Multivariable Cox regression analysis indicated male sex (hazard ratio [HR] 3.29; 95% confidence interval [CI] 1.95-5.56), walking barefoot on sandy ground (HR 2.30; 95% CI 1.03-5.16), poverty (HR 2.13; 95% CI 1.09-4.17) and age between 10 and 14 years (HR 1.87; 95% CI 1.01-3.46) as predictors of HrCLM. Monthly incidence rates ranged between 0.21 and 1.05 cases per person-year with an overall incidence of 0.52 per person-year. CONCLUSIONS/SIGNIFICANCE: HrCLM is a frequent parasitic skin disease in this resource-poor community. Every second child theoretically becomes infected during one year. Boys, 10 to 14 years old, belonging to the poorest households of the community, are the most vulnerable population group. Even in the tropical monsoonal climate of Amazonia there is a considerable seasonal variation with monthly incidence and number of lesions peaking in the rainy season.

Human Hookworm Infection Enhances Mycobacterial Growth Inhibition and Associates With Reduced Risk of Tuberculosis Infection.

Soil-transmitted helminths and Mycobacterium tuberculosis frequently coincide geographically and it is hypothesized that gastrointestinal helminth infection may exacerbate tuberculosis (TB) disease by suppression of Th1 and Th17 responses. However, few studies have focused on latent TB infection (LTBI), which predominates globally. We performed a large observational study of healthy adults migrating from Nepal to the UK (n = 645). Individuals were screened for LTBI and gastrointestinal parasite infections. A significant negative association between hookworm and LTBI-positivity was seen (OR = 0.221; p = 0.039). Hookworm infection treatment did not affect LTBI conversions. Blood from individuals with hookworm had a significantly greater ability to control virulent mycobacterial growth in vitro than from those without, which was lost following hookworm treatment. There was a significant negative relationship between mycobacterial growth and eosinophil counts. Eosinophil-associated differential gene expression characterized the whole blood transcriptome of hookworm infection and correlated with improved mycobacterial control. These data provide a potential alternative explanation for the reduced prevalence of LTBI among individuals with hookworm infection, and possibly an anti-mycobacterial role for helminth-induced eosinophils.

The past matters: estimating intrinsic hookworm transmission intensity in areas with past mass drug administration to control lymphatic filariasis.

BACKGROUND: Current WHO guidelines for soil-transmitted helminth (STH) control focus on mass drug administration (MDA) targeting preschool-aged (pre-SAC) and school-aged children (SAC), with the goal of eliminating STH as a public health problem amongst children. Recently, attention and funding has turned towards the question whether MDA alone can result in the interruption of transmission for STH. The lymphatic filariasis (LF) elimination programme, have been successful in reaching whole communities. There is the possibility of building upon the infrastructure created for these LF-programmes to enhance the control of STH. Using hookworm as an example, we explore what further MDA coverage might be required to induce interruption of transmission for hookworm in the wake of a successful LF programme. RESULTS: Analyses based on the model of STH transmission and MDA impact predict the effects of previous LF control by MDA over five years, on a defined baseline prevalence of STH in an area with a defined transmission intensity (the basic reproductive number R0). If the LF MDA programme achieved a high coverage (70, 70 and 60% for pre-SAC, SAC and adults, respectively) we expect that in communities with a hookworm prevalence of 15%, after 5 years of LF control, the intrinsic R0 value in that setting is 2.47. By contrast, if lower LF coverages were achieved (40, 40 and 30% for pre-SAC, SAC and adults, respectively), with the same prevalence of 15% at baseline (after 5 years of LF MDA), the intrinsic hookworm R0 value is predicted to be 1.67. The intrinsic R0 value has a large effect on the expected successes of follow-up STH programmes post LF MDA. Consequently, the outcomes of identical programmes may differ between these communities. CONCLUSION: To design the optimal MDA intervention to eliminate STH infections, it is vital to have information on historical MDA programmes and baseline prevalence to estimate the intrinsic transmission intensity for the defined setting (R0). The baseline prevalence alone is not sufficient to inform policy for the control of STH, post cessation of LF MDA, since this will be highly dependent on the intensity and effectiveness of past programmes and the intrinsic transmission intensity of the dominant STH species in any given setting.

A Comparison of the Quality of Informed Consent for Clinical Trials of an Experimental Hookworm Vaccine Conducted in Developed and Developing Countries.

Informed consent is one of the principal ethical requirements of conducting clinical research, regardless of the study setting. Breaches in the quality of the informed consent process are frequently described in reference to clinical trials conducted in developing countries, due to low levels of formal education, a lack of familiarity with biomedical research, and limited access to health services in these countries. However, few studies have directly compared the quality of the informed consent process in developed and developing countries using the same tool and in similar clinical trials. This study was conducted to compare the quality of the informed consent process of a series of clinical trials of an investigational hookworm vaccine that were performed in Brazil and the United States. A standardized questionnaire was used to assess the ethical quality of the informed consent process in a series of Phase 1 clinical trials of the Na-GST-1/Alhydrogel hookworm vaccine that were conducted in healthy adults in Brazil and the United States. In Brazil, the trial was conducted at two sites, one in the hookworm non-endemic urban area of Belo Horizonte, Minas, and one in the rural, resource-limited town of Americaninhas, both in the state of Minas Gerais; the American trial was conducted in Washington, DC. A 32-question survey was administered after the informed consent document was signed at each of the three trial sites; it assessed participants' understanding of information about the study presented in the document as well as the voluntariness of their decision to participate. 105 participants completed the questionnaire: 63 in Americaninhas, 18 in Belo Horizonte, and 24 in Washington, DC. Overall knowledge about the trial was suboptimal: the mean number of correct answers to questions about study objectives, methods, duration, rights, and potential risks and benefits, was 45.6% in Americaninhas, 65.2% in Belo Horizonte, and 59.1% in Washington, DC. Although there was no difference in the rate of correct answers between participants in Belo Horizonte and Washington, DC, there was a significant gap between participants at these two locations compared to Americaninhas (p = 0.0002 and p = 0.0001, respectively), which had a lower percentage of correct answers. Attitudes towards participating in the clinical trial also differed by site: while approximately 40% had doubts about participating in Washington, DC and Belo Horizonte, only 1.5% had concerns in Americaninhas. Finally, in Belo Horizonte and Washington, high percentages cited a desire to help others as motivation for participating, whereas in Americaninhas, the most common reason for participating was personal interest (p = 0.001). Understanding of information about a Phase 1 clinical trial of an experimental hookworm vaccine following informed consent was suboptimal, regardless of study site. Although overall there were no differences in knowledge between Brazil and the US, a lower level of understanding about the trial was seen in participants at the rural, resource-limited Brazilian site. These findings demonstrate the need for educational interventions directed at potential clinical trial participants, both in developing and developed countries, in order to improve understanding of the informed consent document.

Changes in duodenal tissue-associated microbiota following hookworm infection and consecutive gluten challenges in humans with coeliac disease.

A reduced diversity of the gastrointestinal commensal microbiota is associated with the development of several inflammatory diseases. Recent reports in humans and animal models have demonstrated the beneficial therapeutic effects of infections by parasitic worms (helminths) in some inflammatory disorders, such as inflammatory bowel disease (IBD) and coeliac disease (CeD). Interestingly, these studies have described how helminths may alter the intestinal microbiota, potentially representing a mechanism by which they regulate inflammation. However, for practical reasons, these reports have primarily analysed the faecal microbiota. In the present investigation, we have assessed, for the first time, the changes in the microbiota at the site of infection by a parasitic helminth (hookworm) and gluten-dependent inflammation in humans with CeD using biopsy tissue from the duodenum. Hookworm infection and gluten exposure were associated with an increased abundance of species within the Bacteroides phylum, as well as increases in the richness and diversity of the tissue-resident microbiota within the intestine, results that are consistent with previous reports using other helminth species in humans and animal models. Hence, this may represent a mechanism by which parasitic helminths may restore intestinal immune homeostasis and exert a therapeutic benefit in CeD, and potentially other inflammatory disorders.

Micronutrient-Fortified Rice Can Increase Hookworm Infection Risk: A Cluster Randomized Trial.

BACKGROUND: Fortification of staple foods is considered an effective and safe strategy to combat micronutrient deficiencies, thereby improving health. While improving micronutrient status might be expected to have positive effects on immunity, some studies have reported increases in infections or inflammation after iron supplementation. OBJECTIVE: To study effects of micronutrient-fortified rice on hookworm infection in Cambodian schoolchildren. METHODS: A double-blinded, cluster-randomized trial was conducted in 16 Cambodian primary schools partaking in the World Food Program school meal program. Three types of multi-micronutrient fortified rice were tested against placebo rice within the school meal program: UltraRice_original, UltraRice_improved and NutriRice. Four schools were randomly assigned to each study group (placebo n = 492, UltraRice_original n = 479, UltraRice_improved n = 500, NutriRice n = 506). Intestinal parasite infection was measured in fecal samples by Kato-Katz method at baseline and after three and seven months. In a subgroup (N = 330), fecal calprotectin was measured by ELISA as a marker for intestinal inflammation. RESULTS: Baseline prevalence of hookworm infection was 18.6%, but differed considerably among schools (range 0%- 48.1%).Micronutrient-fortified rice significantly increased risk of new hookworm infection. This effect was modified by baseline hookworm prevalence at the school; hookworm infection risk was increased by all three types of fortified rice in schools where baseline prevalence was high (>15%), and only by UltraRice_original in schools with low baseline prevalence. Neither hookworm infection nor fortified rice was related to fecal calprotectin. CONCLUSIONS: Consumption of rice fortified with micronutrients can increase hookworm prevalence, especially in environments with high infection pressure. When considering fortification of staple foods, a careful risk-benefit analysis is warranted, taking into account severity of micronutrient deficiencies and local prevalence of parasitic infections. TRIAL REGISTRATION: ClinicalTrials.gov NCT01706419.