http://orcid.org/0000-0002-4853-5384
Figures
Abstract
Schistosomiasis affects over 200 million people worldwide, most of whom are children. Research and control strategies directed at preschool-aged children (PSAC), i.e., ≤5 years old, have lagged behind those in older children and adults. With the recent WHO revision of the schistosomiasis treatment guidelines to include PSAC, and the recognition of gaps in our current knowledge on the disease and its treatment in this age group, there is now a concerted effort to address these shortcomings. Global and national schistosome control strategies are yet to include PSAC in treatment schedules. Maximum impact of schistosome treatment programmes will be realised through effective treatment of PSAC. In this review, we (i) discuss the current knowledge on the dynamics and consequences of paediatric schistosomiasis and (ii) identify knowledge and policy gaps relevant to these areas and to the successful control of schistosome infection and disease in this age group. Herein, we highlight risk factors, immune mechanisms, pathology, and optimal timing for screening, diagnosis, and treatment of paediatric schistosomiasis. We also discuss the tools required for treating schistosomiasis in PSAC and strategies for accessing them for treatment.
Citation: Osakunor DNM, Woolhouse MEJ, Mutapi F (2018) Paediatric schistosomiasis: What we know and what we need to know. PLoS Negl Trop Dis 12(2): e0006144. https://doi.org/10.1371/journal.pntd.0006144
Editor: Giovanna Raso, Swiss Tropical and Public Health Institute, SWITZERLAND
Published: February 8, 2018
Copyright: © 2018 Osakunor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Our ongoing paediatric schistosomiasis project is funded by the Thrasher Research Fund 12440 and the Wellcome Trust 108061/Z/15/Z. Our research is also commissioned by the National Institute of Health Research, using Official Development Assistance (ODA) funding 16/136/33. DNMO is supported by the Darwin Trust of Edinburgh. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute of Health Research, or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Schistosomiasis is a tropical and subtropical disease affecting communities with limited access to safe water and adequate sanitation provision [1–3]. It affects over 200 million people worldwide (90% in sub-Saharan Africa), of which a significant number (123 million) are children [3, 4]. The health impact includes poor growth and cognition in affected children [5, 6].
Despite the higher prevalence of schistosomiasis in children, preschool-aged children (PSAC), i.e., those aged ≤5 years, for a long time were considered to be at a low risk of infection [7]; and even if infected, the impact on their health was unknown or considered negligible. Operational difficulties, including obtaining parasitology samples for diagnosis, failure to detect light infections, and inadequate knowledge about risk factors in PSAC, have biased studies towards school-aged children (SAC), i.e., ≥6 years old and adults. Infection prevalence data from a number of epidemiological studies have led to the estimation that at least 50 million PSAC in Africa are infected with schistosomiasis [8], but the true global infection and disease burden remains to be quantified. This makes it difficult to make operational and economic plans for controlling schistosomiasis in PSAC. Furthermore, gaps relating to infection, disease dynamics, and treatment need addressing if we are to deliver sustainable schistosome infection and disease control in PSAC and strengthen schistosomiasis elimination programmes.
Here, we summarise the current knowledge of paediatric schistosome infection, disease dynamics, and treatment. We also identify important knowledge gaps in paediatric schistosomiasis practice.
Epidemiology of paediatric schistosomiasis
In schistosome-endemic areas, a significant amount of the exposure to infection in PSAC is passive (i.e., use of contaminated water in the home or children being bathed/sitting in a dish of fresh water while the guardian conducts domestic chores), particularly in the youngest children. Exposure becomes more active as the children grow (e.g., accompanying caregivers to water sources for domestic chores) [9, 10]. Therefore, in the early years of infants and young children, exposure to infection is closely linked to that of the caregiver. This disassociates as children grow older, become independent, and frequently visit contaminated water sources with friends and/or older siblings.
Exposure to infection is incremental, and almost all children in high transmission areas will have been exposed to schistosome cercariae by age one [11], with infection prevalence and intensity increasing as children grow up [12]. Thus, there is a need for inclusion of PSAC in large-scale projects that map the distribution of schistosomiasis, to inform planning for drug procurement and operational strategies for including these children in national control programmes.
In addition to the lack of burden estimates of schistosome infection and disease in PSAC, there is a paucity of incidence data in this age group. Longitudinal studies tracking the incidence of schistosome infection are required to identify and quantify exposure patterns, risks, and health impacts of infection at an early age and, most importantly, to plan treatment strategies.
Risk factors for schistosome infection
Several factors influence the risk for schistosome infection in PSAC, including those already identified in other age groups [Fig 1]. Environmental factors (including temperature, seasonal rainfall patterns, and altitudes) influence the survival of the intermediate host snail, as well as parasite development in the snail, affecting the force of transmission and infection [13, 14]. Exposure patterns of the human host are also affected by climatic changes (e.g., hotter seasons prompt increased recreational use of infected water sources), and passive contact with infective water can increase amongst PSAC, while they are waiting for their caregivers to complete chores. Exposure will vary in both the surface area exposed as well as the duration and frequency of exposure [15].
Adapted from: 1 [14]; 2 [14, 15]; 3 [16]; 4 [15], 5 [15, 17, 18]; 6 [13, 14]; 7 [19]; 8 [14]; 9 [18]; 10 [20]; 11 [21].
In addition to these well-studied risk factors, we are beginning to appreciate the impact of the human gut and urinary microbiome [22–24]. The gut microbiome is believed to be particularly variable in the early years of life [25]; for example, we have reported that the relative abundance of different bacterial taxa varies within the first three years of life [26]. The gut microbiome plays a vital role in maintaining barrier integrity, and subsequently impacts the host immune system [27], and contributes to the observed differences in infection patterns [28]. Recently, we demonstrated a significant difference in the microbiome structure (frequency and diversity of the host bacteria species) between schistosome-infected and uninfected Zimbabwean children aged 1 to 10 years [26]. From the study design, the mechanistic direction of this relationship and the influence by other factors was unclear. These aspects together with any mechanistic pathways are yet to be elucidated. In this age group, the impact of gut microbiome dysbiosis on nutritional status is of particular importance.
Emerging ideas from initiatives such as the Human Microbiome Consortium suggest that our focus on PSAC should be to understand how the microbiome functions and influences innate susceptibility to schistosome infection, if at all [29]. Helminths modulate host immune responses for their survival, and this in turn has a negative impact on the host microbiome structure and nutrition [23]. Increasing research in nutraceuticals should thus inform additional child supplementation programmes in affected countries. At present, schistosomiasis interventions targeting the microbiome remain theoretical, as mechanistic studies to establish and quantify causal relationships are lacking.
In schistosome-endemic areas, malnutrition and undernourishment are significant childhood problems. Nonetheless, there are no studies detailing the attributable fraction of malnutrition due to schistosomiasis or more importantly, the impact of treatment on these factors. This information is necessary to advocate for control strategies to prioritise PSAC. Studies have also yet to establish the role/relevance of anthropometric measures as a tool for identification of the risk of malnourishment among PSAC in schistosome-endemic areas.
Schistosome-specific immune responses and clinical relevance
The interest in immunity in schistosome infections is twofold. First, hosts in endemic areas develop protective acquired immunity against infection/reinfection, and second, the severe and chronic clinical manifestations of schistosomiasis are immune mediated. Decades of studying immune responses in both human and experimental models have given insights into the aetiology and clinical manifestation of morbidity and immunopathology and into the development of schistosome-specific protective immune responses. The paradigms presented by these studies are not easy to extrapolate to PSAC, due to differences in the natural history of infection. Human studies have largely focused on SAC and adults with distinct histories of infection, which impacts on their immune phenotype [30]. Furthermore, most experimental studies on schistosome immunology use mouse models, which are limited in their ability to recapitulate morbidity and pathology occurring in the natural human host. For instance, eggs implanted in mice were recently used to develop an experimental model for urogenital schistosome pathology [31], but the relevance of this to the human disease forms in young children is unclear.
Acute and chronic stages of schistosome infection
In endemic areas, the acute stage of schistosome infection—including the Katayama syndrome—receives very little research or clinical intervention compared to other areas [32, 33]. As detailed above, the first infection event in most endemic areas occurs early at the pre-school age, but to date, no studies of schistosome cercarial dermatitis in PSAC have been published. The immune responses occurring in the early stages of infection are poorly documented in humans, and these events in PSAC would be very informative on the nature and development of both pathological and parasite-protective immunity.
In studies of SAC, protective immunity against schistosomiasis is characterized by a dynamic shift in the balance between effector and regulatory (humoral and cellular) immune responses, with effector responses surpassing the regulatory responses as infection progresses and exemplified by Nausch and colleagues [34]. We have previously proposed a threshold hypothesis [35] to explain the switch from a predominantly regulatory phenotype to an effector immune phenotype as infection progresses. Nonetheless, there is a paucity of immunology studies in PSAC detailing the dynamics occurring at the transition of infection from acute to chronic. Knowledge of these responses will be informative for schistosome vaccine development and deployment, as the ideal vaccine would target all children at risk of schistosome infection who may have already experienced their first schistosome infection exposure/infection event.
Drug-induced protective immunity
Studies in SAC and adults have shown that treatment of schistosome infections with Praziquantel (PZQ) enhances schistosome-specific immune responses by (i) removing the immuno-suppressive effects of the adult worms [35–37], and (ii) introducing large amounts of parasite-specific antigens to the immune system to reach the threshold required to induce an immune response [38–40]. These changes are associated with reduced reinfection rates [38, 41]. One of the consequences of the previous schistosome treatment guidelines was that studies on the effects of PZQ were focused more on SAC and adults. Thus, the immunological consequences of PZQ in PSAC remain poorly characterised. In a recent study in Zimbabwean PSAC, we showed an increase in anti-parasite IgM and IgE titres, six weeks after treatment with PZQ, and this was associated with resistance to reinfection [42]. This mimics the development of naturally acquired immunity, albeit (in this case) accelerated by treatment [39, 40, 43].
Evidence from experimental studies suggest that a more rational approach to the timing of helminth treatment may have additional benefits beyond the transient removal of infection and may also speed up the development of protective immunity more effectively than treating chronic infection. These studies have shown that treatment of the first helminth infection induces earlier and greater levels of protection against reinfection by preferentially inducing the effector over regulatory responses [44–46]. In this case, chronic infection induces a constant state of anti-parasite Th2 response, reducing the overall effect of Th1 effector responses required to fight infection [47]. This suggests that treatment of the first schistosome infection could have a longer-lasting impact on susceptibility to reinfection and presents the possibility of targeting treatment for maximum benefit in terms of the future health of the child. As detailed above, a single PZQ treatment can induce resistance to reinfection in PSAC [48], suggesting that if treatment of PSAC is optimally timed then repetitive treatments may be reduced or not required [49, 50]. Longitudinal studies determining the optimal treatment time are needed to inform the treatment guidelines for PSAC. Now, we have a window to conduct these studies, while there is a concerted effort to make a paediatric formulation of PZQ for deployment within the next few years.
Pathology and morbidity
Schistosome pathology and morbidity are still being defined in older children and adults, e.g., only recently was urinary schistosomiasis renamed urogenital schistosomiasis to reflect the increased recognition of the genital manifestations of S. haematobium-related disease [51]. Pathology and morbidity remain poorly described and studied in PSAC [10] compared to SAC. However, studies are beginning to shed light on schistosome morbidity in this group, e.g., a recent study using ultrasound has contributed to describing urinary morbidity in PSAC [52].
Describing morbidity and pathology at all stages of schistosome infection in PSAC will inform overall healthcare in this age group. In PSAC, clinical symptoms upon schistosome exposure and infection (e.g., cercarial dermatitis and fever) may go unrecognised [5, 53, 54] or be mistaken for symptoms of other illnesses such as malaria, which present with similar symptoms (e.g., fever).
It is also possible that schistosome infections have wider impacts in childhood health. In PSAC, chronic prenatal exposure/sensitisation to helminth infection is reported to be associated with reduced efficacy of childhood vaccines through induction of a persistent Th2 response phenotype [55, 56]. Chronic exposure is also thought to be associated with environmental enteropathy, which affects the efficacy of vaccines at infancy [57]. Reduced vaccine efficacy means infection and disease from the vaccine-preventable infections. Thus, controlling schistosomiasis in PSAC may have the added health benefit of improving vaccine efficacy; appropriate studies are required to investigate if this would be the case.
Schistosome infections damage epithelial barriers, resulting in anaemia, poor nutrition, and growth [58, 59]. Thus, even with the low parasite burdens in PSAC, the pro-inflammatory response generated can quickly lead to chronic morbidity [60]. For example, schistosome-associated anaemia and malnutrition in older Kenyan children (5–18 years old) was attributed to pathology beginning much earlier in life [58]. The nutritional effects could also be attributed to microbiome dysbiosis as reported in the experimental mouse model of helminth infection [61]. Thus, the impact of schistosomiasis in PSAC should be an integral part of interventions, targeted at improving early child health and development.
Poor awareness, recognition, and lack of understanding and quantification of schistosome-associated morbidity has previously made schistosome control in PSAC a lower priority than in older children and adults, but concerted efforts are now beginning to correct this. There is a need for biomarkers of environmental enteropathy in PSAC [59], mechanistic studies to infer causality, and well-defined predictors of growth and nutrition in PSAC exposed to schistosomiasis.
Paediatric schistosomiasis in coinfected hosts
Similar to all other age groups in tropical regions, PSAC are at risk of coinfections and therefore, comorbidities. Studies in older children (5–18 years old) indicate that the presence of multiple infections in endemic areas lead to significant morbidity, including anaemia and malnutrition and these are important in the formative years of PSAC [58]. Specific coinfection studies include malaria–schistosomiasis, where studies in SAC suggest that malaria severity is compounded by schistosome infection, and malaria treatment is more effective when schistosome infection is also treated [62, 63]. To date, no detailed studies have been conducted on the fraction of malaria deaths in PSAC that are attributable to schistosome coinfection. In addition, S. haematobium infection has been shown to reduce the level of protective IgG responses to malaria vaccine candidates [64]. In another instance, in vitro studies have shown that Salmonella can evade optimal antibiotic treatment by binding to schistosomes using fimbral proteins (FimH) present on its surface [65], and that effective treatment of schistosomiasis results in the release of Salmonella, causing septicaemia [66]. These findings need validation in PSAC to allow the implementation of appropriate interventions.
Diagnosis of infection
One operational model being proposed for the treatment of schistosomiasis in PSAC is that diagnosis is made before treatment, unlike the mass drug administration (MDA) approach where SAC are treated without diagnosis [67]. This means that in the “diagnose and treat” model, accurate point of care (POC) diagnostics are key to guide the targeted treatment.
Direct parasitological methods (Kato–Katz and urine filtration) are recommended by the WHO [68] and are convenient, specific, rapid, cheap, and suitable for field applications in PSAC [69, 70]. Nonetheless, in addition to the already known limitations of low sensitivity of the parasitological methods in SAC and adults, these methods have the added operational challenge of obtaining adequate urine and stool samples in PSAC [71], particularly the collection of replicate samples on different days to improve sensitivity [72].
Various other methods have been developed in the laboratory to address the issues of sensitivity and are at different stages of translation into field tools. Immunological detection of schistosome-specific antibodies in sera has been shown to be more sensitive in diagnosing infection in PSAC than parasitological methods [12]. The non-invasive detection of worm antigens in urine, i.e., circulating anodic antigen (CAA) [73, 74] and circulating cathodic antigen (CCA) [75] have also been evaluated in PSAC. These have been shown to be a reliable tool in diagnosing S. mansoni [76] but less so in S. haematobium diagnosis [77]. Issues of cost, which pose challenges in low resource settings where schistosomiasis is endemic [78, 79], would also need to be overcome. Molecular techniques detecting parasite DNA in urine have shown promise in PSAC [80, 81], although the absence of POC versions of these tests means they require expertise and specialised equipment [82]. Compared to CCA and parasitology, polymerase chain reaction (PCR) was most effective in detecting low intensity S. mansoni and S. haematobium infections [83, 84]. The use of cell-free parasite DNA present in urine and saliva [85] in PCR techniques can ease sampling difficulties in PSAC and detect early infections [86]. MicroRNAs have been characterised in animal models of S. japonicum [87] and S. mansoni [88]. Despite conflicting reports on the utility of miR–223 as a biomarker for helminth infections [88, 89], microRNAs have great diagnostic potential in PSAC and require further exploration. However reliable these diagnostics turn out to be at the lab bench, their true utility will be tested in the field.
Morbidity markers for schistosomiasis
The majority of morbidity biomarkers associated with schistosomiasis are non-specific, relating to physiological, biochemical, and immunological changes. As such, their interpretation in the light of coinfections and comorbidities is complex. Recent years have seen studies conducted in PSAC to evaluate the utility of morbidity markers described in SAC. These have included evaluation of the classic urine markers, haematuria and proteinuria in S. haematobium infection (e.g., in Nigeria [90] and Zimbabwe [91]), and the urine albumin-creatinine ratio (UACR) in Zimbabwe [91]. Faecal occult blood (FOB), the presence of cryptic blood in stool, results when S. mansoni eggs perforate the intestinal mucosa and cause a small release of blood into the bowel [92, 93], along with calprotectin released by granulocytes in response to the accompanying inflammation [94]. FOB and calprotectin have been evaluated in PSAC in Uganda [92, 95]. In these studies, FOB and calprotectin correlated positively with S. mansoni infection pre- and post-treatment although there may be exceptions.
The challenge with these non-specific markers particularly is to determine how schistosomiasis influences them; this is a difficult task because even determining the fraction attributable to schistosome infection does not indicate causation. Equally important is the lack of specific information on what they mean in terms of the child’s overall current and future health. There is the need for a knowledge base addressing these two issues if these morbidity markers are to form part of the diagnostic tool kit to inform the “diagnose and treat” approach for PSAC.
Schistosome treatment in PSAC
Following the recommendation to treat PSAC infected with schistosomes, there is a need for a drug formulation that is suitable for PSAC. PZQ is the drug of choice for treating schistosomiasis at a recommended dose of 40–60 mg/kg body weight. In ill-resourced endemic areas, a height–dose pole has been developed as a surrogate to weight scales for operational purposes [96]. Modifications were made to extend the original dose pole used for SAC and adults to include PSAC [97, 98]. PZQ is currently administered to PSAC as crushed tablets with juice or bread [4, 10]. Followed by an endorsement from the WHO [99], a recent randomised dose-ranging trial reports that a single 40 mg/kg dose of PZQ can be used for treatment in PSAC [100]. Although PZQ is confirmed safe and efficacious [101], there is little information on its pharmacokinetics in PSAC [102, 103], and this is compounded by variability in bioavailability, influenced by brand [104, 105].
PSAC tolerate PZQ well with few reports of adverse effects: normally abdominal pain, vomiting, fatigue, and diarrhoea that resolve within 24 hours [98, 100, 101]. Contrary to suggestions of a higher efficacy dose (>40 mg/kg) in PSAC [106], a recent study reported on the efficacy and safety of escalating doses (20 mg/kg, 40 mg/kg, and 60 mg/kg) of PZQ in PSAC and SAC [100]. PZQ showed a flat dose-response curve in PSAC compared to that in SAC and the current 40 mg/kg remains the best option in PSAC [99]. In PSAC, PZQ can be administered with other antihelminthics (e.g., Albendazole) as a deworming package. There are currently no drug–drug interaction studies that have been conducted on these drugs in PSAC [107]. PZQ is metabolised by the cytochrome P450 enzymes as shown in experimental studies [108, 109]. With growing evidence of genetic diversity for cytochrome P450 variants in schistosome-endemic regions in Africa [110], there are implications for PZQ metabolism and treatment efficacy which remain to be elucidated in PSAC.
Paediatric PZQ formulation
Operationally, the large size and bitter taste of the existing tablet are associated with administration difficulties in PSAC [100, 111]. To address these issues, the Paediatric Praziquantel Consortium has produced a paediatric PZQ tablet meeting a previously suggested target product profile (TPP) [4, 112]. This formulation—a smaller, orally dispersible tablet with a masked taste—has successfully undergone phase I clinical trials and phase II trials are currently underway (http://www.pediatricpraziquantelconsortium.org/).
Accessing PSAC for schistosome treatment and control
Preventive chemotherapy programmes targeting SAC are conducted via MDA with antihelminthics (usually PZQ and Albendazole) administered in the school setting. PSAC do not go to school (although some may be in early child development centres) and the “diagnose and treat” recommendation makes it difficult to treat them outside a health setting. One strategy is to access PSAC through the Expanded Programme on Immunization (EPI) in primary health centres [4], and our studies in Zimbabwe confirm the feasibility of accessing PSAC at health centres [101]. However, in some health systems, the EPIs may already be “crowded,” implementing other interventions at the same time; hence, alternative access strategies are required. A report from a recent meeting [67] included the approach of empowering health workers to identify clinical cases (i.e., non-specific signs of suspected cases) of schistosomiasis in PSAC and treating them, as a potential means of accessing PSAC. This approach has both advantages and disadvantages; the main disadvantage is the potential of treating non-specific clinical symptoms due to infections/diseases other than schistosomiasis.
Conclusion
There is now a global move to elevate research on paediatric schistosomiasis and to promote control, not only for child health but also to move towards eliminating schistosomiasis. The control of paediatric schistosomiasis will only be prioritised in countries with limited health budgets when (i) there is compelling evidence on the burden of infection and disease on child health and development, (ii) there are cost-effective intervention tools, and (iii) engagement at stakeholder and end-user levels. The research community can contribute to all three aspects, and bridging the knowledge gaps highlighted in this review will make a significant contribution to the control of schistosomiasis in PSAC.
Key learning points
- Preschool-aged children (PSAC) carry significant infection and morbidity to schistosomiasis. There is a treatment gap in mass drug administration, and studies mapping the level of infection and morbidity in this group. Infection and disease quantification is critical to inform planning and deployment of schistosome treatment in PSAC.
- Existing and new morbidity markers, along with improved multiple diagnostic tools, are useful for targeted disease identification and treatment in PSAC. The utility of these along with a proper strategy is important. There is a need for better-defined disease markers for this age group.
- Treatment with Praziquantel is safe and efficacious. Owing to existing challenges with the current formulation, there is a need for a paediatric formulation, a better dosing system, a better treatment strategy, and innovative ways of accessing PSAC for treatment.
- Most PSAC will experience infection early, and there is a need to characterise and quantify the consequences of these early infections in terms of impact on the overall health of children.
- PSAC are capable of mounting an adaptive immune response to schistosome infections, and a single treatment can illicit this response. Exploring the applicability of this in resistance to reinfection and morbidity is important.
Top Papers
- Wami WM, Nausch N, Midzi N, Gwisai R, Mduluza T, Woolhouse M, et al. Identifying and evaluating field indicators of urogenital schistosomiasis-related morbidity in preschool-aged children. PLoS Negl Trop Dis. 2015;9(3):e0003649. doi: 10.1371/journal.pntd.0003649. PubMed PMID: 25793584; PubMed Central PMCID: PMCPMC4368198
- Mutapi F, Rujeni N, Bourke C, Mitchell K, Appleby L, Nausch N, et al. Schistosoma haematobium treatment in 1–5 year old children: safety and efficacy of the antihelminthic drug praziquantel. PLoS Negl Trop Dis. 2011;5(5):e1143. doi: 10.1371/journal.pntd.0001143. PubMed PMID: 21610855; PubMed Central PMCID: PMCPMC3096601.
- Bustinduy AL, Friedman JF, Kjetland EF, Ezeamama AE, Kabatereine NB, Stothard JR, et al. Expanding Praziquantel (PZQ) Access beyond Mass Drug Administration Programs: Paving a Way Forward for a Pediatric PZQ Formulation for Schistosomiasis. PLoS Negl Trop Dis. 2016;10(9):e0004946. doi: 10.1371/journal.pntd.0004946. PubMed PMID: 27658198; PubMed Central PMCID: PMCPMC5033572.
- Rujeni N, Nausch N, Midzi N, Cowan GJ, Burchmore R, Cavanagh DR, et al. Immunological consequences of antihelminthic treatment in preschool children exposed to urogenital schistosome infection. J Trop Med. 2013;2013:283619. doi: 10.1155/2013/283619. PubMed PMID: 23840222; PubMed Central PMCID: PMCPMC3687481.
- Mutapi F. Changing policy and practice in the control of pediatric schistosomiasis. Pediatrics. 2015;135(3):536–44. doi: 10.1542/peds.2014-3189. PubMed PMID: 25687146.
Acknowledgments
We thank our collaborators in the Understanding Bilharzia Project, including Professors Takafira Mduluza and Nicholas Midzi of the University of Zimbabwe, with whom we have conducted collaborative work in paediatric schistosomiasis. We also thank members of our research group (Parasite Immuno-epidemiology Group) at the University of Edinburgh for their comments on drafts of the manuscript.
References
- 1. de Silva NR, Brooker S, Hotez PJ, Montresor A, Engels D, Savioli L. Soil-transmitted helminth infections: updating the global picture. Trends Parasitol. 2003;19(12):547–51. pmid:14642761.
- 2. Hotez P, Raff S, Fenwick A, Richards F Jr., Molyneux DH. Recent progress in integrated neglected tropical disease control. Trends Parasitol. 2007;23(11):511–4. pmid:17951109.
- 3. WHO Expert Committee. Prevention and control of schistosomiasis and soil-transmitted helminthiasis. World Health Organ Tech Rep Ser. 2002;912:i–vi, 1–57, back cover. pmid:12592987.
- 4.
World Health Organization. Report of a meeting to review the results of studies on the treatment of schistosomiasis in preschool-age children. Geneva: World Health Organization, 2010.
- 5. Gryseels B, Polman K, Clerinx J, Kestens L. Human schistosomiasis. Lancet. 2006;368(9541):1106–18. pmid:16997665.
- 6. van der Werf MJ, de Vlas SJ, Brooker S, Looman CW, Nagelkerke NJ, Habbema JD, et al. Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa. Acta Trop. 2003;86(2–3):125–39. pmid:12745133.
- 7.
Jordan P, Webbe G. Human Schistosomiasis: C. C. Thomas; 1969.
- 8. Mutapi F. Changing policy and practice in the control of pediatric schistosomiasis. Pediatrics. 2015;135(3):536–44. pmid:25687146.
- 9. Garba A, Barkire N, Djibo A, Lamine MS, Sofo B, Gouvras AN, et al. Schistosomiasis in infants and preschool-aged children: Infection in a single Schistosoma haematobium and a mixed S. haematobium-S. mansoni foci of Niger. Acta Trop. 2010;115(3):212–9. pmid:20303925.
- 10. Odogwu SE, Ramamurthy NK, Kabatereine NB, Kazibwe F, Tukahebwa E, Webster JP, et al. Schistosoma mansoni in infants (aged < 3 years) along the Ugandan shoreline of Lake Victoria. Ann Trop Med Parasitol. 2006;100(4):315–26. pmid:16762112.
- 11. Woolhouse ME, Mutapi F, Ndhlovu PD, Chandiwana SK, Hagan P. Exposure, infection and immune responses to Schistosoma haematobium in young children. Parasitology. 2000;120 (Pt 1):37–44. pmid:10726264.
- 12. Wami WM, Nausch N, Bauer K, Midzi N, Gwisai R, Simmonds P, et al. Comparing parasitological vs serological determination of Schistosoma haematobium infection prevalence in preschool and primary school-aged children: implications for control programmes. Parasitology. 2014;141(14):1962–70. pmid:24679476; PubMed Central PMCID: PMCPMC4255325.
- 13. Koukounari A, Toure S, Donnelly CA, Ouedraogo A, Yoda B, Ky C, et al. Integrated monitoring and evaluation and environmental risk factors for urogenital schistosomiasis and active trachoma in Burkina Faso before preventative chemotherapy using sentinel sites. BMC Infect Dis. 2011;11:191. pmid:21749703; PubMed Central PMCID: PMCPMC3161883.
- 14. Yang J, Zhao Z, Li Y, Krewski D, Wen SW. A multi-level analysis of risk factors for Schistosoma japonicum infection in China. Int J Infect Dis. 2009;13(6):e407–12. pmid:19398361.
- 15. Rudge JW, Stothard JR, Basanez MG, Mgeni AF, Khamis IS, Khamis AN, et al. Micro-epidemiology of urinary schistosomiasis in Zanzibar: Local risk factors associated with distribution of infections among schoolchildren and relevance for control. Acta Trop. 2008;105(1):45–54. pmid:17996207.
- 16. Kapito-Tembo AP, Mwapasa V, Meshnick SR, Samanyika Y, Banda D, Bowie C, et al. Prevalence distribution and risk factors for Schistosoma hematobium infection among school children in Blantyre, Malawi. PLoS Negl Trop Dis. 2009;3(1):e361. pmid:19156193; PubMed Central PMCID: PMCPMC2614474.
- 17. Sady H, Al-Mekhlafi HM, Mahdy MA, Lim YA, Mahmud R, Surin J. Prevalence and associated factors of Schistosomiasis among children in Yemen: implications for an effective control programme. PLoS Negl Trop Dis. 2013;7(8):e2377. pmid:23991235; PubMed Central PMCID: PMCPMC3749985.
- 18. Ugbomoiko US, Ofoezie IE, Okoye IC, Heukelbach J. Factors associated with urinary schistosomiasis in two peri-urban communities in south-western Nigeria. Ann Trop Med Parasitol. 2010;104(5):409–19. pmid:20819309.
- 19. Pruss A, Kay D, Fewtrell L, Bartram J. Estimating the burden of disease from water, sanitation, and hygiene at a global level. Environ Health Perspect. 2002;110(5):537–42. pmid:12003760; PubMed Central PMCID: PMCPMC1240845.
- 20. Ayalew A, Debebe T, Worku A. Prevalence and risk factors of intestinal parasites among Delgi school children, North Gondar, Ethiopia. J Parasitol Vector Biol. 2011;3(5):75–81.
- 21. Hall A, Zhang Y, Macarthur C, Baker S. The role of nutrition in integrated programs to control neglected tropical diseases. BMC Med. 2012;10:41. pmid:22533927; PubMed Central PMCID: PMCPMC3378428.
- 22. Dubourg G, Lagier JC, Armougom F, Robert C, Audoly G, Papazian L, et al. High-level colonisation of the human gut by Verrucomicrobia following broad-spectrum antibiotic treatment. Int J Antimicrob Agents. 2013;41(2):149–55. pmid:23294932.
- 23. Glendinning L, Nausch N, Free A, Taylor DW, Mutapi F. The microbiota and helminths: sharing the same niche in the human host. Parasitology. 2014;141(10):1255–71. pmid:24901211.
- 24. Saad R, Rizkallah MR, Aziz RK. Gut Pharmacomicrobiomics: the tip of an iceberg of complex interactions between drugs and gut-associated microbes. Gut Pathog. 2012;4(1):16. pmid:23194438; PubMed Central PMCID: PMCPMC3529681.
- 25. Rodriguez JM, Murphy K, Stanton C, Ross RP, Kober OI, Juge N, et al. The composition of the gut microbiota throughout life, with an emphasis on early life. Microb Ecol Health Dis. 2015;26:26050. pmid:25651996; PubMed Central PMCID: PMCPMC4315782.
- 26. Kay GL, Millard A, Sergeant MJ, Midzi N, Gwisai R, Mduluza T, et al. Differences in the Faecal Microbiome in Schistosoma haematobium Infected Children vs. Uninfected Children. PLoS Negl Trop Dis. 2015;9(6):e0003861. pmid:26114287; PubMed Central PMCID: PMCPMC4482744.
- 27. Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nat Immunol. 2016;17(7):765–74. pmid:27328006.
- 28. Zupancic ML, Cantarel BL, Liu Z, Drabek EF, Ryan KA, Cirimotich S, et al. Analysis of the gut microbiota in the old order Amish and its relation to the metabolic syndrome. PLoS ONE. 2012;7(8):e43052. pmid:22905200; PubMed Central PMCID: PMCPMC3419686.
- 29. Arumugam M, Raes J, Pelletier E, Le Paslier D, Yamada T, Mende DR, et al. Enterotypes of the human gut microbiome. Nature. 2011;473(7346):174–80. pmid:21508958; PubMed Central PMCID: PMCPMC3728647.
- 30. Mutapi F, Ndhlovu PD, Hagan P, Woolhouse ME. A comparison of humoral responses to Schistosoma haematobium in areas with low and high levels of infection. Parasite Immunol. 1997;19(6):255–63. pmid:9364555.
- 31. Fu CL, Odegaard JI, Herbert DR, Hsieh MH. A novel mouse model of Schistosoma haematobium egg-induced immunopathology. PLoS Pathog. 2012;8(3):e1002605. pmid:22479181; PubMed Central PMCID: PMCPMC3315496.
- 32.
BMJ Best Practice. Schistosomiasis: Step-by-step treatment approach; 2016 [updated January 15 2016; cited 2017 21/06]. Available from: http://bestpractice.bmj.com/best-practice/monograph/809/treatment/step-by-step.html.
- 33. Doherty JF, Moody AH, Wright SG. Katayama fever: an acute manifestation of schistosomiasis. BMJ. 1996;313(7064):1071–2. pmid:8898604; PubMed Central PMCID: PMCPMC2352353.
- 34. Nausch N, Midzi N, Mduluza T, Maizels RM, Mutapi F. Regulatory and activated T cells in human Schistosoma haematobium infections. PLoS ONE. 2011;6(2):e16860. pmid:21347311; PubMed Central PMCID: PMCPMC3037381.
- 35. Mitchell KM, Mutapi F, Savill NJ, Woolhouse ME. Protective immunity to Schistosoma haematobium infection is primarily an anti-fecundity response stimulated by the death of adult worms. Proc Natl Acad Sci U S A. 2012;109(33):13347–52. pmid:22847410; PubMed Central PMCID: PMCPMC3421178.
- 36. Nausch N, Appleby LJ, Sparks AM, Midzi N, Mduluza T, Mutapi F. Group 2 innate lymphoid cell proportions are diminished in young helminth infected children and restored by curative anti-helminthic treatment. PLoS Negl Trop Dis. 2015;9(3):e0003627. pmid:25799270; PubMed Central PMCID: PMCPMC4370749.
- 37. Schmiedel Y, Mombo-Ngoma G, Labuda LA, Janse JJ, de Gier B, Adegnika AA, et al. CD4+CD25hiFOXP3+ Regulatory T Cells and Cytokine Responses in Human Schistosomiasis before and after Treatment with Praziquantel. PLoS Negl Trop Dis. 2015;9(8):e0003995. pmid:26291831; PubMed Central PMCID: PMCPMC4546370.
- 38. Bourke CD, Nausch N, Rujeni N, Appleby LJ, Mitchell KM, Midzi N, et al. Integrated analysis of innate, Th1, Th2, Th17, and regulatory cytokines identifies changes in immune polarisation following treatment of human schistosomiasis. J Infect Dis. 2013;208(1):159–69. pmid:23045617; PubMed Central PMCID: PMCPMC3666130.
- 39. Mutapi F, Burchmore R, Mduluza T, Foucher A, Harcus Y, Nicoll G, et al. Praziquantel treatment of individuals exposed to Schistosoma haematobium enhances serological recognition of defined parasite antigens. J Infect Dis. 2005;192(6):1108–18. pmid:16107967.
- 40. Mutapi F, Burchmore R, Mduluza T, Midzi N, Turner CM, Maizels RM. Age-related and infection intensity-related shifts in antibody recognition of defined protein antigens in a schistosome-exposed population. J Infect Dis. 2008;198(2):167–75. pmid:18549316.
- 41. Black CL, Muok EM, Mwinzi PN, Carter JM, Karanja DM, Secor WE, et al. Increases in levels of schistosome-specific immunoglobulin E and CD23(+) B cells in a cohort of Kenyan children undergoing repeated treatment and reinfection with Schistosoma mansoni. J Infect Dis. 2010;202(3):399–405. pmid:20560767; PubMed Central PMCID: PMCPMC2897938.
- 42. Rujeni N, Nausch N, Midzi N, Cowan GJ, Burchmore R, Cavanagh DR, et al. Immunological consequences of antihelminthic treatment in preschool children exposed to urogenital schistosome infection. J Trop Med. 2013;2013:283619. pmid:23840222; PubMed Central PMCID: PMCPMC3687481.
- 43. Mutapi F, Ndhlovu PD, Hagan P, Spicer JT, Mduluza T, Turner CM, et al. Chemotherapy accelerates the development of acquired immune responses to Schistosoma haematobium infection. J Infect Dis. 1998;178(1):289–93. pmid:9652458.
- 44. Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, van Gemert GJ, et al. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med. 2009;361(5):468–77. pmid:19641203.
- 45. Roestenberg M, Teirlinck AC, McCall MB, Teelen K, Makamdop KN, Wiersma J, et al. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet. 2011;377(9779):1770–6. pmid:21514658.
- 46. van Riet E, Hartgers FC, Yazdanbakhsh M. Chronic helminth infections induce immunomodulation: consequences and mechanisms. Immunobiology. 2007;212(6):475–90. pmid:17544832.
- 47. Malhotra I, Ouma J, Wamachi A, Kioko J, Mungai P, Omollo A, et al. In utero exposure to helminth and mycobacterial antigens generates cytokine responses similar to that observed in adults. J Clin Invest. 1997;99(7):1759–66. pmid:9120021; PubMed Central PMCID: PMCPMC507997.
- 48. Wami WM, Nausch N, Midzi N, Gwisai R, Mduluza T, Woolhouse ME, et al. Comparative Assessment of Health Benefits of Praziquantel Treatment of Urogenital Schistosomiasis in Preschool and Primary School-Aged Children. Biomed Res Int. 2016;2016:9162631. pmid:27631011; PubMed Central PMCID: PMCPMC5007301.
- 49. de Oliveira Fraga LA, Lamb EW, Moreno EC, Chatterjee M, Dvorak J, Delcroix M, et al. Rapid induction of IgE responses to a worm cysteine protease during murine pre-patent schistosome infection. BMC Immunol. 2010;11:56. pmid:21078176; PubMed Central PMCID: PMCPMC2993659.
- 50. de Oliveira Fraga LA, Torrero MN, Tocheva AS, Mitre E, Davies SJ. Induction of type 2 responses by schistosome worms during prepatent infection. J Infect Dis. 2010;201(3):464–72. pmid:20043751; PubMed Central PMCID: PMCPMC2842083.
- 51.
World Health Organization. Statement- WHO Working Group on Urogenital Schistosomiasis and HIV Transmission, 1–2 October 2009. Geneva, Switzerland: World Health Organization; 2009 [cited 2017 May]. Neglected Tropical Diseases]. Available from: http://www.who.int/neglected_diseases/integrated_media_urogenital_schistosomiasis/en/index.html.
- 52. Barda B, Coulibaly JT, Hatz C, Keiser J. Ultrasonographic evaluation of urinary tract morbidity in school-aged and preschool-aged children infected with Schistosoma haematobium and its evolution after praziquantel treatment: A randomized controlled trial. PLoS Negl Trop Dis. 2017;11(2):e0005400. pmid:28222149
- 53. Bottieau E, Clerinx J, De Vega MR, Van den Enden E, Colebunders R, Van Esbroeck M, et al. Imported Katayama fever: clinical and biological features at presentation and during treatment. Journal of Infection. 2006;52(5):339–45. pmid:16169593
- 54. Lambertucci J. Acute schistosomiasis: clinical, diagnostic and therapeutic features. Revista do Instituto de Medicina Tropical de São Paulo. 1993;35(5):399–404. pmid:8115806
- 55. Chen L, Liu WQ, Lei JH, Guan F, Li MJ, Song WJ, et al. Chronic Schistosoma japonicum infection reduces immune response to vaccine against hepatitis B in mice. PLoS ONE. 2012;7(12):e51512. pmid:23272112; PubMed Central PMCID: PMCPMC3522692.
- 56. Malhotra I, McKibben M, Mungai P, McKibben E, Wang X, Sutherland LJ, et al. Effect of antenatal parasitic infections on anti-vaccine IgG levels in children: a prospective birth cohort study in Kenya. PLoS Negl Trop Dis. 2015;9(1):e0003466. pmid:25590337; PubMed Central PMCID: PMCPMC4295886.
- 57. Levine MM. Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine. BMC Biol. 2010;8:129. pmid:20920375; PubMed Central PMCID: PMCPMC2958895.
- 58. Bustinduy AL, Parraga IM, Thomas CL, Mungai PL, Mutuku F, Muchiri EM, et al. Impact of polyparasitic infections on anemia and undernutrition among Kenyan children living in a Schistosoma haematobium-endemic area. Am J Trop Med Hyg. 2013;88(3):433–40. pmid:23324217; PubMed Central PMCID: PMCPMC3592521.
- 59. Guerrant RL, Leite AM, Pinkerton R, Medeiros PH, Cavalcante PA, DeBoer M, et al. Biomarkers of Environmental Enteropathy, Inflammation, Stunting, and Impaired Growth in Children in Northeast Brazil. PLoS ONEe. 2016;11(9):e0158772. pmid:27690129; PubMed Central PMCID: PMCPMC5045163.
- 60. Leenstra T, Coutinho HM, Acosta LP, Langdon GC, Su L, Olveda RM, et al. Schistosoma japonicum reinfection after praziquantel treatment causes anemia associated with inflammation. Infect Immun. 2006;74(11):6398–407. pmid:16923790; PubMed Central PMCID: PMCPMC1695508.
- 61. Houlden A, Hayes KS, Bancroft AJ, Worthington JJ, Wang P, Grencis RK, et al. Chronic Trichuris muris Infection in C57BL/6 Mice Causes Significant Changes in Host Microbiota and Metabolome: Effects Reversed by Pathogen Clearance. PLoS ONE. 2015;10(5):e0125945. pmid:25938477; PubMed Central PMCID: PMCPMC4418675.
- 62. Getie S, Wondimeneh Y, Getnet G, Workineh M, Worku L, Kassu A, et al. Prevalence and clinical correlates of Schistosoma mansoni co-infection among malaria infected patients, Northwest Ethiopia. BMC Res Notes. 2015;8:480. pmid:26415939; PubMed Central PMCID: PMCPMC4585811.
- 63. Ndeffo Mbah ML, Skrip L, Greenhalgh S, Hotez P, Galvani AP. Impact of Schistosoma mansoni on malaria transmission in Sub-Saharan Africa. PLoS Negl Trop Dis. 2014;8(10):e3234. pmid:25329403; PubMed Central PMCID: PMCPMC4199517.
- 64. Courtin D, Djilali-Saiah A, Milet J, Soulard V, Gaye O, Migot-Nabias F, et al. Schistosoma haematobium infection affects Plasmodium falciparum-specific IgG responses associated with protection against malaria. Parasite Immunol. 2011;33(2):124–31. pmid:21226725.
- 65. Barnhill AE, Novozhilova E, Day TA, Carlson SA. Schistosoma-associated Salmonella resist antibiotics via specific fimbrial attachments to the flatworm. Parasit Vectors. 2011;4:123. pmid:21711539; PubMed Central PMCID: PMCPMC3143092.
- 66. Gendrel D, Kombila M, Beaudoin-Leblevec G, Richard-Lenoble D. Nontyphoidal salmonellal septicemia in Gabonese children infected with Schistosoma intercalatum. Clin Infect Dis. 1994;18(1):103–5. pmid:8054417.
- 67. Bustinduy AL, Friedman JF, Kjetland EF, Ezeamama AE, Kabatereine NB, Stothard JR, et al. Expanding Praziquantel (PZQ) Access beyond Mass Drug Administration Programs: Paving a Way Forward for a Pediatric PZQ Formulation for Schistosomiasis. PLoS Negl Trop Dis. 2016;10(9):e0004946. pmid:27658198; PubMed Central PMCID: PMCPMC5033572.
- 68.
World Health Organization. Schistosomiasis Geneva, Switzerland2016 [updated February 2016; cited 2016 October]. Fact sheet N°115]. Available from: http://www.who.int/mediacentre/factsheets/fs115/en/.
- 69. De Vlas SJ, Engels D, Rabello AL, Oostburg BF, Van Lieshout L, Polderman AM, et al. Validation of a chart to estimate true Schistosoma mansoni prevalences from simple egg counts. Parasitology. 1997;114 (Pt 2):113–21. pmid:9051920.
- 70. Yu JM, de Vlas SJ, Jiang QW, Gryseels B. Comparison of the Kato-Katz technique, hatching test and indirect hemagglutination assay (IHA) for the diagnosis of Schistosoma japonicum infection in China. Parasitol Int. 2007;56(1):45–9. pmid:17188018.
- 71. Stothard JR. Improving control of African schistosomiasis: towards effective use of rapid diagnostic tests within an appropriate disease surveillance model. T Roy Soc Trop Med H. 2009;103(4):325–32. PubMed PMID: WOS:000264976700002. pmid:19171359
- 72. Engels D, Sinzinkayo E, Gryseels B. Day-to-day egg count fluctuation in Schistosoma mansoni infection and its operational implications. Am J Trop Med Hyg. 1996;54(4):319–24. pmid:8615440.
- 73. Feldmeier H, Nogueira-Queiroz JA, Peixoto-Queiroz MA, Doehring E, Dessaint JP, de Alencar JE, et al. Detection and quantification of circulating antigen in schistosomiasis by monoclonal antibody. II. The quantification of circulating antigens in human schistosomiasis mansoni and haematobium: relationship to intensity of infection and disease status. Clin Exp Immunol. 1986;65(2):232–43. pmid:3098475; PubMed Central PMCID: PMCPMC1542304.
- 74. Gundersen SG, Haagensen I, Jonassen TO, Figenschau KJ, de Jonge N, Deelder AM. Quantitative detection of Schistosomal circulating anodic antigen by a magnetic bead antigen capture enzyme-linked immunosorbent assay (MBAC-EIA) before and after mass chemotherapy. Trans R Soc Trop Med Hyg. 1992;86(2):175–8. pmid:1440781.
- 75. Coulibaly JT, N'Gbesso YK, Knopp S, N'Guessan NA, Silue KD, van Dam GJ, et al. Accuracy of urine circulating cathodic antigen test for the diagnosis of Schistosoma mansoni in preschool-aged children before and after treatment. PLoS Negl Trop Dis. 2013;7(3):e2109. pmid:23556011; PubMed Central PMCID: PMCPMC3605147.
- 76. Coulibaly JT, N'gbesso YK, Knopp S, N'guessan NA, Silué KD, van Dam GJ, et al. Accuracy of urine circulating cathodic antigen test for the diagnosis of Schistosoma mansoni in preschool-aged children before and after treatment. PLoS Negl Trop Dis. 2013;7(3):e2109. pmid:23556011
- 77. Ashton RA, Stewart BT, Petty N, Lado M, Finn T, Brooker S, et al. Accuracy of circulating cathodic antigen tests for rapid mapping of Schistosoma mansoni and S. haematobium infections in Southern Sudan. Trop Med Int Health. 2011;16(9):1099–103. pmid:21692957.
- 78. Kanamura HY, Dias LC, da Silva RM, Glasser CM, Patucci RM, Vellosa SA, et al. A comparative epidemiologic study of specific antibodies (IgM and IgA) and parasitological findings in an endemic area of low transmission of Schistosoma mansoni. Rev Inst Med Trop Sao Paulo. 1998;40(2):85–91. pmid:9755561.
- 79. Oliveira EJ, Kanamura HY, Lima DM. Efficacy of an enzyme-linked immunosorbent assay as a diagnostic tool for schistosomiasis mansoni in individuals with low worm burden. Mem Inst Oswaldo Cruz. 2005;100(4):421–5. pmid:16113891.
- 80. He P, Song LG, Xie H, Liang JY, Yuan DY, Wu ZD, et al. Nucleic acid detection in the diagnosis and prevention of schistosomiasis. Infect Dis Poverty. 2016;5:25. pmid:27025210; PubMed Central PMCID: PMCPMC4812660.
- 81. Oliveira LM, Santos HL, Goncalves MM, Barreto MG, Peralta JM. Evaluation of polymerase chain reaction as an additional tool for the diagnosis of low-intensity Schistosoma mansoni infection. Diagn Microbiol Infect Dis. 2010;68(4):416–21. pmid:20884153.
- 82. Pontes LA, Oliveira MC, Katz N, Dias-Neto E, Rabello A. Comparison of a polymerase chain reaction and the Kato-Katz technique for diagnosing infection with Schistosoma mansoni. Am J Trop Med Hyg. 2003;68(6):652–6. pmid:12887022.
- 83. Ibironke O, Koukounari A, Asaolu S, Moustaki I, Shiff C. Validation of a new test for Schistosoma haematobium based on detection of Dra1 DNA fragments in urine: evaluation through latent class analysis. PLoS Negl Trop Dis. 2012;6(1):e1464. pmid:22235360; PubMed Central PMCID: PMCPMC3250497.
- 84. Lodh N, Mwansa JC, Mutengo MM, Shiff CJ. Diagnosis of Schistosoma mansoni without the stool: comparison of three diagnostic tests to detect Schistosoma [corrected] mansoni infection from filtered urine in Zambia. Am J Trop Med Hyg. 2013;89(1):46–50. pmid:23716406; PubMed Central PMCID: PMCPMC3748486.
- 85. Kato-Hayashi N, Yasuda M, Yuasa J, Isaka S, Haruki K, Ohmae H, et al. Use of cell-free circulating schistosome DNA in serum, urine, semen, and saliva to monitor a case of refractory imported schistosomiasis hematobia. J Clin Microbiol. 2013;51(10):3435–8. pmid:23884992; PubMed Central PMCID: PMCPMC3811636.
- 86. Kato-Hayashi N, Kirinoki M, Iwamura Y, Kanazawa T, Kitikoon V, Matsuda H, et al. Identification and differentiation of human schistosomes by polymerase chain reaction. Exp Parasitol. 2010;124(3):325–9. pmid:19948171.
- 87. Cheng G, Luo R, Hu C, Cao J, Jin Y. Deep sequencing-based identification of pathogen-specific microRNAs in the plasma of rabbits infected with Schistosoma japonicum. Parasitology. 2013;140(14):1751–61. pmid:23942009.
- 88. Hoy AM, Lundie RJ, Ivens A, Quintana JF, Nausch N, Forster T, et al. Parasite-derived microRNAs in host serum as novel biomarkers of helminth infection. PLoS Negl Trop Dis. 2014;8(2):e2701. pmid:24587461; PubMed Central PMCID: PMCPMC3930507.
- 89. He X, Sai X, Chen C, Zhang Y, Xu X, Zhang D, et al. Host serum miR-223 is a potential new biomarker for Schistosoma japonicum infection and the response to chemotherapy. Parasit Vectors. 2013;6:272. pmid:24330517; PubMed Central PMCID: PMCPMC3856452.
- 90. Salawu OT, Odaibo AB. Urogenital schistosomiasis and urological assessment of hematuria in preschool-aged children in rural communities of Nigeria. J Pediatr Urol. 2014;10(1):88–93. pmid:23891456.
- 91. Wami WM, Nausch N, Midzi N, Gwisai R, Mduluza T, Woolhouse M, et al. Identifying and evaluating field indicators of urogenital schistosomiasis-related morbidity in preschool-aged children. PLoS Negl Trop Dis. 2015;9(3):e0003649. pmid:25793584; PubMed Central PMCID: PMCPMC4368198.
- 92. Betson M, Sousa-Figueiredo JC, Rowell C, Kabatereine NB, Stothard JR. Intestinal schistosomiasis in mothers and young children in Uganda: investigation of field-applicable markers of bowel morbidity. Am J Trop Med Hyg. 2010;83(5):1048–55. pmid:21036836; PubMed Central PMCID: PMCPMC2963968.
- 93. Proietti FA, Antunes CM. Sensitivity, specificity and positive predictive value of selected clinical signs and symptoms associated with schistosomiasis mansoni. Int J Epidemiol. 1989;18(3):680–3. pmid:2509388.
- 94. Foell D, Wittkowski H, Roth J. Monitoring disease activity by stool analyses: from occult blood to molecular markers of intestinal inflammation and damage. Gut. 2009;58(6):859–68. pmid:19136508.
- 95. Betson M, Sousa-Figueiredo JC, Kabatereine NB, Stothard JR. Use of fecal occult blood tests as epidemiologic indicators of morbidity associated with intestinal schistosomiasis during preventive chemotherapy in young children. Am J Trop Med Hyg. 2012;87(4):694–700. pmid:22927499; PubMed Central PMCID: PMCPMC3516321.
- 96. Hall A, Nokes C, Wen ST, Adjei S, Kihamia C, Mwanri L, et al. Alternatives to bodyweight for estimating the dose of praziquantel needed to treat schistosomiasis. Trans R Soc Trop Med Hyg. 1999;93(6):653–8. pmid:10717759.
- 97. Sousa-Figueiredo JC, Betson M, Stothard JR. Treatment of schistosomiasis in African infants and preschool-aged children: downward extension and biometric optimization of the current praziquantel dose pole. Int Health. 2012;4(2):95–102. pmid:22876272; PubMed Central PMCID: PMCPMC3407873.
- 98. Sousa-Figueiredo JC, Day M, Betson M, Kabatereine NB, Stothard JR. An inclusive dose pole for treatment of schistosomiasis in infants and preschool children with praziquantel. Trans R Soc Trop Med Hyg. 2010;104(11):740–2. pmid:20832093.
- 99. Montresor A, Garba A. Treatment of preschool children for schistosomiasis. Lancet Glob Health. 2017;5(7):e640–e1. pmid:28619212.
- 100. Coulibaly JT, Panic G, Silue KD, Kovac J, Hattendorf J, Keiser J. Efficacy and safety of praziquantel in preschool-aged and school-aged children infected with Schistosoma mansoni: a randomised controlled, parallel-group, dose-ranging, phase 2 trial. Lancet Glob Health. 2017;5(7):e688–e98. pmid:28619227; PubMed Central PMCID: PMCPMC5471607.
- 101. Mutapi F, Rujeni N, Bourke C, Mitchell K, Appleby L, Nausch N, et al. Schistosoma haematobium treatment in 1–5 year old children: safety and efficacy of the antihelminthic drug praziquantel. PLoS Negl Trop Dis. 2011;5(5):e1143. Epub 2011/05/26. [pii]. pmid:21610855; PubMed Central PMCID: PMC3096601.
- 102. Cioli D, Pica-Mattoccia L, Basso A, Guidi A. Schistosomiasis control: praziquantel forever? Mol Biochem Parasitol. 2014;195(1):23–9. pmid:24955523.
- 103. Olliaro P, Delgado-Romero P, Keiser J. The little we know about the pharmacokinetics and pharmacodynamics of praziquantel (racemate and R-enantiomer). J Antimicrob Chemother. 2014;69(4):863–70. pmid:24390933.
- 104. Dayan AD. Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics. Acta Trop. 2003;86(2–3):141–59. pmid:12745134.
- 105. Mandour ME, el Turabi H, Homeida MM, el Sadig T, Ali HM, Bennett JL, et al. Pharmacokinetics of praziquantel in healthy volunteers and patients with schistosomiasis. Trans R Soc Trop Med Hyg. 1990;84(3):389–93. pmid:2124391.
- 106. Olliaro PL, Vaillant MT, Belizario VJ, Lwambo NJ, Ouldabdallahi M, Pieri OS, et al. A multicentre randomized controlled trial of the efficacy and safety of single-dose praziquantel at 40 mg/kg vs. 60 mg/kg for treating intestinal schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil. PLoS Negl Trop Dis. 2011;5(6):e1165. pmid:21695161; PubMed Central PMCID: PMCPMC3114749.
- 107. Pawluk SA, Roels CA, Wilby KJ, Ensom MH. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole. Clin Pharmacokinet. 2015;54(4):371–83. pmid:25691367.
- 108. Li XQ, Bjorkman A, Andersson TB, Gustafsson LL, Masimirembwa CM. Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. Eur J Clin Pharmacol. 2003;59(5–6):429–42. pmid:12920490.
- 109. Masimirembwa CM, Hasler JA. Characterisation of praziquantel metabolism by rat liver microsomes using cytochrome P450 inhibitors. Biochem Pharmacol. 1994;48(9):1779–83. pmid:7980647.
- 110. Rajman I, Knapp L, Morgan T, Masimirembwa C. African Genetic Diversity: Implications for Cytochrome P450-mediated Drug Metabolism and Drug Development. EBioMedicine. 2017;17:67–74. pmid:28237373; PubMed Central PMCID: PMCPMC5360579.
- 111. Sousa-Figueiredo JC, Pleasant J, Day M, Betson M, Rollinson D, Montresor A, et al. Treatment of intestinal schistosomiasis in Ugandan preschool children: best diagnosis, treatment efficacy and side-effects, and an extended praziquantel dosing pole. Int Health. 2010;2(2):103–13. pmid:20640034; PubMed Central PMCID: PMCPMC2892744.
- 112. Mduluza T, Mutapi F. Putting the treatment of paediatric schistosomiasis into context. Infect Dis Poverty. 2017;6(1):85. pmid:28388940; PubMed Central PMCID: PMCPMC5384153.