Sensitive diagnostic tools and targeted drug administration strategies are needed to eliminate schistosomiasis

Although preventive chemotherapy has been instrumental in reducing schistosomiasis incidence worldwide, serious challenges remain. These problems include the omission of certain groups from campaigns of mass drug administration, the existence of persistent disease hotspots, and the risk of recrudescent infections. Central to these challenges is the fact that the diagnostic tools currently used to establish the burden of infection are not sensitive enough, especially in low-endemic settings, which results in underestimation of the true prevalence of active Schistosoma spp infections. This central issue necessitates that the current schistosomiasis control strategies recommended by WHO are re-evaluated and, possibly, adapted. More targeted interventions and novel approaches have been used to estimate the prevalence of schistosomiasis, such as establishing infection burden by use of precision mapping, which provides high resolution spatial information that delineates variations in prevalence within a defined geographical area. Such information is instrumental in guiding targeted intervention campaigns. However, the need for highly accurate diagnostic tools in such strategies is a crucial factor that is often neglected. The availability of highly sensitive diagnostic tests also opens up the possibility of applying strategies of sample pooling to reduce the cost of control programmes. To interrupt the transmission of, and eventually eliminate, schistosomiasis, better local targeting of preventive chemotherapy, in combination with highly sensitive diagnostic tools, is crucial.


Introduction
Despite years of sustained control efforts, the global burden of schistosomiasis remains high.An estimated 221 million people worldwide require chemotherapy to prevent schistosomiasis, of whom 90% reside in sub-Saharan Africa. 1 This immense burden is exacerbated by the fact that schistosomiasis is strongly linked to poverty, limited access to potable water, and a paucity of adequate sanitation. 2 Since 2001, WHO has strongly advocated for the control of schistosomiasis morbidity through preventive chemotherapy 3 and, in 2012, urged countries to expand schistosomiasis control programmes towards the elimination of schistosomiasis as a public health problem. 4lthough there have been successes in reducing the intensity of infections and the morbidity associated with infections through sustained mass drug administration (MDA) campaigns, schistosomiasis remains highly prevalent. 5In regions that have successfully reduced the intensity of infection, the diagnostic tools that are currently prescribed are no longer reliable for control programmes.These diagnostic methods are not sensitive enough to accurately detect low intensity infections and thereby underestimate the prevalence of active Schistosoma spp infections. 6,7To stop transmission and sustain the elimination of schistosomiasis, changes to the current global strategies to control schistosomiasis are urgently needed. 8,9The availability of more sensitive diagnostic tools presents an opportunity to revisit these strategies in regions where an interruption of transmission might be feasible.
Strategic changes to advance the global control of schistosomiasis were discussed at an international workshop hosted by Leiden University Medical Center in the Netherlands in September, 2017.The workshop brought together representatives from national control programmes, industry, funders, and aca demia (research scientists, clinicians, and mathe matical modellers) to develop a vision for the sustained, local interruption of transmission and the eventual successful elimination of schistosomiasis.

Challenges related to the current approach
WHO's current strategy for controlling schistosomiasis focuses on reducing disease morbidity and transmission through periodic, targeted MDA with praziquantel (40 mg/kg of bodyweight) administered to populations at risk of infection. 1As part of this strategy, the mean prevalence of schistosomiasis is measured in an implementation unit: a geographical area where an MDA programme is being rolled out.This implementation unit can be a whole district or a subdistrict, such as an administrative, health, or education district, and varies in size from country to country (figure A).Usually, in five to ten sentinel sites within such an implementation unit, a parasitological survey is done to measure the overall prevalence of schistosomiasis in the entire unit (figure B). 9,11 Sentinel sites can be places like schools, with 50 children per school being surveyed.On the basis of the mean prevalence measured by the survey, the burden of schistosomiasis is categorised as low (<10%), moderate (10-49%), or high (≥50%) for the whole implementation unit (figure C), a classification that defines the intervention strategy applied within this geographical area. 12Even though the burden of infection can be measured in more detail at a subdistrict level, this strategy does not sufficiently capture the focality of schistosomiasis, which results in areas either receiving over-treatment, or, more importantly, under-treatment. 11lthough initial implementation of WHO's MDA strategy has been successful in reducing morbidity from schistosomiasis, [13][14][15] there are several opportunities to optimise this strategy.MDA strategies traditionally target school-age children (aged 5-15 years), a group within which the prevalence of schistosomiasis is often high and that can be conveniently reached by programmes at one location (a school).However, this strategy does not protect other groups that are also at a high risk of Schistosoma spp infection, including preschool-age children (aged 1-4 years) and adults exposed to infested water through their occupations (eg, fishers, farmers, people who do laundry, and irrigation workers). 1,16As such, these groups remain potential active reservoirs for con tinued transmission of schistosomiasis in the com munity.Children aged 1-4 years are excluded from MDA programmes because of safety concerns and poor adherence to praziquantel.However, the development of a paediatric formu lation for praziquantel in 2022 is probable and so this concern is likely to be addressed. 17Likewise, WHO guidelines recommend the inclusion of pregnant and lactating women in MDA campaigns, but these groups are often excluded because of safety concerns, despite the growing body of evidence that shows the efficacy and safety of praziquantel for treatment of these women. 18,19he burden of infection in each implementation unit is measured and monitored by sampling from five to ten sentinel sites by use of conventional parasitological diagnostic tools.(C) The burden of infection within an implementation unit is then categorised as low, moderate, or high.(D) By further dividing subdistrict implementation units into smaller transmission units, and, instead of sampling from five to ten sentinel sites, applying a pooling strategy to the whole transmission unit, a bigger area will be sampled from.This strategy results in more accurate data to map and quantify the distribution of schistosomiasis and to identify communities at risk.
For more on a paediatric formulation for praziquantel see https://www.pediatricpraziquantelconsortium. org/ Exclusion of certain groups in MDA programmes becomes a crucial issue when the goal of these campaigns is community-wide control and elimi nation of schistosomiasis.
The commitment of Merck to support WHO, through the donation of praziquantel for preventive chemotherapy in children aged 5-15 years in sub-Saharan Africa, has been pivotal to schistosomiasis control efforts. 20However, because of the scale-up of MDA programmes, many African countries have been challenged to equate the demand for praziquantel and the availability of praziquantel in the donation scheme. 21Moreover, the currently recommended MDA dosage for praziquantel might be leading to suboptimal cure rates and prolonged low intensity infections within some communities.These consequences will be even more substantial and pronounced when the proportion of population coverage by MDA programmes is reduced, leaving large numbers of infected people untreated.
3][24][25] Persistent hotspots have been identified across Africa, including ones in Kenya, 26 Mali, 27,28 Sudan, 29 and Tanzania. 22,30][33][34][35] Another challenge in the control of schistosomiasis exists in parts of Asia where the prevalent schistosome species (ie, Schistosoma japonicum, Schistosoma mekongi, and Schistosoma malayensis) are known to be zoonotic and have several animal definitive hosts as reservoirs of infection. 36Animal reservoirs for schisto some species have also been described in Africa. 37,38In such areas, the control and elimination of schistosomiasis is even more difficult because the management of animal reservoirs is imperative. 36In addition, molecular studies in Africa have also found evidence of genetic interactions between schistosomes in humans and schistosomes in animals and the emergence of hybrid species, indicative of some zoonotic spillover. 39,40iagnosis of schistosomiasis in control programmes is often still based on parasitological assessments of urine or stool samples, depending on the schistosome species endemic in the area.These diagnostic methods are not sensitive enough to detect infections of low intensity and result in an underestimation of infection burden. 7dentifying areas with low infection intensities by implementing accurate diagnostic tools combined with cost-effective treatment strategies is essential for the elimination of schistoso miasis.This identification is also important for dealing with the so-called subtle morbidities of schistosomiasis, including its effect on cognitive development, which could have long-term effects on the quality of life of individuals. 41Control programmes are not as effective in low prevalence settings where the factors sustaining low-level transmission are poorly understood and trans mission has not yet been interrupted. 9,31,32In addition, low-endemic areas probably require continuous surveil lance with highly sensitive diagnostic tools because the risk of stopping MDA prematurely might cause infection levels to return to those present before MDA (recrudescent infections). 35,42As for persistent hotspots, an integrated control approach is probably required to achieve these epidemiological targets in these areas.

The importance of precision mapping and more targeted interventions
Locating exactly where active transmission occurs and identifying which individuals within a community still harbour living adult worms is particularly relevant because schistosomiasis is heterogeneously distributed, which means that an endemic region can be considered as a collection of microfoci. 43There are no clear guidelines that account for the potential effects of this natural heterogeneity, or focality, on programme design.Studies by the Schistosomiasis Consortium for Operational Research and Evaluation (known as SCORE) have shown a large variability in MDA efficacy at the community level. 22,26herefore, existing control guidelines need to be adapted to extend focus to geographical areas of low endemicity in which transmission is likely to be interrupted.In these areas, sampling grids can be narrowed by increasing the number of sites being sampled, a concept that has been termed precision mapping. 11Using the precision mapping approach in Cameroon, Tchuem Tchuenté and colleagues 11 exhaustively sampled all schools in two schistosomiasis endemic districts representing geographical areas with low and high transmission.This approach produced high-resolution mapping information that showed considerable variations in schistosomiasis pre valence between districts and subdistricts (implemen tation units), which would not have been detected with the conventional mapping approaches included in current global control strategies.Analysis of data from precision mapping can be used to guide targeted and intensified interventions in high-risk areas, making treatment with donated praziquantel cost-efficient and judicious.Further more, this approach presents an opportunity to identify both areas of considerable disease transmission within implementation units and individuals living in low-endemic communities who harbour high intensities of living adult worms (the so-called super-spreaders). 44

The importance of highly sensitive diagnostics
The success of any strategy to tackle schistosomiasis hinges on the ability to obtain an accurate measure of infection burden in a given community, as rationalised by Lord Kelvin in 1883: "when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind". 45The necessity of accurate diagnostic tools with high sensitivity in these strategies is often neglected.To achieve the goal of schistosomiasis elimination, highly sensitive and highly specific diagnostic tools, which ideally are fieldapplicable, are needed to monitor the burden of infection.
Several diagnostic tools, such as the widely used and field-applicable point-of-care circulating cathodic antigen test (POC-CCA), have been shown to be useful alternatives to conventional diagnostic methods currently used by national control programmes. 46,47Although the POC-CCA test has been recommended as a replacement for traditional microscopy, 48 it is limited to the detection of intestinal schistosomiasis and is not sensitive enough to detect infections of low intensity. 49,502][53][54] The UCP-LF CAA test is a genus-specific test that detects all Schistosoma species in blood and urine samples, and might poten tially be able to detect a single worm pair by increasing sample volume. 54,55urthermore, the UCP-LF CAA test is amenable to testing strategies that use pooled samples. 56Individuals whose pooled urine samples are found negative by the UCP-LF CAA test can be assumed to be free of schistosome worms or have a quantity below a set threshold of worm load.In CAA-positive urine pools, one or more individuals harbour a worm burden that might be relevant for further transmission.Individual urine samples can then be subsequently tested to identify infected individuals within a positive sample pool, which allows clinicians to only treat infected individuals and thereby save drugs.Compared with more exhaustive sampling approaches, such pooling strategies can poten tially reduce the costs of schistosomiasis control programmes. 57Although the UCP-LF CAA test is still lab-based, steps are underway to develop a version of this test that can be used in the field. 53,56,58Clearly, a reliable, easy-to-use, and rapid diagnostic test is a prerequisite for the development of test-and-treat strategies, with or without pooled sampling, the facilitation of clinical diagnosis of schistosomiasis in point-of-care settings, and the targeted use of praziquantel.
Other more sensitive and specific diagnostic methods include PCR for the detection of schistosome-specific DNA in clinical samples (ie, urine, stool, or blood). 7,591][62] Isothermal recombinase polymerase amplification for the detection of DNA specific to schistosomes is a technique that is potentially applicable for field use in the identification of Schistosoma haematobium 63 and Schistosoma mansoni. 64

Integrating sensitive diagnostics into an intensified, focal test-and-treat strategy
In a theoretical, schistosomiasis-endemic area comprised of one or more imple mentation units where the prevalence of infection is low as measured by standard parasitological methods (ie, an overall preva lence <10% and a prevalence of heavy infections <1%), an intensified, focal test-andtreat strategy, which uses highly accurate diagnostic tools, should be implemented to interrupt transmission.When applying the precision mapping approach in such an area, the burden of infection within an implementation unit should be estimated from a larger number of sentinel sites than the five to ten sampling sites conventionally recommended.To save costs when sampling from a larger number of sentinel sites, multiple samples can be pooled to reduce the total number of tests needed. 56,57Given the focal nature of schistosomiasis, sampling designs should also consider proximity to water contact points (ie, the source of infection) where transmission is suspected.
An implementation unit at subdistrict level can be divided into separate transmission units: a proposed geographical area limited to one or few transmission sites (figure D).So, instead of the current strategy in which five to ten sentinel sites within an implementation unit are being sampled, the whole implementation unit is divided into smaller transmission units.By integrating a pooling strategy that uses a highly sensitive diagnostic test, a whole transmission unit will be sampled and tested, leading to a quantitative evaluation of the overall infection burden within each transmission unit.Mathematical modelling could provide valuable information on the best pooling strategy by taking into consideration age groups or risk groups and expected infection levels (estimated by precontrol endemicity and control histories) to determine optimal pool size. 56,57Information from existing databases on the correlation between different diagnostic tests could also be used to develop a predictive model to estimate, for example, CAA or DNA loads, and to link these individual measurements to transmission potential within a given area.The outcome of testing pooled samples with a highly sensitive diagnostic test, in combination with the predictions of models, would then guide the prevalence thresholds that should be set to establish the appropriate control strategy for each transmission unit.
From the aforementioned strategy, we envisage four scenarios that might reflect the burden of infection from surveying each transmission unit (panel).The corresponding recommended strategy should then also be implemented at the level of the transmission unit.In transmission units found to have a high infection burden (eg, potential hotspots or persistent hotspots), intense MDA of yearly, or twice-yearly, treatment should be rolled out, following existing control strategies.Additional samples should be taken from children aged 5-15 years and from other groups at high risk of infection (such as fishers, farmers, people who do laundry, and irrigation workers) and testing should be stratified according to these groups.The strategy could be adapted to treat each positive group in addition to all children aged 5-15 years and the entire group could be monitored and followed up over a 2 year period.For transmission units in which a moderate infection burden is established, a regular MDA programme of yearly community-wide treatment should be implemented.In areas where the burden of infection is found to be low, an intensified test-and-treat strategy, with multiple rounds of testing and treating per year, should be implemented after the identification of groups at high risk of infection within each community.In addition, this strategy should include the identification, treatment, and monitoring of individuals who still harbour high worm numbers, despite multiple rounds of community-wide treatment.Furthermore, knowledge about local transmission sites, with respect to aquatic biology and social behavioural patterns, is indispensable in reducing exposure to schistosomes.Individual worm burdens (eg, in the case of super-spreaders) could also be included within programmes to guide local or regional interventions.In transmission units found to be negative for schistosomiasis, MDA would not be done, but groups should be followed up and tested over a given period of time by use of a cost-efficient sample pooling strategy.Knowing whether these areas have always been negative or are now negative after prolonged control programmes is important, and is best reflected by the precontrol endemicity, because the monitoring approach depends on the potential for transmission in the area.Obviously, all strategies also need to integrate other multisectoral approaches, such as health education, snail control, and water, sanitation, and hygiene initiatives.Classic xenomoni toring, augmented with DNA methods that can identify infected snail hosts, is especially important to accurately establish environmental risk and monitor schistosome infection in locations where zoonotic spillover might occur. 65Further innovations, such as the analysis of environmental DNA in water for schistosome signatures with taxon-specific probes, could be very powerful to verify putative interruptions of transmission. 66t the national level, a surveillance response mechanism would need to monitor these focal test-and-treat strategies.This mechanism includes predictive modelling to guide the intervention, monitoring of infections, and mecha nisms to evaluate interventions. 67Global positioning system (known as GPS) mapping could be used to identify the precise locations of infected people and their households. 68owever, privacy issues need to be taken into consid eration.Certain innovations, such as surveying snail environmental DNA in bodies of water, can be used to monitor transmission. 66,69Lessons can also be learnt from the Global Polio Eradication Initiative, which monitors poliovirus by use of the environmental survei llance of sewage. 70fter transmission is presumed to be interrupted, communities should still, ideally, be monitored longitudinally by use of highly sensitive and highly specific assays (ie, the UCP-LF CAA test and, eventually, antibody detection assays).After several years without the detection of new infections, newborn babies and young children should be assessed for their exposure to schistosomes, 42,71 which can be done through targeted testing of anti schistosomal antibodies. 72,73In addition, the movement of individuals from regions that are still endemic for schistosomiasis into post-transmission areas should be monitored, and infected individuals promptly treated. 74The development of commercially available, highly sensitive tests would be indispensable in targeting these groups in this post-transmission phase.
Given that current programmes to control schistosomiasis in sub-Saharan Africa rely heavily on donated praziquantel for MDA campaigns, the proposed testand-treat strategy will enhance cost-efficiency.The availability of a paediatric praziquantel formulation for young children will further support and strengthen a community-wide approach towards targeted treatment.
The successful implementation and efficient roll-out of the proposed strategy would hinge on close cooperation between key international players (such as WHO) and stakeholders within endemic countries.Within these countries, engagement with national and local authorities would guarantee local ownership and responsibility for the strategy and its implementation.Targeted imple men tation at more local levels, such as within a transmission unit, could be more complex because of logistical challenges and the paucity of adequate health-care system structures.Therefore, strengthening overall neglected tropical disease coordination at national and subnational levels, including the building of local capacity, would assure the proper execution of the proposed strategy and effective long-term monitoring, evaluation, and overall strategic sustainability.
Additionally, endemic countries must adopt and incorporate the strategy into the development of their master plans for neglected tropical disease.Incorporation would be achieved through having local and international stakeholders work closely with expert committees from endemic countries, which are responsible for coordinating the direction of national goals and policies for neglected tropical disease (including for schisto somiasis), and ensuring that these policies are in line with regional and global targets.Combining all these efforts to improve the focal implementation of preventive chemotherapy with highly sensitive diagnostic tools is essential to interrupt transmission of, and eventually eliminate, schistosomiasis.

Conclusion
The persistent and global burden of schistosomiasis despite continuous large-scale MDA requires us to rethink and revise intervention strategies and the diagnostic tools that enable these strategies.Non-invasive testing of pooled samples with highly accurate diagnostic tools should be used by national control programmes in adapted control strategies that ensure cost-efficiency in monitoring and evaluation and as longer term surveillance, especially in areas of low infection intensity.We believe that this proposed strategy will interrupt the transmission of, and eventually eliminate, schistosomiasis.
Contributors ASA, GJvD, and PTH led the writing of this Personal View.All authors contributed to the writing, critical revision, and the discussions of the scope of this Personal View, and approved the final manuscript.

Figure :
Figure:Schematic representation of the current strategy of sampling within an implementation unit and the proposed mapping strategy of pooled sampling within subdistricts or transmission units (A) According to WHO, areas are divided into implementation units, which can vary in size (eg, a whole district or a subdistrict).(B) The burden of infection in each implementation unit is measured and monitored by sampling from five to ten sentinel sites by use of conventional parasitological diagnostic tools.(C) The burden of infection within an implementation unit is then categorised as low, moderate, or high.(D) By further dividing subdistrict implementation units into smaller transmission units, and, instead of sampling from five to ten sentinel sites, applying a pooling strategy to the whole transmission unit, a bigger area will be sampled from.This strategy results in more accurate data to map and quantify the distribution of schistosomiasis and to identify communities at risk. 10

Panel: Recommended treatment strategy based on infection burden established by pooled sampling
LEC declares funding for the Neglected Tropical Diseases Modelling Consortium by the Bill & Melinda Gates Foundation (OPP1184344) and funding from the Dutch Research Council (grant 016.Veni.178.023).CFM declares financial support from the National Science Foundation and the Graduate Research Opportunities Worldwide Fellowship, outside the submitted work.JR-R and BG were employed by Merck KGaA at the time this Personal View was written, which did not affect their contribution to the article.All other authors declare no competing interests.AcknowledgmentsLogistics for the workshop on advancing CAA testing in low endemic settings of schistosomiasis held by Leiden University Medical Center in the Netherlands in September, 2017, were provided by funding through the Bill & Melinda Gates Foundation.The funders of the study had no role in the study design, data collection, data analysis, manuscript preparation, or the decision to publish.The views, opinions, assumptions, or any other information set out in this Personal View are solely those of the authors and should not be attributed to the funders or any person connected with the funders.