Mapping the Process and the Resources That Are Needed to Implement a Praziquantel Mass Drug Administration Program for Children Aged Five Years Old and Below in Resource Limited Settings: a Scoping Review

Background: The early childhood development of millions of children in some low and medium income countries may be compromised by schistosomiasis infections contracted at the age of 5 years or below. Currently there are no standard guidelines for treating schistosomiasis in children that are ve years and younger using praziquantel (PZQ), the only drug that the WHO recommends to treat schistosomiasis. This review is on processes and resources involved in the treatment of schistosomiasis in children aged ve years and below. Methods: An electronic search for peer-reviewed articles published in the period from 2008 to 2018 (August) was done in the Academic Search Complete, CINAHL with Full Text, Health Source: Nursing/Academic Edition, and MEDLINE databases via EBSCOHost and Google Scholar databases. The search targeted journals that described the treatment of schistosomiasis in children ve years and below using praziquantel. Results: Twelve studies met the inclusion criteria. The process of treating schistosomiasis in the children aged ve years old and below included the following activities: enrolment of the children into the treatment program; clinical examination; diagnosis; taking anthropometric measurements; feeding the children, making the PZQ palatable to the children; administration of PZQ and monitoring of side effects. There was also a variation in the resources used to treat children aged ve- and below for schistosomiasis. Conclusions: A PZQ mass drug administration program for children aged ve years old and below in endemic areas should exclude diagnosis of schistosomiasis before treatment. The resources required in the treatment process should be affordable, should not require skills and maintenance resources that are beyond those that are available at primary healthcare level. for the diagnosis of intestinal schistosomiasis on the eld for use in schistosomiasis control MDA programs for children aged under ve years. Questionnaires and the child health booklet(Garba, Lamine et al. 2013) were used for clinical assessments. We also recommend that both be used for clinical assessments in the schistosomiasis control MDA programs for children aged under ve years old and below years old. Some the studies that we reviewed reported using weight scales, while others used stadiometers (Sousa-Figueiredo, Pleasant et al. 2010, Amin, Swar et al. 2012) and one used dose poles(Sousa-Figueiredo, Pleasant et al. 2010) to obtain the anthropometric measurement that were used to calculate the dose amount of PZQ. We recommend the use of the dose pole and/or tape measures to make these measurements in schistosomiasis control MDA programs for young children.

The World Health Organization recommends the use of Praziquantel (PZQ) to treat schistosomiasis(WHO 2018). PZQ has been used to control schistosomiasis in affected communities through mass drug administration (MDA) (Olveda, McManus et al. 2016). MDA programs have excluded children aged ve years and below based on the misconception that this age group is not exposed to schistosomiasis (Stothard, Sousa-Figueiredo et al. 2011) and also because they do not attend school where the programs focus (Osakunor, Mduluza et al. 2018). Some children in communities where schistosomiasis is endemic have been diagnosed for schistosomiasis in their rst year of lif e (Stothard, Sousa-Figueiredo et al. 2011). These children remain infected and unwell until the age of six when they start school and are enrolled in school-based treatment programs. Early treatment of these children will prevent morbidity, promote early childhood development and facilitate socio-economic development in affected communities (Dabo, Bary et al. 2013).
The recommended dose of PZQ to treat schistosomiasis is 40mg/kg(WHO 2018). Merk and Bayer, when registering PZQ, overlooked its purpose for the use of the drug to treat children below the age ve . When the need to treat this age group was realized, the use of the drug on children was done without legal protection, or evidence of safety and e cacy ( Children with stunted growth, who are in need of treatment, may fall outside the scale of the dose pole. PZQ also causes minor side effects that require close monitoring (Bayer 2010). Any treatment process that is developed needs to consider these challenges.
We reviewed the processes followed in the use of PZQ to treat schistosomiasis in children aged ve years and below. We reported on: the PZQ treatment process and resources that were used to treat schistosomiasis in children aged ve years old and below different clinical studies; and the process followed and resources that could be used in the implementation of a PZQ MDA program targeting children under ve. MDA programs for children are essential in promoting early childhood development and to contribute to ending poverty(Dabo, Bary et al. 2013).

Methods
We used the scoping review methodology for this study because scoping reviews are recommended when the purpose of the study is "to examine how research is conducted on a certain topic or eld." (Munn, Peters et al. 2018 The searches covered a ten-year period; January 2008 to August 2018. Only peer reviewed journal articles reporting on primary data were included in the review. Peer reviewed journal articles reporting on treatment of schistosomiasis in children aged ve years and below using drugs other than praziquantel were excluded because PZQ is the only drug that has been approved by WHO for use in schistosomiasis treatment programs.
Studies, reporting on the use of Epiquantel were, however included because PZQ is the active ingredient in the Epiquantel syrup. Peer reviewed journal articles not written in English were excluded because we did not have translation resources. The searches were initially saved on libraries created in the EBSCOHost and Google Scholar databases. Completed searches were merged on to Endnote X10. EBSCOHost removed several duplicates during the transfer process. The remaining duplicates were removed using ENDNote.
The scope of the review was limited to studies reporting on the technical activities involved in the treatment of schistosomiasis of the species S. hematobium and S. mansoni in children aged ve and below. We thus included all studies that reported on the use of praziquantel to treat schistosomiasis in children aged ve years old and below. Studies that reported on treatment of schistosomiasis in children above ve years were included if the studies also reported on treatment of under-ve years old as a category. Since it is not necessary to diagnose schistosomiasis during a PZQ MDA program (WHO 2006), studies reporting exclusively on the diagnosis of schistosomiasis (and did not include treatment of under children aged ve years old and below in the methodology) were excluded. Title, abstract and full article screening were used to identify articles that met our inclusion criteria A modi ed Donabedian framework was used to analyse the ndings in our study (Donabedian 2005). The Donabedian framework separates operations into structure (resources), processes and outcomes (Donabedian 2005). We identi ed the processes and resources involved in the treatment of schistosomiasis in children under ve years old. We then used the processes that were reported in the studies as a framework on which we constructed a treatment process that can be used to implement a schistosomiasis control MDA program for children under ve years old. We also used the resources identi ed in the study to select those that would be appropriate for use in a schistosomiasis control MDA program for children aged ve years and below.
A PRISMA checklist was used to assess the manuscript (Moher, Liberati et al. 2010).

Results
Our initial search yielded 1088 titles. After removing duplicates, titles reporting exclusively on children older than ve years, review papers and studies that focused on diagnosis remained with 35 studies.
Twenty-three (23) of those studies were removed after full article screening because they were focused on diagnosis or did not describe the processes, materials and outcomes that were used in the treatment process. Twelve studies met the search criteria ( Fig. 1).
Twelve peer reviewed articles met our inclusion criteria (table 1). The studies in these articles were from ve different countries: Ghana (41.7%), Ivory Coast (16.7%), Niger (8.3%), Sudan (8.3%) and Zimbabwe (16.7%). The lowest age of the children reported in the studies was 1 month old and the highest age reported was 93 months. Ten of the studies reported on the use of the praziquantel (PZQ) tablet, 1 study reported on the use of PZQ syrup and one study reported on the use of both the PZQ tablet and the PZQ syrup.

Outcomes
All the studies that we reviewed reported that praziquantel is e cacious against schistosomiasis in children under ve years. The lowest PZQ dose that was e cacious against schistosomiasis in this age group was 20 mg/kg ( All the studies we reviewed reported PZQ to be safe for use to treat schistosomiasis in children aged ve years old and below. The highest safe dose of PZQ reported was 60mg/kg (Coulibaly, Panic et al. 2017, Coulibaly, Panic et al. 2018). All the studies reported that there were no serious adverse events reported after treating schistosomiasis in children aged ve years and below with PZQ doses of between 20mg/kg to 60mg/kg. We recommend that the WHO recommended dose of 40mg/kg should be used to treat schistosomiasis during schistosomiasis control MDA programs for children aged ve years old and below years old.

Process
All the studies followed the same treatment sequence: enrolment of children into the program; clinical examination; diagnosis; weight and height measurements; treatment and the monitoring of side effects. Enrolment involved acquiring consent from parents and recording all the children that participated in the study. The enrolled children were subjected to clinical examination to make sure that the children were safe to treat. Based on the clinical examinations the children who were considered safe for treatment were those who: were generally well ( Using the processes carried out in the 12 clinical studies to treat schistosomiasis in children aged ve years and below, we designed a treatment process that can be used to implement a schistosomiasis mass drug administration (MDA) program for this age group (Fig. 2). In the MDA treatment process diagnosis of schistosomiasis could be done only on a sample of the children before the clinical examination is done.

Structure
The materials that were used to treat schistosomiasis in children under ve years old in the studies are listed in table 2. In the same table we have proposed materials that could be used in a schistosomiasis MDA program for children under ve years old in resource limited settings. Registers were used to enroll

Discussion
The objective of this study was to map the processes, and resources that are required to implement a schistosomiasis control MDA program for children aged ve years old and below. A schistosomiasis control MDA program for children aged ve years old and below years old has not been reported on. The closest to a schistosomiasis MDA program for this age group is mainly clinical studies that were recommended by WHO to determine the safety and e cacy of treating schistosomiasis in children aged ve years old and below using praziquantel . We modi ed the processes that were used in these studies to propose a treatment process to execute a schistosomiasis control MDA program for children aged ve years and below.

Process
The praziquantel treatment process used in an MDA program for children aged ve years old and below could follow the sequence: enrolment of children; clinical examination; weight and height measurements; treatment and the monitoring of side effects for all the children. This is in line with recommendations of the WHO that individual diagnosis of schistosomiasis prior to treatment is not required before treatment during an MDA program (WHO 2006). The studies we reviewed diagnosed all the children in order to determine the prevalence of schistosomiasis in the children that are aged ve years and below and also to determine the e cacy of PZQ in treating schistosomiasis in these children. The diagnosis of schistosomiasis in the MDA program is important to determine the baseline prevalence and burden of infectivity of schistosomiasis in the children for the purposes of monitoring and evaluation (Olveda, Acosta et al. 2016). Diagnosis of schistosomiasis in a schistosomiasis control MDA program for children aged ve years old and below for monitoring and evaluation could be done on a random sample of the children soon after they have been enrolled into the treatment program (Martin, Bid et al. 2015). In some cases, the baseline prevalence and infection intensity could be done separately from the MDA program during disease surveillance programs making the treatment process to move directly from enrolment of the children to clinical assessments(Health 2019). The disease surveillance programs when present could be used to monitor and evaluate the schistosomiasis control MDA program for children aged ve years and below.

Structure
The Donabedian framework refers to resources as structural components of a healthcare system (Donabedian 2005). The resources that are required to implement a schistosomiasis control MDA program for children aged ve years old and below should be applicable to the environment in which the MDA program will be implemented ). Most of the places where schistosomiasis is endemic are economically disadvantaged and therefor suffer from resource constraints. We used relative cost and ease of access to select the resources that we recommended to be the best for use in a schistosomiasis control MDA program for children aged ve years and below. The resources used should also be eco-friendly (Avinash, Avinash et al. 2013).
None of the studies described the nature of the registers that they used for enrolment. Electronic registers that are embedded in tablets could be used to enrol children into a schistosomiasis control MDA program. The use of electronic information management systems in the MDA program could be extended to storing and analysing: the clinical assessments of the children to identify other childhood illnesses that need mass intervention. Tablets can be used for controlling the quality of the medical information about the children that is requested using questionnaires; for managing and monitoring the program's consumables inventory and for monitoring and evaluation of the progress and impact of the MDA program. A multinational study conducted in low and medium income countries (Ghana, Kenya, India and Pakistan) reported that the initial cost of purchasing electronic tablets and software licensing costs for healthcare program data management could be high (Dickinson, McCauley et al. 2019). However, because the tablets could be used multiple times in the same program and also across different programs, the purchase of tablets could be a justi able investment when taking into account economies of scale and economies of scope in healthcare program implementation cost analysis (Turner, Toor  The activities that are involved in treating schistosomiasis in children aged ve years and below include taking weight or height measurements; calculating dosage; feeding the children; making PZQ more palatable to the children and administering the PZQ to the children. Height rather than weight could be used to determine the dose of PZQ to be given to the children(Sousa-Figueiredo, ). This is because the dose poles that are used to measure height are less expensive to buy and to maintain compared to the weight scales that could be used in the event that weight is used to determine dosage (Mutapi 2015 We recommend that bread and juice are the most suitable foods to feed the children before treatment. This is because bread and juice are lling and yet easily available in most communities and also require very little labour to prepare (Leyvraz, Mizéhoun-Adissoda et al. 2018). Forti ed spreads could be used on the bread to enhance the nutritional value of the bread (Matilsky, Maleta et al. 2009). Juice also has the added capability to sweeten the PZQ making it more palatable for the children (Bunupuradah, Wannachai et al. 2006). An alternative to bread and juice could be forti ed cereal (Bulusu, Laviolette et al. 2007). Forti ed has the advantage of providing multi-nutrients to children (Bulusu, Laviolette et al. 2007) thereby addressing the needs of the schistosomiasis control MDA program for children aged ve years old and below and also tackling the challenge of malnutrition (Frigerio, Macario et al. 2016 Considerations of the disruption of routine curative functions of the nurses in the clinics where the nurses normally work and the remuneration motivation of community care givers should be taken into account when developing a human resources strategy for the implementation of an MDA program (Coulibaly, Cavalli et al. 2008, Hodges, Sonnie et al. 2012 to control schistosomiasis in children aged ve years old and below. The strengths of this study are that the studies are from ve different countries which makes them generalizable to resource limited settings in Africa and similar settings globally. The limitations of the study are that we did not perform interviews as recommended by Arksey and O'Malley's framework for systematic reviews (Arksey and O'Malley 2005). The interviews would have given us more information on the resources that are applicable for use in schistosomiasis control MDA programs for children under ve years in different settings. We, however could not perform these interviews due to challenges in getting authorization from several countries to conduct the interviews within the duration of the study.

Conclusion
The process that could be followed in the implementation of a schistosomiasis control MDA program for children aged ve years old and below is: enrolment of children into the treatment program; clinical examination; weight and height measurements; treatment and the monitoring of side effects for all the children (Fig. 2). Diagnosis could be done for the purpose of monitoring and evaluation either before the MDA program or immediately after the enrolment stage of the MDA program. The resources that could be used for the treatment program are: electronic tablets; urine dipsticks; POC-CCA; child health booklet; questionnaire; dose pole; tape measures; bread, juice, pestle and mortar; spoons; PZQ tablets; clinics and ECD centres. The availability of these resources in different healthcare centres may vary resulting in the need for unavailable resources to be purchased prior to the program. Resources that are already available and routinely in use at primary healthcare care level should be prioritized for use in the MDA program.  Figure 1 PRISMA chart describing the search process for selecting nal papers for the review Figure 2 Treatment process ow diagram for a schistosomiasis control MDA program for children aged ve years old and below.