Paediatric schistosomiasis: dynamics and consequences
Osakunor, Derick Nii Mensah
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.