Paediatric schistosomiasis: dynamics and consequences

Urogenital schistosomiasis, caused by the parasite helminth Schistosoma haematobium, is one of the major parasitic diseases affecting millions of preschool-aged children (PSAC), i.e. aged 5 years and below, in sub-Saharan Africa. Diagnosis is via microscopic detection of parasite eggs in urine, and treatment is by administration of the antihelminthic drug of choice, praziquantel. Epidemiological studies show that PSAC are infected as early as a year old, with negative impacts on nutrition, growth, cognition, and overall health. Despite recommendations to treat PSAC with schistosomiasis, this age group is still excluded from treatment programmes for various reasons including: a) the lack of a child-friendly formulation of praziquantel, b) lack of a coherent strategy to access PSAC for screening and treatment, and c) lack of compelling evidence on infection, disease and treatment dynamics. Currently, the global infection and disease burden is not fully known in this age group, and longitudinal studies to describe the incidence of infection and morbidity, especially the early events that occur during the very first infection and treatment in PSAC are lacking. In addition, the mechanistic pathways of disease, treatment, and immunity are poorly understood in this age group. Operational difficulties including obtaining parasitology samples for diagnosis, failure to detect light infections, and inadequate knowledge about risk factors have also contributed to a lower research focus on PSAC, relative to school-aged children and adults. To address these, I completed a series of studies, based on a larger longitudinal study on paediatric urogenital schistosomiasis (population age range: 6 months–5 years) conducted in the Shamva district of Zimbabwe. The aim was to determine the dynamics of infection, morbidity and treatment of the first S. haematobium infection, and to examine the impact of a regular screening and treatment strategy on (re)infections. I also determined the early host metabolic changes associated with the first S. haematobium infection as well as the impact of schistosome infection on the gut microbiome, and how these relate to disease progression, morbidity and overall health. I determined that 92% of microhaematuria, 38% of stunting, and between 9%–34% of malnutrition (depending on what index is used) are attributable to S. haematobium infection in PSAC; schistosome-positive children were more likely to present with microhaematuria (25 times) and stunting (2 times), compared to uninfected children. I demonstrated the annual incidence of first schistosome infections (17.4%) and urinary morbidity (microhaematuria; 20.4%), with significant incidences recorded every quarter. I showed that within 3 months of the first infection, a significant amount of urinary morbidity, i.e. microhaematuria (61%) occurs, and is resolved 3 months post-praziquantel treatment. In PSAC with no history of schistosome infection, regular quarterly screening and treatment of the first S. haematobium infection reduces the actual time at risk of infection in the population, and results in reduced rates of subsequent new infections. A single praziquantel treatment of schistosome infections (upon first infection) was associated with reduced reinfection rates and intensity a year later; an effect comparable to that observed post-treatment in chronically-infected children. In young children experiencing their first schistosome infection, there are significant increases (≥2-fold) in serum metabolites primarily linked with energy (glycolysis, pentose phosphate pathway, starch, and galactose) and purine metabolism. The observed changes were commensurate with increasing infection intensity and were restored 3 months post-curative antihelminthic treatment. The affected metabolic pathways and its implications on the natural adaptive metabolic responses were consistent with parasite survival and development of schistosome morbidity in PSAC, including malnutrition, stunting and poor physical and cognitive performance. Metagenomic analysis of the gut microbiota showed that the abundance of bacteria and fungi phyla from Proteobacteria, Ascomycota, and Basidiomycota, differed between schistosome-infected versus uninfected children. Specifically, infection was associated with increases in Pseudomonas, Stenotrophomonas, Derxia, Thalassospira, Aspergillus, Tricholoma, and Periglandula, and a decrease in Azospirillum. I found evidence of 262 antimicrobial resistance genes, from 12 functional drug classes, but these showed no association with individual-specific data, including schistosome infection. This points to microbiome dysbiosis as an additional consequence of schistosome infection, with implications for morbidity, immunity, and overall health. Taken together, the findings of this thesis show that early in the first S. haematobium infection, PSAC present with significant morbidity, and this resolves quickly with praziquantel treatment. A routine screen-and-treat strategy will optimise the chances of detecting and treating infections early, while reducing the risk of new and reinfections. The findings further highlight microbiome and metabolic alterations during schistosome infection, which may be relevant for disease pathogenesis. This thesis presents an integrative approach to schistosomiasis studies in PSAC, which contributes to evidence on infection/disease burden and dynamics, the applicability of currently available tools in the diagnosis, treatment and control of schistosomiasis, as well as the systemic impacts of infection on the host microbiome, metabolism, and overall health. It also adds to the repository of information, by providing a novel metagenomics and metabolomics dataset of PSAC from Zimbabwe. The findings reaffirm the need for early diagnosis and treatment of schistosome infections in PSAC to avert accumulative morbidity, and will inform stakeholders in providing new and appropriate interventions targeted at reducing schistosome-related pathology in young children

Seroprevalence of Hepatitis B and C Viral Infections among Type 2 Diabetics: A Cross-sectional Study in the Cape Coast Metropolis

Background: Type 2 diabetes comes with various complications and this may be compounded by morbidities of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.Aims: This study examined the prevalence of HBV and HCV infectionst among type 2 diabetics as well as its associated factors. This randomized cross-sectional study was conducted at the Diabetic Clinic of the Central Regional Hospital, Cape Coast between December 2012 and April 2013. Subjects and Methods: A well.structured questionnaire was used to recruit 110 type 2 diabetics. Venous blood samples were collected for the estimation of blood glucose and to screen for HBV and HCV infections. Data analysis was carried out using SPSS Version 17.0. Descriptive analysis was performed and results expressed as means (SD) and n (%). P < 0.05 was considered significant.Results: Prevalence of HBV in type 2 diabetics was 5.5% (6/110). No type 2 diabetic was positive for HCV. The prevalence of HBV infection in the type 2 diabetes mellitus (T2DM) participants was higher (5.5% [6/110]) than that of HCV (0/110). A total of 69.1% (76/110) T2DM patients had poor  glycemic control. Mean waist and hip circumference was higher amongHBV-negative T2DM participants (99.3; 106.9) than HBV-positive participants (87.2; 101.8).Conclusions: The seroprevalence of HBV was higher than that of HCV in T2DM patients. T2DM patients would require necessary preventive measures like prophylaxis, to reduce the risk of HBV infection and its ramifications.Keywords: Diabetes mellitus, Ghana, Hepatitis B, Hepatitis C, Prevalenc

Schistosoma haematobium infection is associated with alterations in energy and purine-related metabolism in preschool-aged children

Helminths are parasitic worms that infect over a billion people worldwide. The pathological consequences from infection are due in part, to parasite-induced changes in host metabolic pathways. Here, we analyse the changes in host metabolic profiles, in response to the first Schistosoma haematobium infection and treatment in Zimbabwean children. A cohort of 83 schistosome-negative children (2-5 years old) as determined by parasitological examination, guardian interviews and examination of medical records, was recruited at baseline. Children were followed up after three months for parasitological diagnosis of their first S. haematobium infection, by detection of parasite eggs excreted in urine. Children positive for infection were treated with the antihelminthic drug praziquantel, and treatment efficacy checked three months after treatment. Blood samples were taken at each time point, and capillary electrophoresis mass spectrometry in conjunction with multivariate analysis were used to compare the change in serum metabolite profiles in schistosome-infected versus uninfected children. Following baseline at the three-month follow up, 11 children had become infected with S. haematobium (incidence = 13.3%). Our results showed that infection with S. haematobium was associated with significant increases (>2-fold) in discriminatory metabolites, linked primarily with energy (G6P, 3-PG, AMP, ADP) and purine (AMP, ADP) metabolism. These observed changes were commensurate with schistosome infection intensity, and levels of the affected metabolites were reduced following treatment, albeit not significantly. This study demonstrates that early infection with S. haematobium is associated with alterations in host energy and purine metabolism. Taken together, these changes are consistent with parasite-related clinical manifestations of malnutrition, poor growth and poor physical and cognitive performance observed in schistosome-infected children

Investigating a strategy for quantifying schistosome infection levels in preschool-aged children using prevalence data from school-aged children

In 2012, the World Health Organisation (WHO) set out a roadmap for eliminating schistosomiasis as a public health problem by 2025. To achieve this target, preschool-aged children (PSAC; aged 6 years and below) will need to be included in schistosomiasis treatment programmes. As the global community discusses the tools and approaches for treating this group, one of the main questions that remains unanswered is how to quantify infection in this age group to inform treatment strategies. The aim of this study was thus to determine whether a relationship exists between levels of schistosome infection in PSAC and school-aged children (SAC), that can be used to determine unknown schistosome infection prevalence levels in PSAC. A systematic search of publications reporting schistosomiasis prevalence in African PSAC and SAC was conducted. The search strategy was formulated using the PRISMA guidelines and SPIDER search strategy tool. The published data was subjected to regression analysis to determine if a relationship exists between infection levels in PSAC and SAC. The interaction between SAC and community treatment history was also entered in the regression model to determine if treatment history significantly affected the relationship between PSAC and SAC prevalence. The results showed that a significant positive relationship exists between infection prevalence levels in PSAC and SAC for Schistosoma mansoni (r = 0.812, df (88, 1), p = <0.0001) and S. haematobium (r = 0.786, df (53, 1), p = <0.0001). The relationship was still significant after allowing for diagnostic method, treatment history, and the African sub-region where the study was conducted (S. mansoni: F = 25.63, df (88, 9), p = <0.0001; S. haematobium: F = 10.20, df (53, 10), p = <0.0001). Using the regression equation for PSAC and SAC prevalence, over 90% of the PSAC prevalence studies were placed in the correct WHO classifications category based on the SAC levels, regardless of treatment history. The study indicated that schistosome prevalence in SAC can be extended as a proxy for infection levels in PSAC, extending on its current use in the adult population. SAC prevalence data could identify where there is a need to accelerate and facilitate the treatment of PSAC for schistosomiasis in Africa

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology.

Urogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology are not well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology. Purified S. haematobium eggs or control vehicle were microinjected into the bladder walls of mice. Mice were sacrificed seven days post-injection and bladder proteins isolated and processed for proteome profiling using mass spectrometry. We demonstrate that biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism were significantly enriched in S. haematobium infection. S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Our findings highlight the potential bladder protein indicators for host-parasite interplay and provide new insights into the complex dynamics of pathology and characteristic bladder tissue changes in urogenital schistosomiasis. The findings will be relevant for development of improved interventions for disease control

Six rounds of annual praziquantel treatment during a national helminth control program significantly reduced schistosome infection and morbidity levels in a cohort of schoolchildren in Zimbabwe

BackgroundThe World Health Organization recommends that schistosomiasis be treated through Mass Drug Administration (MDA). In line with this recommendation, Zimbabwe commenced a national helminth control program in 2012 targeting schoolchildren throughout the country for 6 years. This study, part of a larger investigation of the impact of helminth treatment on the overall health of the children, determined the effect of annual praziquantel treatment on schistosome infection and morbidity in a cohort of children during Zimbabwe's 6-year national helminth control program.Methodology/principal findingsA school-based longitudinal study was carried out in 35 sentinel sites across Zimbabwe from September 2012 to November 2017. The sentinel sites were selected following a countrywide survey conducted in 280 primary schools. Schistosoma haematobium was diagnosed using the urine filtration technique. Schistosoma mansoni was diagnosed using both the Kato-Katz and formol-ether concentration techniques. S. haematobium morbidity was determined through detection of macro and microhaematuria. A cohort of children aged 6-15 years old was surveyed annually before MDA and 6 weeks post treatment. Maximum treatment coverage reached 90% over the 6 rounds of MDA. At baseline S. haematobium infection prevalence and intensity were 31.7% (95% CI = 31.1-32.2) and 28.75 eggs/10ml urine (SEM = 0.81) respectively, while S. mansoni prevalence and intensity were 4.6% (95% CI = 4.4-4.8) and 0.28 eggs/25mg (SEM = 0.02). Prior to the 6th round of MDA, S. haematobium infection prevalence had reduced to 1.56% (pConclusionZimbabwe's helminth control program significantly reduced schistosome infection intensity and prevalence and urogenital schistosomiasis morbidity prevalence in a cohort of school-aged children, moving the schistosome prevalence in the children from moderate to low by WHO classification. These findings will inform the design of the country's next stage interventions for helminth control and eventual elimination

Assessing early child development and its association with stunting and schistosome infections in rural Zimbabwean children using the griffiths scales of child development

There is a paucity of reference early childhood development (ECD) data at community level in rural Africa. Our objective was to conduct a comprehensive assessment of ECD in rural Zimbabwe and determine the impact of stunting and schistosome infections on ECD. Using the Griffiths Scales of Child Development, we conducted a cross sectional assessment of Eye and Hand Coordination (EHC), Personal-Social-Emotional (PSE), Language and Communication (LC), Foundations of Learning (FL) and Gross Motor (GM) domains and the summary General Development (GD) in 166 children aged 6-72 months. The effects of stunting, malnutrition and Schistosoma haematobium infection on ECD was determined. The impact of praziquantel curative treatment of schistosome infection on the developmental scores was determined through a longitudinal follow up at 6 and 12 months. From an initial 166 children, 11 were found to have developmental deficits warranting further investigation. Of the remaining 155, 58.7% recorded a good (≥ average) score for the overall General Development (GD). Proportions of children scoring above the cut-off (≥ average) for each domain were GM (84.5%), PSE (80.6%), EHC (61.9%), FL (43.9%) and LC (44.5%). The prevalence of stunting was 26.8% (95% CI = 20.1%-34.8%) Scores for stunted children were significantly lower for EHC (p = 0.0042), GM (p = 0.0099), and GD (p = 0.0014) with the fraction of lower scores attributable to stunting being GM = 63.4%, GD = 46.6%, EHC = 45%, and LC = 21%. S. haematobium infection prevalence was 39.7% and mean infection intensity was 5.4 eggs/10 ml urine. Infected children had poorer cognitive performance scores for the FL (p = 0.0005) with 30.8% of poor FL attributable to the infection. Performance in all domains improved to the expected normal or above reference levels at 6 and 12 months post curative treatment of schistosome infections. Our study documented reference values for ECD in rural Zimbabwean children. The study detected deficiencies in the FL domain, which were more pronounced in children, infected with schistosomes, highlighting the need for provision of cognitive stimulation tools and access to early childhood foundation education. There is also need for improved child nutrition and treatment of schistosome infections to improve child development outcomes

Schistosomiasis Control: Leave No Age Group Behind

Despite accelerating progress towards schistosomiasis control in sub-Saharan Africa, several age groups have been eclipsed by current treatment and monitoring strategies that mainly focus on school-aged children. As schistosomiasis poses a threat to people of all ages, unfortunate gaps exist in current treatment coverage and associated monitoring efforts, preventing subsequent health benefits to preschool-aged children as well as certain adolescents and adults. Expanding access to younger ages through the forthcoming pediatric praziquantel formulation and improving treatment coverage in older ages is essential. This should occur alongside formal inclusion of these groups in large-scale monitoring and evaluation activities. Current omission of these age groups from treatment and monitoring exacerbates health inequities and has long-term consequences for sustainable schistosomiasis control

Host tissue proteomics reveal insights into the molecular basis of Schistosoma haematobium-induced bladder pathology

Article Authors Metrics Comments Media Coverage Abstract Author summary Introduction Methods Results Discussion Conclusion Supporting information Acknowledgments References Reader Comments Figures Abstract Urogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology are not well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology. Purified S. haematobium eggs or control vehicle were microinjected into the bladder walls of mice. Mice were sacrificed seven days post-injection and bladder proteins isolated and processed for proteome profiling using mass spectrometry. We demonstrate that biological processes including carcinogenesis, immune and inflammatory responses, increased protein translation or turnover, oxidative stress responses, reduced cell adhesion and epithelial barrier integrity, and increased glucose metabolism were significantly enriched in S. haematobium infection. S. haematobium egg deposition in the bladder results in significant changes in proteins and pathways that play a role in pathology. Our findings highlight the potential bladder protein indicators for host-parasite interplay and provide new insights into the complex dynamics of pathology and characteristic bladder tissue changes in urogenital schistosomiasis. The findings will be relevant for development of improved interventions for disease control