English pdf, 1.64Mb - World Health Organization

Scientific Working GroupReport on14–16 November 2005Geneva, SwitzerlandSpecial Programme for Research & Trainingin Tropical Diseases (TDR) sponsored byUNICEF/UNDP/WorldBank/WHOwww.who.int/tdrTDR/SWG/07

Report of the Scientific Working Groupmeeting on SchistosomiasisGeneva, 14–16 November, 2005

ContentsExecutive summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Background and rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Objectives and overview. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Priorities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Annex 1AGENDA: Scientific Working Group on Schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Annex 2LIST OF PARTICIPANTS: Scientific Working Group on Schistosomiasis . . . . . . . . . . . . . . . . . 21Annex 3WORKING PAPERS: Scientific Working Group on Schistosomiasis. . . . . . . . . . . . . . . . . . . . . 27 WORKING PAPER 1. Research needs of the national schistosomiasis control programmein China . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 WORKING PAPER 2. Current situation and research needs for schistosomiasis controlin Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 WORKING PAPER 3. Implementation strategies for schistosomiasis control in Uganda,and research needs under the programme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 WORKING PAPER 4. Quantification of disease burden due to schistosomiasis . . . . . . . . . . . 46 WORKING PAPER 5. Schistosomiasis in women of childbearing age, including in pregnancy. . 53 WORKING PAPER 6. Measuring schistosomiasis morbidity . . . . . . . . . . . . . . . . . . . . . . . . 57 WORKING PAPER 7. Clinical schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 WORKING PAPER 8. Progress towards the detection of schistosomiasis. . . . . . . . . . . . . . . . 67 WORKING PAPER 9. Research towards new treatments for schistosomiasis . . . . . . . . . . . . . 72 WORKING PAPER 10. The sociocultural context of schistosomiasis control: currentknowledge and future research needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 WORKING PAPER 11. The social determinants of schistosomiasis . . . . . . . . . . . . . . . . . . . 84 WORKING PAPER 12. Ecological and other factors related to schistosomiasis . . . . . . . . . . . 91 WORKING PAPER 13. Research on the molluscan intermediate hosts for schistosomiasis:what are the priorities?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 WORKING PAPER 14. Schistosomiasis and immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . .105 WORKING PAPER 15. Genomics and proteomics: towards new targets in schistosomeresearch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .109SchistosomiasisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07iii

SchistosomiasisivReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Executive summaryMore than 600 million people worldwide are at risk of schistosomiasis, and close to 200million are actually infected continuously or intermittently. One of the main problems facingcontrol of this major public health threat is, paradoxically, caused by previous successes in thebattle against the disease. For example, reduction in the intensity of schistosomiasis during thepast 25 years has made assessment of the disease less reliable in areas under sustained controlsince currently used diagnostic methods are not sufficiently sensitive to accurately determinethe prevalence and worm burdens in these environments. Sustained control not only makessurveillance increasingly difficult but also holds back the clinical testing of vaccine candidatesand contributes to the perception of the disease as a problem of the past. In fact, transmissionis at the root of the problem and is unaffected by current control activities, resulting in high reinfectionrates, even after mass treatment. The need for frequent re-treatment thus limits thesuccess of control efforts, particularly in sub-Saharan Africa, which harbours about 85% of allschistosomiasis in the world.The Scientific Working Group (SWG) on Schistosomiasis was convened in Geneva, 14–16 November 2005, to review the current situation in relation to research needs. Against abackground of the need to better define the impact of schistosomiasis, discussions focusedon the fact that the disability-adjusted life year (DALY) index, which is generally used as ayardstick when comparing the relative importance of diseases, does not accurately accountfor the full range of morbidities caused by schistosomiasis. For instance, the DALY indexleaves out less well recognized (subtle) pathology of schistosomiasis such as anaemia, delayedgrowth and development, cognitive impairment, and sexual dysfunction. It was agreed thata revision of the DALY index to better reflect the true burden of disease is long overdue.To facilitate a move in this direction, the SWG recommended that investigators regularlycollect straightforward data on, for example, anaemia in endemic populations, and developstandardized measures for more intricate outcomes of infection such as on work capacityand cognition. The SWG also recognized the need to support training, capacity buildingand collaboration across borders. It encouraged TDR to expand its role in initiating andmaintaining research networks, including forming partnerships with industry, particularly withsmall to medium-sized businesses in endemic countries. In addition, the SWG encouragedcoordination and, when possible, integration between control activities targeting differentdiseases in the same geographical area. Acknowledging the link between schistosomiasisand poverty, the SWG pointed to the acute need for research on the social determinants ofschistosomiasis as well as the need for health systems research to improve programming. Thepotential benefits of cross-disciplinary research were particularly emphasized.SchistosomiasisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Background and rationaleSchistosomiasisSchistosomiasis is the collective name for infection by one (or more) of five Schistosomaspecies (trematode worms) adapted to humans, i.e. S. mansoni, S. japonicum, S. haematobium,S. mekongi and S. intercalatum, or by species adapted to other mammals which canoccasionally infect humans, e.g. S. bovis and S. magrobowei. This complex helminth infectionrequires alternate development between an intermediate snail host and the final mammalianhost, both of which are indispensable for maintaining the parasite. In humans, the nature ofthe disease is largely immunological and only indirectly due to the parasitic worm itself; thepathological lesions emanate from inflammatory reactions to the large number of parasite eggswhich are retained in host tissues rather than excreted with the faeces or urine (to infect thesnail). The majority of schistosome species cause intestinal schistosomiasis, where the adultworm lives in the mesenteric venules of the host. However, the highest number of humaninfections is caused by S. haematobium, which has a predilection for the blood vessels aroundthe bladder and causes urinary disease.Spectrum of clinical pathologyMorbidity S. mansoni/S. japonicum S. haematobiumGeneral Acute schistosomiasis Acute schistosomiasisOrgan-specificpathologyDevelopmentalimpairmentAnaemiaHepatomegalySplenomegalyEctopic egg granulomasAlternative venous circulationGenital schistosomiasisCognitive dysfunctionDelayed growth/stuntingAnaemiaVesicular wall hardeningBladder cancerEctopic egg granulomasKidney malfunctionGenital schistosomiasisCognitive dysfunctionDelayed growth/stuntingUnderstanding the problem and initiating the correct avenues of research to deal with it arepivotal in improving the lot of people living in areas endemic for the major tropical diseases.There is strong evidence (from China, Brazil and Egypt) that morbidity due to schistosomiasiscan be controlled in areas where the necessary financial resources exist. However, eliminationas a public health threat has proved difficult. Schistosomiasis is reported to exist in 76countries in the Middle East, South America, South-East Asia, and particularly in Africa,where its long-term impact is staggering. Although the prevalence has hardly improved at allover the last few decades, the overall situation changed dramatically following introductionReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

of the drug praziquantel, particularly after its price was reduced making mass chemotherapypossible. The resulting reduction in morbidity represents a major step forward, but high reinfectionrates, even after repeated cycles of mass chemotherapy, limit the success of controlefforts owing to the need for frequent re-treatment. This is particularly the case in sub-Saharan Africa but re-infection is also seen in areas of countries with highly successful controlprogrammes such as Brazil, Egypt and The Philippines. China’s successful control programmereduced the number of infected cases from about 12 million in the 1950s to below 800 000,but very recently the number of infected people again climbed above one million. This clearlydemonstrates the risk of re-emergence of schistosomiasis when a control programme movesinto the consolidation phase and focuses on the final endemic areas while being less vigilant inother areas. The role that management and health system aspects of control programmes oftenplay in such scenarios is understudied.The rapid and sustained fall in morbidity in all areas under control has smoothed over the factthat control approaches have not evolved further, resulting in a widening of the gap betweenwhat is demanded from the field and what can be delivered. One paradoxical outcome of thereduction in morbidity is the dearth of improvements in available control tools. Surprisingly,even if research has generated various novel serological assays of potential application, thefall in intensity of the disease has not been met with more sensitive diagnostic capabilities inthe field. The situation is similar in other areas. For example, although some progress has beenmade on the pre-clinical assessment of synthetic peroxides, the number of available effectivedrugs has been reduced from three to one, while the development of vaccines, which mighthave their strongest potential as a complement to chemotherapy, has lost widespread support.Overall, lack of new basic knowledge is limiting progress at one end of the pipeline, whileslow process development and a lack of industrial participation is hampering the developmentof new tools at the other end. The need for improvement, evident from a number of recentWHO informal consultations, resulted in this long-delayed SWG meeting on Schistosomiasis.SchistosomiasisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Objectives and overviewSchistosomiasisThe objectives of the SWG were to define the research needs in the field of schistosomiasis andto assess the effectiveness of currently available tools and strategies for control. In addition, theSWG was asked to review global research activities, identify gaps between needs and ongoingresearch efforts, and indicate the means to address these gaps. The SWG was also expectedto indicate ways of strengthening existing and new partnerships and to provide TDR with anoverall strategy and scientific direction for research on schistosomiasis for the next five years.GeneralThe SWG met in Geneva, 14–16 November 2005, to review the current needs for research andmake recommendations regarding support. Fourteen invited working papers on various topics(annex 2) were presented by members of the SWG.It was unanimously felt that research priorities, although important for the SWG to agreeon, would be of little value unless the impact of schistosomiasis was better defined. Athorough meta-analysis, presented by Dr C. King, pointed out that the strong negative biasof the current disease-adjusted life years (DALY) index for schistosomiasis is largely due tofailure to include less well recognized (subtle) pathological signs such as anaemia, delayedgrowth/development, cognitive impairment, and sexual dysfunction. Rather than exclusivelyaddressing organ-specific morbidity arising from egg-associated inflammatory reactions andfibrosis, a wider morbidity spectrum should be acknowledged. It was generally felt that arevision of the DALY index to better reflect the true burden of disease is thus overdue. As thisquestion influences all other activities under review, the SWG recommended that investigatorsregularly collect straightforward data, e.g. on anaemia, and also develop standardized measuresfor more intricate outcomes of infection such as on work capacity and cognition. Longitudinalclinical studies and operational research should be initiated in endemic areas and target notonly the general population but particularly the many high-risk sub-groups. Such studiesshould include treatment interventions combined with outcome assessments at multiple timepoints following therapy and results should be linked to studies of socioeconomic status aswell as patients’ estimates of the impact of infection on quality of life.DiagnosticsTo gain a more complete view of schistosomiasis and its impact on society demands thedevelopment of better tools in terms of rapid diagnostic techniques, image-assisted clinicaldiagnosis, and reliable predictive risk maps based on geographical information systems(GIS) and satellite-based remote sensing (RS). Field diagnosis continues to rely on directmicroscopy, as it has since the beginning of control programmes. However, the relativeinsensitivity of this technique is a problem which has gained prominence during the lastReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

decades of continued reduction of the disease intensity in relatively controlled areas. In fact,the consolidation phase of control cannot easily be completed without better assessment ofinfection (both in humans and snails), while it can be argued that vaccine development ispremature until the effects of vaccines can be reliably verified in clinical trials. Currently onlyvery pronounced effects are verifiable, which is not sufficient since even a partially effectivevaccine would be useful as a complement to chemotherapy. As a first step, a standardizedapproach allowing a non-refutable comparison of detection methods needs to be established.The more varied clinical picture that has been ushered in by a stronger emphasis on ‘subtlepathology’ and ectopic presentations of egg-associated pathology requires the application notonly of ultrasound but also of novel image techniques such as computer-assisted tomography,magnetic resonance imaging and tissue harmonic imagining. There is also a need for new noninvasivetechniques to be extended to conditions such as genital schistosomiasis, infectionduring pregnancy, cardio-pulmonary disease, and intestinal schistosomiasis.Data derived from national programmes provide detailed knowledge regarding local, regionaland global prevalence. Regular updates of prevalence, based on both reported and adjustedestimates including information about the assays used, would facilitate follow-up of the impactof control measures. In addition, parasitic diseases control programmes would benefit fromintegration with other public health interventions; coordination of control would be useful inareas where several parasitic infections overlap. For example, studies on co-infection and cotherapywith malaria, geohelminth infections, and filariasis would clearly be fruitful in relationto the outcomes of infection e.g. on cognition, work capacity, and anaemia. The opportunitynow exists to study the impact of artemisinins on the epidemiology of schistosomiasis in areaswhere it co-exists with malaria, for which these drugs are used widely. This opportunity shouldnot be missed. In the same vein, randomized placebo-controlled trials of praziquantel treatmentin pregnant and lactating women in both high and low areas of transmission would augmentthe safety record for this drug. It is also important to consider the potential impact on drugefficacy of HIV (and HTLV-1) infection or immunosuppressive drugs.SchistosomiasisChemotherapyCurrently, schistosomiasis control relies almost entirely on chemotherapy and yet only onedrug, praziquantel, is available. This is a potentially dangerous situation which points tothe need to identify effective new drugs. However, while the identification of new drugsis important, additional work on praziquantel is also required. For example, a formulationcontaining only the effective stereoisomer rather than the current mixture of isomers wouldhave better effect and fewer side effects, while randomized placebo-controlled trials ofReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Schistosomiasispraziquantel in pregnancy, lactating women and children would furnish needed information onthe impact of treatment on birth outcomes and maternal and child health. Even if praziquantelis a very safe and effective drug, pharmacovigilance should be kept up and any treatmentfailure and incidence of severe side effects systematically investigated. Perceived side-effectsof treatment should also be analysed in the context of control programme activities as a wholein order to throw light on the social dynamics behind adherence (‘socio-vigilance’). There isan urgent need to develop tools to detect the onset of drug resistance against praziquantel.Regarding alternative drugs, it is interesting to note that artemisinins act not only againstmalaria but also have schistosomicidal properties. Studies of their mechanisms of actionshould be encouraged and efforts should be made to produce and test analogue compoundswhich also act against the adult worm. Drug development and production should be ensured byestablishing a developmental pipeline following the example of Medicines for Malaria Venture(MMV) for antimalarial drugs. The capacity to move through the discovery process fromtarget identification to lead compound (including optimization, safety, and pharmacokinetics)is in place in several centres in various countries. However, while there is capacity for highthroughputscreening in drug discovery allowing the rapid development of candidate drugs,the centres/countries are not designed to scale-up to the good manufacturing practice (GMP)-grade production needed for phase I/II trials. This significant bottleneck in the process must beaddressed before development of new drugs for schistosomiasis can begin in earnest.The treatment offered by control programmes is purely anti-schistosomicidal and, while periodictreatment prevents the development of severe disease, it does not always ameliorate existingsevere disease. Therefore drugs able to reverse severe pathology or to halt severe diseaseprogression are also required. There is thus a need to investigate drugs that are used for otherfibrotic diseases, or to develop drugs such as immunomodulators for use in schistosomiasis.Immunology and genomicsBasic research with a focus on immunology and genomics plays an important role in anumber of areas, such as in vaccine and drug development, and for elucidating the immunemechanisms which result in morbidity. We need to identify immunological markers ofmorbidity and resistance, and their relation to genetics, in order to facilitate studies onimmunoregulation and mechanisms of human resistance (naturally acquired and vaccineinduced).This research is also important for determining the impact of schistosomiasis onother infections and perhaps for assisting in the design of childhood vaccination programmes.It is important also to investigate immunological involvement in the ‘subtle morbidities’ and toclarify the occurrence and immunological mechanisms of rebound morbidity after treatment.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Sequencing of the genomes of S. mansoni and S. japonicum is nearing completion and thereis now a need for full annotation of the genomes. The S. haematobium genome also requiressequencing, and later the genome of Oncomelania (the S. japonicum intermediate snailhost). These tasks plus the sequencing of other schistosome strains (such as the Philippinestrain of S. japonicum) will allow studies on comparative genomics. As annotation of thegenomes is being carried out, the nomenclature in relation to transcriptome and proteomelibraries should be harmonized, and post-genomics tools such as microarrays and proteomicsapplied to identify stage-specific antigens or pathways that can be targeted for developmentof vaccines, drugs and diagnostics. Resources, e.g. microarrays representing the completegenome for each schistosome species, and combined host/parasite microarrays to study host/parasite interactions, should be developed and standardized and made available for the wholeschistosomiasis community. Other worthy goals are to identify host alleles that aggravate orreduce infection intensity or morbidity and resistance, and evaluate their mechanisms of action.The genomics and post-genomics tools now available can also be used to study the basicbiology of schistosomes and to produce immortalized schistosome cell lines for screening fornew vaccine antigens and drug targets.Vaccine developmentWith unabated transmission, ubiquitous re-infection after cure, and only one drug available,vaccines must be considered a crucial part of the overall integrated control strategy. Mostscientists are convinced that effective vaccines against schistosomiasis can be developedsince irradiated cercariae regularly induce 70% or better protection, and human populationsin endemic areas exhibit various degrees of resistance. While less than 10% of all antigensdiscovered have been targeted for further development as vaccine candidates, severalpromising candidates have been identified and thoroughly researched, and the results validatedin different laboratories. However many of these have suffered subsequent challenges at thestage of scaling-up production according to GMP, now an important selection criterion inassessing vaccine candidacy.SchistosomiasisSince the original list of priority antigens was chosen by a TDR committee in 1997, only a fewmore vaccine candidates have appeared. Of the original antigens, Sh28-GST and Sm14-FABPcontinue to be of interest, the former because it has successfully passed all developmental stepsincluding phase I/II trials, and the latter because further fundamental and applied productionresearch has moved it close to industrial production. Although all candidates produced so fartarget infection (except Sh28-GST and Sm28-GST, which target both infection and parasitefecundity), all research directions should be pursued including anti-morbidity effects andblocking of transmission.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

SchistosomiasisEcology and transmissionThere is a clear need for markers to assess transmission, especially in areas of low endemicityand in pre-elimination foci. These areas also need to be examined regarding the evidencethat some feral animals can act as reservoir hosts, at least for S. mansoni. Methods to assesscercarial density and to detect early-stage infection in snails would be very useful and wouldcomplement diagnosis in humans (and reservoir hosts) and help evaluate the details oftransmission. RS is well suited for determining snail habitats and should be used with GIS toproduce predictive risk maps and mathematical models of transmission. With regard to snailcontrol, both environmental management and use of focal chemical molluscicides should beevaluated. Apart from biological factors, social factors play an important role in transmissionin specific ecological zones, where their role should be assessed and cross-disciplinary studiespursued to better understand the dynamics.Social IssuesOverall, schistosomiasis can be characterized as a disease of poverty. However, the evidencelinking social resources, economic status, and infection at community and household levelsneeds to be better defined. These relationships can be described through quantitative as wellas qualitative analysis of changes taking place over time, taking into account the focal natureof transmission and following the migration of households/family members. Suitable sites forresearch on social and economic determinants would be locations where new water resourcesdevelopment projects are taking place and where control programmes are being implemented.Here, exploratory studies of social change could be combined with investigations of shiftsin asset ownership over time in order to make the targeting of interventions more equitableand provide tools for measuring impact of interventions. Furthermore, such studies couldexplore how control programmes can respond to vulnerability, which constrains people’sability to seek health care, cope with illness and suffering, and adhere to therapy schemes.Understanding the contexts and processes that create vulnerability to infection, weakenresilience, and compromise equity in access to diagnostics, health information, treatment andthe benefits of preventive measures, e.g. safe water supply and sanitation, necessitates an ecobio-socialapproach. Research using this approach needs to address micro- as well as macrolevelsof analysis and be sensitive to asymmetries of gender, age, occupation, ethnicity, andincome level.The recognition of ‘subtle morbidities’ in schistosomiasis creates a new platform forresearching the social and economic impacts of this disease. Community-based studiescombining quantitative and qualitative methods can explore the impact of infection onReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

everyday life, quality of life, working capacity, cognitive development, school performance,and general functionality, as well as explore the strategies used by individuals and householdsto compensate for the impacts of infection. The same combination of methods can explore thesocial and economic impacts of chronic disease and genital schistosomiasis in men and womenand the possible stigma associated with these conditions. An understanding of these processeswill provide valuable information for designing control programmes.It can be assumed that the emergence, resurgence, and persistence of schistosomiasis areclosely linked to the specific social and eco-epidemiological setting as well as to large-scaleforces such as shifts in resource flows and environmental change. Insights gained by previouscontrol initiatives and regional or national experiences offer opportunities to strengthen thedesign and management of current and future control initiatives. Important issues include,for example, use of community-based social research to identify the most vulnerable groups,definition of strategies to ensure access of vulnerable groups to treatment, and determinationof the cost-effectiveness of various control approaches. Furthermore, health systems researchwill help in understanding how the impact and sustainability of control programmes also relyon the financial and managerial context, e.g. on price, availability of drugs at the periphery,public expenditure, out-of-pocket payments, vertical vs. horizontal approaches, and, not least,on coordination with the national health system.Post-schistosomiasis controlEven if prevalence has so far only been affected marginally, sustained reduction in intensityof disease and morbidity is evident in all areas under control. The case for elimination ofschistosomiasis as a public health threat, at least for its elimination in some parts of the world,is thought to be feasible. There are reasons to believe that this will one day become reality andthus there is a need to plan for it in advance.SchistosomiasisWhen externally funded control programmes have come to an end, and to maintain the benefitsof these, studies need to be extended to include post-control interventions. Care for patientswith post-transmission schistosomiasis will eventually become the only activity in this field,as it already is in Japan. This is a very different activity than the current one, but high-levelplanners would do well to think about it at an early stage and also to calculate the possiblebenefits of coordination with and linkage to established programmes such as the LymphaticFilariasis Elimination Programme, the Expanded Programme on Immunization (EPI), and theWorld Food Programme’s school feeding programme and maternal/child health initiatives.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

SchistosomiasisCapacity building and partnershipsHealth issues in developing countries are now moving from an area of ignorance and neglectto a more prominent standing on the political agenda. Evidence of this can be seen in thestrengthened management of existing initiatives which has resulted in tangible improvementsof public health, while specific diseases are starting to be tackled by new public–privatepartnerships. Such collaborations bring advantages for resource-poor environments resultingin unique engagements in the health-related problems of disease-endemic countries. Thefirst serious collaboration between those dealing with a neglected disease and industry cameabout through the observation that ivermectin, a drug used to treat heartworm infection indogs, was effective for the treatment of human onchocerciasis (river blindness). TDR workedwith the US pharmaceutical corporation Merck to develop the product, which was finallyregistered for human use in 1989. Merck has since made the commitment to produce the drugfree of charge for endemic areas in Africa for as long as it is needed. This commitment hasbecome the cornerstone of the very successful control programme for onchocerciasis thathas been joined by numerous governments and non-governmental agencies. However, thissuccessful collaboration was not immediately followed by similar ventures. It took almost adecade before the idea took root and similar partnerships started to form, which shows that itis not easy to convince industry of the mutual benefits of collaboration and that it falls on thedonor agency to follow up and develop the partnership. Several industrial partnerships nowexist, but none in the field of schistosomiasis. However, an artemesinin partnership with thepharmaceutical industry is run through MMV, and this may yet benefit schistosomiasis. Also, aChinese institution ran a number of large-scale clinical trials in the 1990s, in collaboration withKunming Pharmaceutical Corporation, which demonstrated that artemether and derivatives ofthis drug can reach 100% protection against S. japonicum.Training issues in schistosomiasis mirror those found with other neglected tropical diseases,as schistosomiasis is generally a non-fatal disease and people perceive there to be an effectivetool for control and treatment; this perception is compounded by the focal nature of the diseaseand its low prevalence in relatively well controlled areas. As a result, there are few incentivesfor students and researchers to engage in postgraduate training, and few opportunities to applytheir new skills, while funds for research subsequent to postgraduate training appear to beevaporating. Further, many scientists who were previously engaged in schistosomiasis researchhave now either moved on to other diseases or are aging and nearing retirement withoutadequate replacements having been trained. It is difficult for a disease like schistosomiasis tocompete with the opportunities and funds currently available for training and research in HIV/AIDS, TB, malaria, and more recent emerging and re-emerging infections such as SARS and10Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

influenza. Nevertheless, there is a strong need to train scientists in disciplines that contributeto research on new or improved methods for the prevention, control and treatment ofschistosomiasis. Priority areas for training include new diagnostics, clinical trials, managementof new treatment regimens and future vaccine trials, and cost-effective methods for identifyingtransmission areas using GIS/RS. In addition, well-trained social scientists are needed who canaddress the issue of social determinants and human behaviour fundamental to controlling andperhaps one day eliminating schistosomiasis.Several organizations with similar goals to TDR are now working together to improve thelot of the people in the third world. While the signs of change are slowly but unmistakablyappearing, and capability strengthening and training are becoming more important, there is noquick solution to remedying the imbalance between supply and demand for trained scientistsspecializing in schistosomiasis research. Possible avenues to pursue include involvingyoung graduate students in schistosomiasis networks early in their training before they havechosen a disease speciality, and increasing mentoring throughout their training by seniorscientists. Overall, the profile of the importance and public health impact of schistosomiasismust be raised in universities and research organizations so that scientists are encouraged toparticipate in the global schistosomiasis research agenda.SchistosomiasisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 11

PrioritiesSchistosomiasisResearch needs in the field of schistosomiasis were discussed by the SWG members. Theresearch priorities distilled from the recommendations are presented below.Disease burden and assessment of morbidity• Revise the DALY index for schistosomiasis so that the full morbidity spectrum including theless well recognized (subtle) pathological signs are taken into account, better reflecting thetrue burden of disease.• Investigators to regularly collect data on subtle morbidities (e.g. anaemia, physical andcognitive development) and to develop standardized measures for intricate outcomes ofinfection such as on work capacity and cognition both for schistosomiasis and for coinfectionswith malaria, geohelminths, lymphatic filariasis, etc.• Conduct systematic studies on the prevalence of ectopic presentations of schistosomiasis, inparticular of neuroschistosomiasis.• Conduct longitudinal clinical studies and operational research targeting various high-risksub-groups in endemic areas.• Prepare regular updates of prevalence based on standardized measures for outcomes,enabling the disease impact to be compared over time and across multiple areas andpopulations.• Determine schistosomiasis distribution preferably together with other parasitic diseases tobenefit coordination by the control programme in overlapping areas.Ecology, transmission and monitoring• Develop methods for the detection of early-stage infection in snails for use in low-endemicand pre-elimination foci.• Sequence the Oncomelania genome.• Develop a strong focus on risk map prediction (determination of possible and real snailhabitats) using geographical information systems and remote sensing.• Develop mathematical transmission models applicable for different species.• Elucidate the role of reservoir hosts in transmission to humans in low-endemic areas.Diagnostics• Compare the sensitivity of available serological (or other) techniques and encouragedevelopers and industrial partners to standardize assays.• Define ultrasound findings using computerized tomography, magnetic resonance imaging andtissue harmonic imaging.12Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

• Publish without delay the current recommendations for a standardized image patternmethodology by ultrasound for S. japonicum and S. mekongi morbidity.Chemotherapy• Identify and produce new drugs as a priority.• Study alternative drug formulations of praziquantel, including how to cost-effectivelygenerate the single, effective praziquantel stereoisomer.• Study the mechanisms of action of schistosomicidal drugs (artemisinins) and continueresearch on combination therapies (including praziquantel + oxamniquine, and praziquantel +artemisinins).• Develop tools to detect the development of drug resistance by schistosomes.• Monitor adherence and compliance during implementation of large-scale drug therapy andsystematically investigate any treatment failure of praziquantel and incidence of severe sideeffects.• Conduct without delay randomized, placebo-controlled trials of praziquantel treatment inpregnancy for all species of human schistosome in areas of both high and low transmission.• Monitor the impact of immunosuppression (including infection by HIV, HTLV-1 or use ofimmunosuppressive drugs) on the efficacy of praziquantel.• Carry out cost-effectiveness studies of morbidity control at national and regional levels,and integrate cost-effectiveness evaluations in relation to other established interventionprogrammes.Immunology and genomics• Define the mechanisms of human resistance and the impact of immunoregulation, anddevelop immunological markers for morbidity and resistance to infection, relating them togenetic findings.• Identify host alleles that aggravate or reduce infection intensities or morbidity and resistance,and evaluate their mechanisms of action and use as genetic markers for the risk of heavyinfection and/or severe disease.• Investigate immunological involvement in the subtle morbidities and the impact ofschistosomiasis on pregnancy outcomes.• Clarify the occurrence and immunological mechanisms of rebound morbidity after treatmentin S. japonicum, and investigate rebound morbidity in infections due to S. mansoni and S.haematobium.SchistosomiasisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 13

Schistosomiasis• Develop a toolbox permitting genetic manipulations (RNAi, transfections, transgenics) toadvance knowledge of basic schistosome biology and lead to the development of drugs,vaccines and diagnostics.• Encourage rapid completion and annotation of the S. mansoni, S. japonicum genomes, andsequencing of the S. haematobium genome, and support comparative genomic studies ofother schistosome strains, especially the Philippine strain of S. japonicum.• Develop schistosome cell lines to facilitate drug screening.• Establish harmonization networks to coordinate nomenclature related to transcriptome andproteome libraries, and protocols for human immunologic field studies.Vaccine development• Consider vaccines a crucial part of any overall integrated control strategy.• Identify new vaccine targets, preferably using genomics and post-genomics (e.g. proteomics,glycomics) tools.• Support scale-up to GMP for phase I/II trials (this step is currently a bottleneck).Social issues• Study the social and economic determinants of vulnerability to infection at the individual,household, and community levels, including how these interact with factors that aresignificant at the national level.• Assess the social and economic impact of the disease on individuals, households,communities, and societies.• Investigate how community-based social research can enhance identification of the mostvulnerable groups and define strategies to ensure access to and acceptability of diagnostics,health information, chemotherapy and provision of safe water and sanitation.• Identify the most important financial and managerial contextual factors and processes inrelation to control programmes and their linkages to other interventions as well as healthsystems with the view to increase the impact of control programmes and the sustainability ofachievements.Post-transmission• After schistosomiasis has been eliminated, continue the surveys and maintain the benefitsthat have been achieved, documented and promulgated.• Investigate the possible benefits of coordination with, and linkage to, control programmes forother parasitic diseases, and to established initiatives in the health sector in general.14Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Capacity building• Train more people in GIS in the field of schistosomiasis, focusing on the use of GIS-basedtools and statistical analysis to produce predictive models (rather than simply to producedistribution maps of parasites and infected hosts).• Reinforce the training of malacologists and taxonomists, particularly in disease endemiccountries, and encourage networking.• Establish a schistosome vaccine network to encourage productive collaborations andstandardization of study protocols (schistosomiasis vaccine development has, to date, beenhighly fragmented).• Establish an immunological network to harmonize protocols for human field studies.SchistosomiasisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 15

Annex 1AGENDA: Scientific Working Group on SchistosomiasisSchistosomiasisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 17

Day 1, Monday 14 NovemberTime Item Name09.00–09.30 Introduction of participantsWelcome address09.30–09.45 Meeting objectives and process Dr L. Chitsulo, TDR09.45–10.00 Introductory remarks and overview Dr D. Colley10.00–10.20 Global status of schistosomiasis and its control Dr D. Engels, CPE10.20–10.30 Current strategic emphases for schistosomiasis research in TDR Dr L. Chitsulo, TDR10.30 – 11.00 Coffee BreakDr D. Colley, ChairpersonDr J.H. Remme, TDRDr L. Savioli, Director, WHO CommunicableDiseases Control, Prevention and Eradication (CPE)11:00–12.00 Research needs of national schistosomiasis control programmes National control managers: China, Egypt, Uganda12:00–12.30 Quantifying the disease burden due to schistosomiasis control Dr. C.H. King12.30–14.00 Lunch14:00–14.30 Schistosomiasis in women of child-bearing age, including pregnancy Dr G.R. Olds14.30–15.00 Measuring schistosomiasis morbidity Dr B. Vennerwald/Dr D. Dunne15.00–15.30 Clinical schistosomiasis Dr J. Lambertucci15.30–16.00 Coffee Break16.00–16:30 Progress towards detecting schistosomiasis Dr A. Rabello16.30–17.00 Research towards new treatment for schistosomiasis Dr D. Cioli17.00–17.30 The socio-cultural context of schistosomiasis control Ms B. Bruun/Dr J. Aagaard-HansenClosure – 1st dayDay 2, Tuesday 15 NovemberTime Item Name08.30–09.00 Ecological and other factors influencing schistosomiasis transmission Dr S. McGarvey09.00–09.30 The intermediate host for schistosomiasis Dr E. Loker09.30–10.00 Immunity in schistosomiasis Dr K. Hirayama10.00–10.30 The current status of schistosomiasis vaccines Dr P. LoVerde10.30–11.00 Coffee Break11.00–11.30 Genomics and proteomics: towards novel targets in schistosomiasisresearchDr R.A. Wilson11.30–12.00 Scientific progress with respect to S. japonicum Dr Feng Zheng11.30–13.00 Lunch break13.00–15.00 Working groups15.00–15.30 Coffee break15.30–17.30 Working groupsClosure – 2nd day18 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Day 3, Wednesday 16 NovemberTime Item Name08.30–09.10 Plenary report: Working Group I Rapporteur09.10–09.50 Plenary report: Working Group II Rapporteur09.50–10.30 Plenary report: Working Group III Rapporteur10.30–11.00 Coffee break11.00–11.40 Plenary report: Working Group IV11.40–12.30 Small group to review draft conclusions and recommendations SWG Chairperson/rapporteurs12.30–14.00 Lunch break14.00–15.30 Plenary discussion and amendment of conclusions and recommendations All15.30–16.00 Coffee break16.00–16.30 Any other business16.30–17.00 Concluding remarksClosure of the meetingClosure – finalChairperson, Director TDRReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0719

Annex 2LIST OF PARTICIPANTS:Scientific Working Group on SchistosomiasisSchistosomiasisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 21

Temporary advisorsDr Jens Aagaard-HansenDanish Bilharziasis LaboratoryInstitute for Health Research and DevelopmentJaegersborg Allé 1DDK 2920 CharlottenlundDENMARKTel: (45) 77 32 7784Fax: (45) 77 32 7733Email: jaagaard-hansen@dblnet.dkProfessor Rashida BarakatProfessor of Medical ParasitologyTropical Health DepartmentHigh Institute of Public Health165 El Horreya AvenueAlexandriaEGYPTTel: (20) 3 542 7010Fax: (20) 3 428 8436Email: barakat@dataxprs.com.egDr Robert BergquistIngerod 407S-45494 BrastadSWEDENTel: (46) 5 234 33 36Email: robert@ ingerod.netDr Birgitte BruunDanish Bilharziasis LaboratoryInstitute of Health Research and DevelopmentJaegersborg Allé 1DDK 2920 CharlottenlundDENMARKTel: (45) 77 32 7784Fax: (45) 77 32 7733Email: bruunbirgitte@get2net.dkDr Donato CioliInstitute of Cell Biology32 via Ramarini00016 Monterotondo Scalo RomaITALYTel:(39) 06 9009 1355Fax: (39) 06 9009 1259Email: dcioli@ibc.rm.cnr.itDr Daniel ColleyCentre for Tropical and Emerging Global DiseasesUniversity of GeorgiaBiological and Sciences BuildingRoom 629, 100 Cedar StreetAthens, Georgia 30602USATel: (1) 706 542 4112Fax: (1) 706 542 3582Email: dcolley@uga.eduDr Rodrigo Correa-OliveiraM.S. FIOCRUZ, Centro de Pesquisas“René Rachou”Av. Augusto de Lima 1715Caixa Postal 173430190-002 Belo Horizonte MGBRAZILTel: (55) 31 295 3566Fax: (55) 31 295 3115Email: Correa@netra.cpqrr.fiocruz.brDr Alain DesseinLaboratoire d’Immunologie etGénétique des Maladies parasitairesFaculté de Médecine27 boulevard Jean Moulin13385 Marseille Cedex 5FRANCETel: (33) 4 91 32 44 52Fax: (33) 4 91 79 60 63Email: alain.dessein@medecine.univ-mrs.frDr Michael John DoenhoffUniversity of WalesSchool of Biological SciencesBangorGwynedd LL57 2UWUKTel: (44) 01248 35 1151Fax: (44) 01248 37 0731 or 1644Email: M.doenhoff@bangor.ac.ukDr David William DunneUniversity of CambridgeDepartment of PathologyMicrobiology and Parasitology DivisionTennis Court RoadCambridge CB2 1QPUKTel: (44) 1223 333690 or 333695Fax: (44) 1223 333346 or 353492Email: Dd@mole.bio.cam.ac.uk22 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Professor Alan FenwickSchistosomiasis Control InitiativeDept. of Infectious Disease EpidemiologyImperial CollegeSt Mary’s Campus, Norfolk PlaceLondon W2 1PGUKTel: (44) 20 794 3418Email: a.fenwick@imperial.ac.ukDr Zheng FengNational Institute of Parasitic DiseasesChinese Center for Disease Control andPrevention207 Rui Jin Er Road200025 ShanghaiCHINATel: (86) 21 6437 6308Fax: (86) 21 6433 2670Email: zzfeng@sh163.netDr Paul HaganFaculty/Institute of Biomedical and Life ScienceDivision of Infection and ImmunityUniversity of GlasgowWolfson Link Building (Room 365)Glasgow G12 8QQUKTel: (44) 141 330 2545Fax: (44) 141 330 4758Email: P.Hagan@bio.gla.ac.ukDr Christoph HatzSwiss Tropical InstitutePO Box4002 BaselSWITZERLANDTel: (41) 61 284 8255Fax: (41) 61 284 8183Email: Christoph.Hatz@unibas.chProf Kenji HirayamaDepartment of Molecular ImmunogeneticsInstitute of Tropical MedicineNagasaki University1-12-4 Sakamoto, Nagasaki 852-8523JAPANTel: (81) 95 849 7818Fax: (81) 95 849 7821Email: hiraken@net.nagasaki-u.ac.jpProfessor Mamoun M.A. HomeidaAcademy of Medical Sciences and TechnologyP.O. Box 12810, KhartoumSUDANTel: (249) 11 223 385Fax: (249) 11 224 799Email: amst33@hotmail.comDr Sung-Tae HongDepartment of Parasitologyand Tropical Medicine and Institute of Endemic DiseasesSeoul National University College of MedicineSeoul 110-799KOREATel: (82) 2 740 8343Fax: (82) 2 765 6142Email: hst@snu.ac.krDr Narcis B. KabatereineVector Control DivisionMinistry of HealthP.O. Box 1661KampalaUGANDATel: (256) 41 251 927Fax: (256) 41 346 885Email: vcdmoh@imul.comDr Charles KingCentre for Global Health and DiseasesCase Western Reserve University10900 Euclid AvenueCleveland, Ohio USA 44106-7286USATel: (1) 216 368 3667Fax: (1) 216 368 4825Email: chk@po.cwru.eduProfessor Jose Roberto LambertucciUniversidade Federal de Minas GeraisEstudos de Medicina ExperimentalNucleo de Estudos Sobre Esquistoss.Avenida Alfredo Balena 190Belo Horizonte 3000BRAZILEmail: lamber@net.em.com.brDr Eric S. LokerUniversity of New MexicoDepartment of BiologyAlbuquerque, NM 87131USATel: (1) 505 277 5508Fax: (1) 505 277 0304Email: ESLoker@unm.eduProfessor Philip LoVerdeState University of New YorkSchool of Medicine and Biomedical Sciences(Microbiology)138 Farber Hall, 3435 Main StreetBuffalo NY 14214-3078USATel: (1) 716 829 2459Fax: (1) 716 829 2169Email: LoVerde@buffalo.eduReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0723

Dr Henry MadsenDanish Bilharziasis LaboratoryInstitute for Health Researchand DevelopmentJaegersborg Alle 1DDK-2920 CharlottenlundDENMARKTel: (45) 3162 6168Fax: (45) 3962 6121Email: DBL@bilharziasis.dkDr Margaret MafeNigerian Institute of Medical ResearchPublic Health Division6 Edmond CrescentYaba, LagosNIGERIATel: (234) 803 349 1386Email: margmafe@yahoo.co.ukDr Stephen T. McGarveyInternational Health InstituteBrown UniversityBox G-B 497Providence RI 02912USATel: (1) 401 863 1186Fax: (1) 401 863 1243Email: Stephen_McGarvey@brown.eduProfessor James H. McKerrowUniversity of California, San FranciscoTropical Disease Research UnitQB3 508B, UCSF box 2550, 1700 4th StreetSan Francisco, CA 94143-2550USAEmail: jmck@cgl.ucsf.eduDr Donald Meter McManusQueensland Institute of Medical ResearchMolecular Parasitology Laboratory300 Herston RoadBrisbane QLD 4020AUSTRALIATel: (61) 7 3362 0401Fax: (61) 7 3362 0104Email: Don.McManus@qimr.edu.auDr Victor MwanakasaleTropical Disease Research CentreParasitology unitPO Box 71769NdolaZAMBIATel: (260) 2 680 059Fax: (260) 2 621 112Email: bízcale@zamtel.zmProfessor Francois NoelUniversidad Federal do Rio de JaneiroCentro de Ciencias da Sauda, Sala J1-17-ICBDep. Farmacología Basica e ClinicalIlha do Fundao,21491-590 Rio de Janeiro, RJBRAZILTel: (55) 21 25 62 67 32Fax: (55) 21 25 62 66 59Email: fnoel@pharma.ufrj.brDr G. Richard OldsMedical College of WisconsinDepartment of Medicine9200 W. Wisconsin AvenueMilwaukee, Wisconsin 53226USATel: (1) 414 456 6705Fax: (1) 414 456 6219Email: grolds@mail.mcw.eduDr Ana RabelloLaboratório de Pesquisas ClínicasReferência/Treinamento em LeishmaniosesCentro de Pesquisas René RachouFundaçao Oswaldo CruzAv. Augusto de Lima 171530190-002 Belo Horizonte, MGBRAZILTel: (55) 31 32 95 35 66Fax: (55) 31 32 95 21 15Email: ana@cpqrr.fiocruz.brDr Joachim RichterTropical Diseases UnitClinics for GastroenterologyHepatology and Infectious DiseasesUniversity of DuesseldorfMoorenstr 5D-40225 DuesseldorfGERMANYTel: (49) 211 81 16800Fax: (49) 211 3190639Email: richter1@uni-duesseldorf.deDr Andreas RuppelUniversity of HeidelbergDepartment of Tropical HygieneIm Neuenheimer Feld 324D-69120 HeidelbergGERMANYTel: (49) 6221 56 50 44Fax: (49) 6221 56 59 48Email: Andreas.Ruppel@urz.uni-heidelberg.de24 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Dr Ronaldo Santos do AmaralPrograma de Controle da EsquistossomoseMinistério da SaúdeFundaçao Nacional de SaúdeQuadra 4 – Bloco N – Sala 715CEP 79958-902 – BrasiliaBRAZILTel: (55) 061 314 6543Fax: (55) 061 321 72 82Email: ronaldo.amaral@funasa.gov.brDr William Evan SecorCenters for Disease Control and PreventionDivision of Parasitic DiseasesMailstop F-13Atlanta GA 30341-3742USATel: (1) 770 488 4115Fax: (1) 770 488 3115Email: was4@cdc.govDr Juerg UtzingerSwiss Tropical InstituteSocinstrasse 57BaselSWITZERLANDTel: (41) 61 284 8129Fax: (41) 61 284 8105Email: juerg.utzinger@unibas.chProfessor Louis-Albert Tchuem TchuenteNational Program for Control of Schistosomiasis andSTHCentre for Schistosomiasis and ParasitologyP.O. Box 7244YaoundeCAMEROUNTel: (237) 221 01 83Fax: (237) 221 50 77Email: tchuemtchuente@schisto.comDr Birgitte VennervaldDanish Bilharziasis LaboratoryDepartment of Parasitology/ImmunologyJaegersborg Alle 1 DCharlottenlund 2920DENMARKTel: (45) 3962 6168Fax: (45) 3962 6121Email: DBL@bilharziasis.dk*Dr Susan J. WattsAmerican University inCairoSocial Research CenterP.O. Box 2511Cairo 11511EGYPTTel: (20) 2 797 6954Fax: (20) 2 797 7298Email: sjwatts@aucegypt.eduProfessor Robert Alan WilsonUniversity of YorkDepartment of BiologyP.O. Box 373York, Y010 5YWUKTel: (44) 1904 32 86 00Fax: (44) 1904 32 85 99Email: RAW3@york.ac.ukDr Thomas A. WynnNational Institute of HealthLaboratory of Parasitic Diseases900 Rockville Pike Buld.71 Rm 318Bethesda MD 20892USATel: (1) 301 496 47 58Fax: (1) 301 402 00 77Email: twynn@niaid.nih.govMs Guojing YangSwiss Tropical InstituteBaselSWITZERLANDEmail: guojingyang@hotmail.comDr Mohamed Mostafa YoussefSchistosomiasis and Intestinal Parasites ControlDepartment/Ministry of Health and Population3 Magles El-Shaab StreetCairo 11467EGYPTTel: (20) 2 794 7199Fax: (20) 2 794 8187Email: mohamedmostafayh@netscape.comProfessor Xiao-Nong ZhouNational Institute of Parasitic DiseasesChinese Center for Disease Control and Prevention207 Rui Jin Er Road200025 ShanghaiCHINATel: (86) 21 64 73 80 58Fax: (86) 21 6433 26 70Email: zhouxn@hotmail.com/ pdzhouxn@sh163.net* unable to attendReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0725

WHO Regional Office staff*Dr Thomas T.Y. SukwaMalaria (MAL)/Communicable Disease Prevention andControl (DDC), WHO Regional Office for Africa (AFRO)Tel: 263 233 17193Email: nkunkus@afro.who.intDr Sebastio NkunkuDDC/DDC, AFROWHO Headquarters staffDr Robert Ridley, Director TDRDr Jane Kengeya-Kayondo, Coordinator,Implementation Research and Methods (TDR/IRM)Dr Janis Lazdins-Helds, Acting Coordinator, ProductDevelopment and Evaluation (TDR/PDE)Dr Ayoade Oduola, Coordinator, Strategic and DiscoveryResearch (TDR/SDR)Dr J.H.F. Remme, Coordinator, Science Strategy andKnowledge (TDR/SSK)Dr Fabio Zicker, Coordinator, Research CapabilityStrengthening (TDR/RCS)Dr Lester Chitsulo, Schistosomiasis Disease ResearchCoordinator, TDRDr Hashim Ghalib, Leishmaniasis Disease ResearchCoordinator, TDRDr Deborah Kioy, Human African TrypanosomiasisDisease Research Coordinator, TDRDr Axel Kroeger, Dengue Disease Research Coordinator,TDRDr Philip Onyebujoh, TB/HIV Disease ResearchCoordinator, TDRDr Yeya Toure, Malaria Disease Research Coordinator,TDRDr Johannes Sommerfeld, TDR/SDRMs Henrietta Allen, WHO Communicable Diseases,Strategy Development and Monitoring for ParasiticDiseases and Vector Control (CDS/CPE/PVC)Dr Colin Douglas Mathers, WHO Management andHealth Information Systems (EIP/MHI)Dr Dirk Engels, CDS/CPE/PVCDr Lorenzo Savioli, CDS/CPE/PVC* unable to attend26 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Annex 3WORKING PAPERS:Scientific Working Group on Schistosomiasis1. Research needs of the national schistosomiasis control programme in China . .282. Current situation and research needs for schistosomiasis control in Egypt . . . .353. Implementation strategies for schistosomiasis control in Uganda, andresearch needs under the programme . . . . . . . . . . . . . . . . . . . . . . . . . . . . .384. Quantification of disease burden due to schistosomiasis . . . . . . . . . . . . . . . .465. Schistosomiasis in women of childbearing age, including in pregnancy . . . . . .536. Measuring schistosomiasis morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577. Clinical schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .628. Progress towards the detection of schistosomiasis . . . . . . . . . . . . . . . . . . . . 679. Research towards new treatments for schistosomiasis . . . . . . . . . . . . . . . . . .7210. The sociocultural context of schistosomiasis control: current knowledgeand future research needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7611. The social determinants of schistosomiasis . . . . . . . . . . . . . . . . . . . . . . . . .8412. Ecological and other factors related to schistosomiasis . . . . . . . . . . . . . . . . . 9113. Research on the molluscan intermediate hosts for schistosomiasis: whatare the priorities? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .95Schistosomiasis14. Schistosomiasis and immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10515. Genomics and proteomics: towards new targets in schistosome research. . . . 109Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 27

WORKING PAPER 1. Researchneeds of the nationalschistosomiasis controlprogramme in ChinaXiao-Nong ZhouNational Institute of Parasitic Diseases,Chinese Center for Disease Control and Prevention,Shanghai 200025, ChinaINTRODUCTIONSchistosoma japonicum is unique among all humanschistosomes by being a true zoonosis with over 40animal reservoir hosts in nature, including cattle, buffaloes,pigs, dogs, cats and goats. This poses specialdifficulties in controlling transmission to humans,especially in areas with infected bovines and waterbodies close to villages. Generally, there are three ecotypesof endemic areas, i.e. plain regions, marshlandand lake regions, hilly and mountainous regions.This stratification is based on epidemiological patternsand the ecology of the intermediate host snail,Oncomelania hupensis. Occupational activities offarmers and fishermen, such as cattle herding, fishing,reed cutting as well as recreational and domesticactivities involving prolonged water contact leadto intensive exposure and increased risk of infectionor re-infection. Upon infection, many patients experiencesevere morbidity resulting in disability andsometimes death if they are not treated adequately.The main goal of the national schistosomiasis controlprogramme, initiated in 1955, is to eliminatethe disease from all endemic areas where feasibleby integrated approaches including chemotherapy,snail elimination, environmental modification,health education and improved sanitation and safewater supply. With the progress of the national controlprogramme, different approaches were applieddepending on the period and local setting. Forexample, during the 1950s, nationwide case surveysand active treatment of patients prevailed. Inthe 1960s and 1970s, apart from screening and treatmentof infected persons, the focus was on snailelimination by environmental modification, oftenassociated with water resources development andwater conservancy projects, creation of new farmlandby setting up embankments in areas with hightransmission potential, and chemical mollusciciding.Since the 1980s, large-scale chemotherapy withpraziquantel has become the mainstay of control.Extended chemotherapy both for man and domesticanimals in combination with snail elimination bychemical mollusciciding has been the major controlstrategy adopted by the World Bank Loan Projecton schistosomiasis control in China, implemented1992–2001.The sustained commitment of the central and localgovernments were key to letting China become oneof the most successful countries in the world to controlschistosomiasis. By the end of 1995, transmissionof the disease had been interrupted successfullyin five provinces, namely Guangdong and Shanghai(in 1985), Fujian (1987), Guangxi (1989) and Zhejiang(1995). Importantly, these achievements are mainlydue to the advent of praziquantel in the 1970s, andthe programme has been versatile enough to permitadjustments over time to adapt to changing eco-epidemiologicalconditions. The experience gained thusfar can be summarized as follows: first, insisting onthe system of ‘government planning, intersectoralcollaboration and broad-based community participation’was a key factor for setting up and implementingthe control programme in a sustainablemanner. Second, progress in schistosomiasis controlgoes hand-in-hand with socioeconomic development.Third, results obtained from pilot studiescomparing different control approaches proved usefulfor designing and implementing control activitieson a larger scale; control has to readily adapt tothe specific eco-epidemiological setting. Fourth, collaborationof the health sector with various othergovernmental sectors (e.g. agriculture, water conservancy,forestry) is of key importance for successfuland sustainable schistosomiasis control. Finally,tightly linking control efforts with operationalresearch can enhance the programme outcome.With the economic reforms initiated in 1978 and theadvent of globalization, Chinese society experiencedremarkable changes in both urban and rural areas.The social and economic transition has affected thehealth sector in three ways. First, responsibilities inthe economic and social sectors are shared betweenall five levels of government (national, provincial,prefecture, county, township). Second, social servicesare more responsive to individual than collectiveneeds, and are strongly subject to market mechanisms.Third, certain institutions originally belongingto the public sector are now gradually being privatized.Therefore, the traditional strategy of schistosomiasiscontrol is hardly implemented effectivelyany more in the endemic areas, and the transmissionpattern of schistosomiasis has altered along withthe changes in socioeconomic and environmentalconditions. New challenges have arisen, includingschistosomiasis now being found in the increasinglymobile population (e.g. migratory workers), andnew transmission foci appearing as snail-infestedareas expand along water courses or into urban28 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

areas. The fluctuations in transmission intensity andinfection rate are closely related to changing environmentalconditions such as flood events, and newthreats arise from global warming which leads toan expansion of potential snail habitat. Due to variouscombinations of the above factors, schistosomiasisjaponica is still transmitted in the lake regionsof Anhui, Hubei, Hunan, Jiangsu and Jiangxi provinces,with their vast areas of O. hupensis habitats,and it also remains endemic in mountainous regionsof Sichuan and Yunnan provinces. It is more difficultto control transmission in the former lake regionsbecause of large grazing areas contaminated bylivestock (especially bovines), and the high risk forwater contact by mobile populations working in thelakes and along the Yangtze River. The latter areasare characterized by diverse and complex ecologies,lower human and snail population densities, andweaker economic growth when compared to otherprovinces of China. The latest available data suggestthat schistosomiasis has re-emerged in the pastfive years, especially in the highly endemic areas inthe lake and mountainous regions. It is also reportedthat schistosomiasis transmission has re-emerged in38 counties which had previously reached the criterionof transmission interruption or control.When taking into account the aforementioned biological,ecological and socioeconomic factors, itbecomes obvious that it is essential to conduct furtherresearch to understand the impact of the changes onthe epidemiology of schistosomiasis japonica and toprovide sound evidence to the policy-makers at variouslevels. This will help to adjust control strategiesefficiently, and improve the control programme’scost-effectiveness and maximize its impact. For thispurpose, we identified the research gaps and needsof the Chinese control programme and made recommendationson future research priorities.RESEARCH NEEDS OF THENATIONAL CONTROL PROGRAMMEDespite the large body of experience and expertisegained through 50 years of implementation by thenational schistosomiasis control programme, theultimate goal of eliminating the disease as a publichealth problem in China has not been reached. Thiscalls for further research in various fields.Development of improved tools and strategiesIn view of the experience gained so far, furtherprogress in the control of schistosomiasis in hyperendemicregions and elimination of the disease inlow-endemic regions will depend on sustainedresearch of local conditions and the developmentof improved tools and control strategies in relevantareas. For instance, decreased compliance rates forcase detection due to residents’ unwillingness tocooperate with personnel from antischistosomal stationsfor faecal sample collection, low sensitivity ofthe Kato-Katz technique in areas where the overallendemicity has become low, and the high costs andenvironmental toxicity of the only available molluscicide(i.e. niclosamide) are some of the factorscompromising further progress in schistosomiasiscontrol. In addition, there is a need to standardizethe available serological diagnostic techniques andrapid diagnostic reagents. Furthermore, repeatedlarge-scale administration of praziquantel for morbiditycontrol poses the risk of development ofresistance. The rapid changes in socioeconomic andenvironmental conditions due to market reformsand major ecological transformations can poseadditional challenges for control efforts, especiallywhen the control strategy is largely dependent ona single measure as it is today, i.e. chemotherapy.Effective and sustainable control of schistosomiasiswill remain an elusive goal when these challengesare not tackled.Exploring efficient management structuresWith the ongoing and rapidly expanding marketreform in China, it becomes increasingly difficultto maintain the old infrastructure of organizationsdealing with schistosomiasis control and to adapt thecurrent strategies to the changing needs. Especiallythe re-emerging nature of the disease calls for amore efficient management structure closely cooperatingwith other sectors. There are, for example,pressing needs to further adjust control strategies, toeffectively handle surveillance data so that epidemictrends can be forecast, and to design and implementsound control measures that are adapted to specificeco-epidemiological settings.Predicting the impact of changes inecological factorsIt has been noted that re-emergence of schistosomiasisin the Yangtze River basin in recent years isclosely associated with flooding events that occurredin schistosome-endemic areas along the YangtzeRiver. The floods in 1998, for example, were accompaniedby snail dispersal into areas previously freeof snails, which in turn led to an enlarged S. japonicum-endemicarea. Additionally, global warminghas two potential impacts on the frequency andtransmission dynamics of schistosomiasis. First, itis likely that the potential habitat of O. hupensis willexpand northwards into currently snail-free areas.The underlying reason is that the distribution of theintermediate host snail is limited by the temperatureReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0729

of the coldest month of the year (i.e. January) andis likely to shift north. Hence, disease transmissionis also likely to shift northwards. Second, humansare at an elevated risk of becoming infected with S.japonicum because more schistosomes might developfrom a single snail due to elevated temperatures.Understanding the impact of socioeconomicfactorsIt is conceivable that over the course of the ongoingmarket reforms in China, various social factorswill come into conflict with the traditional measuresagainst schistosomiasis. For example, mobilizationof people involved in schistosomiasis controlactivities needs to be supported by the new systems.Furthermore, regulations should foster intersectoralcollaboration, as integrated control methods needsupport by different governmental sectors, e.g. ministriesof health, agriculture, and infrastructure anddevelopment. Major water-resource developmentand management projects are going hand-in-handwith economic development, and are often implementedin schistosome-endemic areas. There is particularconcern with regard to the construction andoperation of the Three Gorges dam and the Southto-Northwater transfer project. Both projects arelikely to have negative health effects, i.e. spread ofschistosomiasis into previously non-endemic areas;and hence there is a need to develop and implementsound mitigation strategies. In addition, some ofthe anti-flood policies, such as ‘returning reclaimedland into lake, levelling dykes between main levees,and building new towns for resettlement’, will causemany snail-eliminated areas to become snail habitatsagain, which will not only increase the transmissionrisk for the local population but also change thetransmission pattern. It is estimated that large partsof 6670 km 2 of farmland will be transformed backinto lake areas and are at considerable risk of intermediatehost snail infestation.SHORTCOMINGS IN RESEARCHThe following research gaps and needs were identifiedin the Chinese national schistosomiasis controlprogramme.Innovation in theory and techniqueInnovations in theory and techniques could help usto better understand the dynamic epidemiology ofschistosomiasis, as well as to improve the currentcontrol strategies. Additional research is necessaryto develop new knowledge and technology to overcomeproblems such as the weak linkages betweenbasic research and operational research which isblocking the sustainable development of knowledgeand technology for schistosomiasis control.The most important issue that needs to be tackled isthat few products or patents generated from studieson schistosomiasis are available to the control programme.For example, some surveillance techniques(e.g. C6 membrane for cercaria detection) and drugs(e.g. artemisinins) have not been widely used in theendemic areas although both the quick detection ofS. japonicum cercariae in infested water and the efficacyof artemisinins to prevent acute infection withS. japonicum were demonstrated several years agoby Chinese scientists. In another example, the conceptof post-transmission schistosomiasis has beendeveloped since the disease will require medicalcare and attention long after transmission has beeninterrupted in an area. This concept has not beenstudied further in China although transmission wasinterrupted more than a decade ago in many previouslyendemic areas.Financial support for operational researchand implementation of research findingsIn the previous system of planned economy, bothcentral government and local government committedmuch effort on applied research to improve controlactivities. Even during the World Bank LoanProject in the 1990s, about 2% of the loan was usedfor operational research, which helped to monitorand improve the quality of the national controlprogramme. But after the end of the World BankLoan Project, the investment in research activities onschistosomiasis control was reduced by about 90%annually when compared to the amount during theproject. Hence it is urgent to support operationalresearch to cope with the growing needs due to thehigher priority given to schistosomiasis control bythe State Council since 2004. Missing support for theimplementation of research findings is to be blamedfor the fact that not a single diagnostic kit had beenofficially certificated by the end of 2004 althoughvarious diagnostic kits were being widely used indifferent endemic provinces. As a result, qualitycontrol is difficult and the epidemiological data generatedfrom the provincial surveillance systems cannotbe compared to each other.Research capacityResearch capacity is still at a low level. Manyresearch projects operate at a low level of innovation,merely repeating what has been done before byothers and not responding to changes in social andeconomic context or to scientific advances. Thus thecapacity is not able to contribute to improvementand adaptation of control strategies. Other researchprojects follow the global progress in science, but donot contribute to the further development of con-30 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

trol strategies. For example, the technology of geographicinformation systems (GIS) has been usedfor snail habitat surveillance and risk prediction formore than five years in several provincial institutesand universities in China, but its use is still limited toa few institutions and it has not been used in hyperendemicmountainous areas. Also the developmentof a candidate vaccine and genome studies of S.japonicum are limited to only a few laboratories.Internal and external collaborationsRecently, much attention has been paid to collaboration,both with regard to information sharingand technology transfer. For example, the RegionalNetwork on Asian Schistosomiasis (RNAS) involvesscientists from a dozen countries and was initiatedby scientists from China and the Philippineswith the assistance of TDR. The Tropical MedicineResearch Centre (TMRC) was established by the USNational Institutes of Health (NIH) in the ShanghaibasedNational Institute of Parasitic Diseases (IPD).These initiatives are needed since a phenomenonlike global climate change could lead to new foci ofschistosomiasis transmission becoming establishedin previously non-endemic areas of endemic countriesof Asia, but these can only be assessed by internationallycoordinated efforts. Such effects must beincluded in any serious discussion of future epidemiologicaldevelopments, since little knowledge isavailable on the impact of changes in environmentaland social context on a wider scale.RECOMMENDATIONSSchistosomiasis japonica is re-emerging in China,and the top priorities in communicable diseases controlhave been re-defined to place schistosomiasisalongside HIV/AIDS and tuberculosis. New goalsfor schistosomiasis control have been set for the nexttwo five-year periods, together with the adoption ofnational guidelines for control. Transmission is aimedto be under control by 2008, and interrupted by 2015,in the plains and mountainous regions; and controlof infection and transmission are, respectively, scheduledfor 2008 and 2015 in the lake regions. Taking intoaccount the current status of schistosomiasis control,the research priorities mentioned below were recommendedto the Chinese government and WHO missionmembers who visited the field in February 2005.All the priorities have an emphasis on operationalresearch based on available knowledge and supportedby research capacity building. Due to scarceresources, it is recommended that the research prioritiesbe those areas able to improve linkages betweenresearch and control activities, or able to improve thecontrol strategies directly.Operational research relevant to controlstrategyOperational research has an emphasis on new technology,eco-epidemiological determinants, technicalstandardization, social justice on disease burden,and novel products to be implemented in controlprogrammes. The ultimate goal of the proposedresearch is to further focus the control programmeson crucial points to make them more sustainableand cost effective.New technologyBased on the current background and capacity, thefollowing technologies will be developed in order toimprove the national control programme:• Techniques for assessment of treatment effectiveness– looking for special techniques able toidentify the effectiveness of a drug when used inlarge and diverse communities.• Methods for rapid evaluation of communityprevalence – developing rapid evaluationapproaches with combinations of informationgenerated from serum tests, stool examinationand questionnaires.• Morbidity assessment by ultrasonography –standardizing morbidity indicators to provideinformation for evaluation of disease burden.• Methods for detection of infected snails – developingnew and simple detection methods for thelarval stage of S. japonicum inside snails to allowrapid investigation of outbreaks of acute schistosomiasisjaponica.• Techniques for surveillance of Oncomelania snailhabitats – improving both large and small-scalesurveillance of snail habitats by application ofGIS and remote sensing (RS) data, as well as spatialanalysis methods, for use in the national surveillancesystem.Eco-epidemiological determinantsWith regard to the rapidly changing contextualdeterminants of the environment and socioeconomiclevel, the following epidemiological investigationsshould be pursued with an emphasis on eco-epidemiologicalfactors, health care resources and morbidityevaluation. This will also help to improve thecontrol strategies in terms of cost-effectiveness.Investigations of the:• Interaction between schistosomiasis transmissionand ecosystem diversity – to provide informationfor designing control strategies based on environmentalmanagement.• Burden of disease attributable to schistosomiasisand its impact on society – to provide informa-Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0731

tion to policy-makers on the actual disease burdencaused by schistosomiasis in relation to otherconditions by defining and ranking their respectiveburdens with an index termed ‘disabilityadjusted life year’ (DALY) and demonstrating thereductions achievable by schistosomiasis control.• Equity of control services in rural areas – to provideevidence to policy-makers on the ideal allocationof schistosomiasis control and preventionresources.• Importance of animal schistosomiasis in differentenvironmental settings – to understand theroles of different animals in the transmission ofhuman schistosomiasis in different settings andto provide information to policy-makers for usein designing local control strategies.• Animal management models to control transmission– to develop new tools for animalmanagement to prevent contamination of theenvironment by animal faeces.• Impact of environmental changes on snail habitatand schistosomiasis transmission – studies offactors furthering the expansion of snail-endemicareas, such as floods, water resources developmentprojects, and climate changes, to provideevaluation indicators for surveillance systemsand guidance for planning.• Impact of social and economic context on thesuccess of transmission control programmes – toimprove control programmes and adapt them todifferent eco-epidemiological settings.Technical standardizationThe formulation of technically standardized proceduresand policies readily adaptable to cope withchanges in the local socioeconomic and eco-epidemiologicalcontext should be investigated. Studiesin the following areas are proposed:• Standardization of strategy adjustment – determinationof the technical criteria for classificationof epidemic status and technical indicators toadjust the control strategy based on local eco-epidemiologicalstatus.• Procedures for surveillance and management –determination of technical indicators for surveillancefrequency and intensity, as well asstandardization of management and surveillanceprocedures adapted to the local setting. The surveillancesystems should operationally respondto ecological and epidemiological challenges in atimely and cost-effective manner.• Evaluation criteria and control measures for outbreaksurveillance and epidemic status determination– determination of the technical criteriadefining outbreak scale and intensity, and epidemiologicalsituation, in order to provide stand-ardized guidance on disease management,control measures and procedures in a schistosomiasisoutbreak.Novel productsThe development of the following novel productsfor the control of schistosomiasis could provide valuabletools for surveillance and control interventionsin the national control programme.• Novel drugs and treatment schemes – there is aneed to assess the safety, efficacy and cost-effectivenessof alternative treatment schedules anddelivery mechanisms, to further investigate theuse of artemisinins alone and in combinationwith praziquantel, and to screen for novel, orallyactive antischistosomal drugs with a broad spectrumof activity against the juvenile and adultstages of the parasite.• Rapid diagnostic kits – there is a need to standardizetests which are sensitive enough to monitorthe achievements of the national controlprogramme, and to set criteria on sensitivity andspecificity with consideration of species-specificity,shelf life, suitability for quality-controlledindustrial production, intellectual propertyrights, availability and costs.• Molluscicides – there is a need to develop newcompounds with low toxicity to non-targetorganisms which are easy and safe to administer,and to develop new biological controlapproaches to eliminate Oncomelania snails.• Candidate vaccine – a vaccine targeting domesticanimals should be developed which reinforcesthe effect of animal chemotherapy to permanentlyreduce schistosome egg excretion by animals.Research platforms to maintain andstrengthen capacity buildingIt is essential to build up research platforms tostrengthen research capacity and optimize limitedresources by establishing collaboration mechanismsfor sharing information, experience, expertise andresources.Networking between laboratoriesIn order to take advantage of the potential of allinvolved institutions in the country, the setting up ofnetworks between laboratories is urgent in order tostandardize the quality of intervention approachesand diagnostic products and to unify the evaluationcriteria. The following networks are proposed: 1) networkof laboratories working on the development ofdiagnosis kits; 2) network of laboratories involved indrug screening; 3) network of laboratories workingon the development of candidate vaccines.32 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Resource banksIn order to provide standardized reference samplesof various strains of S. japonicum and its intermediatehost snail with the purpose of improvingresearch, surveillance and control strategies, a varietyof resource banks are proposed to be set up,including a schistosomiasis serum bank, a genebank of S. japonicum and Oncomelania snails, and abank of standardized species or strains of S. japonicumand Oncomelania snails.Information databasesIt is crucial to establish computerized databases forinformation sharing and exchange between researchersand personnel involved in the implementationof control programmes to improve the surveillancesystems and allow quick and adequate response toschistosomiasis outbreaks. These databases shouldencompass a schistosomiasis epidemiology database,a snail distribution database, a GIS databaseon schistosomiasis and intermediate snail host distribution,and a research database for knowledgesharing among the scientific community.Regional networkInternational collaboration is a mutually beneficialactivity facilitating progress in general and encouragingthe training of the next generation of researchersand control staff in particular. The RegionalNetwork for Asian Schistosomiasis (RNAS), establishedin 1998, has been very useful in this respectand is providing an excellent platform for teachingand exchange of expertise and experiences onresearch, control and surveillance. The growth ofRNAS will further strengthen collaboration in fieldssuch as training, risk mapping, and advocacy onintegrating schistosomiasis control into programmesfocusing on other parasitic diseases e.g. food-bornetrematodiasis and soil-transmitted helminthiasis.Basic researchAlthough the national schistosomiasis control programmeis proceeding at a good pace, new ideasand innovative methods to consolidate achievementsmade to date are needed. This includes thefields of basic research in the biology of S. japonicumand Oncomelania snails, epidemiology of schistosomiasis,and immunology.Biology of S. japonicum• The genetic basis of human re-infection with S.japonicum – to elucidate the genetic backgroundof human infection and re-infection with S. japonicumin hyper-endemic areas.• Bioinformatics, genome and proteome researchon S. japonicum – to find the specific molecularmarkers and immunological characteristicsof specific genes or antigens of S. japonicum atdifferent stages, to be used for product development(e.g. novel diagnostic tools, drugs andvaccine candidates).Biology of the Oncomelania snail• Systems biology of the interaction between S.japonicum and the Oncomelania snail – to understandthe genetic variation and genetic co-evolutionof S. japonicum and the Oncomelania snail.• Genetic basis of snail susceptibility to S. japonicuminfection – to understand the biological characteristicsand immunological mechanisms ofvariations in susceptibility.• Identification of functional genes – to investigatethe functional genes of Oncomelania for resistanceagainst S. japonicum infection through genomeand proteome studies.Epidemiology of schistosomiasis• The transmission dynamics of schistosomiasisjaponica in different environmental settings – toelucidate schistosomiasis transmission patternsby developing transmission models employingenvironmental, demographic and socioeconomicvariables, to provide the theoretical basis forassessment and estimation of transmission.• Risk and vulnerability analysis of acute schistosomiasisjaponica – to investigate risk factorsleading to increased vulnerability to acuteS. japonicum infection in order to identify mitigationmeasures and develop resilience strategiesagainst acute infections in hyper-endemic areas.• Assessment of socioeconomic impact of schistosomiasison disease burden – to provide anapproach for defining the disease burden ofschistosomiasis and its impact by different socioeconomicdimensions in specific environmentalsettings in order to provide new tools andknowledge to update the control strategy.Immunology of schistosomiasis japonica• Immunological mechanisms in definitive hostsinfected with S. japonicum – to understand theimmune response and immunological mechanismof infection to provide background informationfor field trials of diagnostic kits andvaccine candidates.• Study on drug design by functional genomics –to explore the possibility of discovering noveldrugs through functional genome investigationsto provide new targets based on knowledge ofthe genome and proteome.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0733

References on which this text is basedBergquist NR, Leonardo LR, Mitchell GF. Vaccinelinkedchemotherapy: can schistosomiasis controlbenefit from an integrated approach? Trends inParasitology, 2005, 21:112–117.Bergquist R et al. Blueprint for schistosomiasis vaccinedevelopment. Acta Tropica, 2002, 82:183–192.Bian,Y et al. Market reform: a challenge to publichealth – the case of schistosomiasis control inChina. The International Journal of Health Planning andManagement, 2004, 19(suppl. 1):S79–S94.Chen MG, Feng Z. Schistosomiasis control in China.Parasitology International, 1999, 48:11–19.Chen XY. The challenges and strategies in schistosomiasiscontrol program in China. Acta Tropica, 2002,82:279–282.Chen XY et al. Schistosomiasis control in China: theimpact of a 10-year World Bank Loan Project (1992–2001). Bulletin of the World Health Organaziation, 2005,83:43–48.Chitsulo L et al. The global status of schistosomiasisand its control. Acta Tropica, 2000, 77:41–51.Engels D et al. The global epidemiological situationof schistosomiasis and new approaches to control andresearch. Acta Tropica, 2002, 82:139–146.Hu W et al. Evolutionary and biomedical implicationsof a Schistosoma japonicum complementary DNAresource. Nature Genetics, 2003, 35:139–147.Huang YX, Manderson L. The social and economiccontext and determinants of schistosomiasis japonica.Acta Tropica, 2005, 96:223–231.Ishizaki T, Kamo E, Boehme K. Double-blind studiesof tolerance to praziquantel in Japanese patients withSchistosoma japonicum infections. Bulletin of the WorldHealth Organization, 1979, 57:787–791.Qing-Wu J et al. Morbidity control of schistosomiasisin China. Acta Tropica, 2002, 82:115–125.Li YS et al. Five-year impact of repeated praziquanteltreatment on subclinical morbidity due to Schistosomajaponicum in China. Transactions of the Royal Society ofTropical Medicine and Hygiene, 2002, 96:438–443.McManus DP et al. Schistosome transcriptome analysisat the cutting edge. Trends in Parasitology, 2004,20:301–304.Murray CJL, Lopez AD. The global burden of disease: acomprehensive assessment of mortality and disability fromdiseases, injuries, and risk factors in 1990 and projected to2020. Harvard, Harvard School of Public Health, 1996.Ross AGP et al. Schistosomiasis in the People’sRepublic of China: prospects and challenges forthe 21st century. Clinical Microbiology Reviews, 2001,14:270–295.Taylor MG. Schistosomiasis vaccines: farewell to theGod of Plague? The Journal of Tropical Medicine andHygiene, 1994, 97:257–268.Utzinger J et al. Sustainable schistosomiasis control –the way forward. Lancet, 2003, 362:1932–1934.Utzinger J et al. Conquering schistosomiasis in China:the long march. Acta Tropica, 2005, 96:69–96.Verjovski-Almeida S et al. Schistosome transcriptome:insights and perspectives for functional genomics.Trends in Parasitology, 2004, 20:304–308.The control of schistosomiasis: second report of the WHOexpert committee. Geneva, World Health Organization,1993 (WHO Technical Report Series, No. 830).Wu GL. A historical perspective on the immunodiagnosisof schistosomiasis in China. Acta Tropica, 2002,82:193–198.Xiao SH et al. Recent investigations of artemether,a novel agent for the prevention of schistosomiasisjaponica, mansoni and haematobia. Acta Tropica, 2002,82:175–181.Xiao X et al. Field evaluation of a rapid, visually readcolloidal dye immunofiltration assay for Schistosomajaponicum for screening in areas of low transmission.Bulletin of the World Health Organization, 2005,83:526–533.Yuan HC et al. The 1992–1999 World Bank schistosomiasisresearch initiative in China: outcomeand perspectives. Parasitology International, 2000,49:195–207.Zhou XN et al. Regional network for research, surveillanceand control of Asian schistosomiasis (RNAS).Acta Tropica, 2002, 82:305–311.Zhou XN et al. Application of geographic informationsystems and remote sensing to schistosomiasis controlin China. Acta Tropica, 2001, 79:97–106.Zhou XN et al. The public health significance and controlof schistosomiasis in China – then and now. ActaTropica, 2005, 96:97–105.Zhou XN et al. Potential impact of global warming onthe transmission of schistosomiasis. Chinese Journal ofEpidemiology, 2002, 23:83–86.Zhu YC et al. Development of a rapid, simple dipstickdye immunoassay for schistosomiasis diagnosis.Journal of Immunological Methods, 2002, 266:1–5.34 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

WORKING PAPER 2. Currentsituation and researchneeds for schistosomiasiscontrol in EgyptMohamed Moustafa YoussefSchistosomiasis and Intestinal Parasites ControlDepartment, Ministry of Health and Population, EgyptINTRODUCTIONSchistosomiasis caused by both S. haematobiumand S. mansoni has been considered a major publichealth problem in Egypt for several decades due tohigh prevalence and morbidity of the disease, especiallyamong rural populations. After discovery ofthe parasite’s life cycle in 1915, Egypt started to fightagainst the disease by implementing pilot projectsusing either snail control or chemotherapy.The Ministry of Health and Population (MOHP)began planning for the National SchistosomiasisControl Programme (NSCP) in 1975. The implementationof NSCP started in 1977 through the primaryhealth care (PHC) system.The national control programme is based on selectivepopulation chemotherapy and mass chemotherapysupported by health education and localapplication of chemical molluscicides. These controltools were implemented through NSCP (funded bythe Government of Egypt, the African DevelopmentBank, and the World Bank).The United States Agency for InternationalDevelopment (USAID) and MOHP funded theSchistosomiasis Research Project (SRP) from 1988to 1998 to develop new tools (vaccines, improveddiagnostics, chemotherapy, and epidemiologic, socioeconomicand operational research). After completionof the SRP, USAID awarded a new project toone of the SRP components in need of further effort:the Schistosomiasis Vaccine Development Program(SVDP, 1998–2003), directed towards developing avaccine as an additional tool for control.OBJECTIVES OF THE NSCP• Control of morbidity by reduction of prevalenceand intensity of infection, thereby limitingcomplications.• Protection of young age groups and populationsat risk.• Protection of new settlers in areas of landreclamation.• Prevention of spread of S. mansoni into upperEgypt.CURRENT CONTROL ACTIVITIES(STRATEGIES)• Selective population chemotherapy and masschemotherapy for rural school children and populationsin areas of high prevalence and risk.• Health education and community participation.• Focal snail control.• Environmental improvement.CURRENT SITUATION AND MAINACHIEVEMENTSThe current situation is that S. haematobium has virtuallydisappeared from the Nile Delta but is prevalentin the Upper Egypt governorates, while S. mansoni isprevalent in the Nile Delta governorates. In 1983,the prevalence of S. haematobium was 35%, and thatof S. mansoni 38.6%. By the end of 2004, both infectionshad been significantly reduced below 2%: S.haematobium with a prevalence in Upper Egypt of1.6%; S. mansoni with a prevalence in the Nile Deltagovernorates of 1.9% (table 1; fig. 1). Progress hasbeen achieved in controlling schistosomiasis morbiditythrough improved health education, diagnosis,selective and mass chemotherapy, and snailcontrol within the activities of the PHC system.Table 1: Control of schistosomiasis in EgyptYearPrevalence ofS. haematobiumPrevalence ofS. mansoni* 1935 48.0% 32.0%** 1983 35.0% 38.6%*** 1988 11.9% 16.4%*** 1993 6.6% 14.8%*** 1996 5.0% 11.9%*** 2000 3.0% 4.2%*** 2004 1.6% 1.9%S. haematobium represents prevalence of urinary schistosomiasis in Upper EgyptS. mansoni represents prevalence of intestinal schistosomiasis in Lower Egypt* Data from: Scott, JA. The incidence and distribution of the humanschistosomes in Egypt. American Journal of Hygiene, 1937, 25:566–614.** Data from: Cline BL et al. 1983 Nile Delta schistosomiasis survey: 48 yearsafter Scott. American Journal of Tropical Medicine and Hygiene, 1989,41(1):56–62.*** Data from: Ministry of Health and Population, Endemic Diseases ControlDepartment. Annual reports on schistosomiasis control, 1988–2004.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0735

Figure 1. Control of schistosomiasis in Egypt will need strong commitment and significantresources to maintain the achievements and preventresurgence.Other challenges include:• The hot spots where schistosomiasis transmissionstill occurs, which require a good surveillancesystem.• Limitations in the use of chemical molluscicides(niclosamide, copper sulphate) due to environmentalconditions.• The spread of schistosomiasis into newlyreclaimed areas, and of S. mansoni into UpperEgypt.• The ambitious social and economic agenda asEgypt rapidly develops into a middle incomecountry – poverty related diseases such as schistosomiasishave no place in 21st century Egypt.LESSONS LEARNED FROM THE NSCP• Egypt has demonstrated that schistosomiasiscontrol is a long-term but feasible process if toolsare used on a regular basis.• Experience suggests that the control of schistosomiasisis optimal when specific control tasksare carried out within the PHC system.• External financing by foreign donors helped thenational authorities to accomplish their objectiveswith local staff more rapidly than would otherwisehave been possible.• Egyptian experience in schistosomiasis controldemonstrates that no single approach is sufficientto control schistosomiasis morbidity andtransmission effectively. An integrated approachbased on chemotherapy with supporting healtheducation and snail control wherever appropriateproved to be the ideal intervention.• The local production of praziquantel (tablets andsuspension) was cost effective. The suspensionformulation overcame the problem of treatingyoung children who were unable to swallow thetablet formulation.• A regular surveillance system is key to a successfulcampaign against schistosomiasis.MAJOR CONSTRAINTS ANDCHALLENGESThe current objective of the NSCP is to reduce schistosomiasisto a level where it is no longer a publichealth problem. The available evidence confirmsthat this objective has largely been achieved in mostof the governorates in Egypt. The main challengenow is to:• Keep the disease under control – as long astransmission has not been eradicated, the NSCPRESEARCH NEEDED FOR THE NSCP• Assessment of: the sensitivity and predictivevalue of the hematuria dip-stick for schistosomiasishaematobium; the sensitivity and value of theKato-Katz technique for schistosomiasis mansoniin low prevalence and intensity areas; the needfor development of more sensitive and specificdiagnostic tools for use in low-endemic schistosomiasisareas.• Operational research and a plan of action forcontaining the spread of disease into newlyreclaimed land areas (east of the Suez Canal inSinai, the areas surrounding Nasser lake andToshke). Close monitoring and surveillance inthese areas will be required as the consequencesof new immigration, irrigation and drainageon the spread of schistosomiasis are difficult topredict.• Studies to strengthen the governorate-levelhealth teams for monitoring epidemiological dataand ensuring that data are systematically collected,analysed, and reported accurately and ina timely manner to the national authorities aswell as fed back to local and district level authorities.Surveillance, planning and quality controlsystems at district and local levels also need to bedeveloped.• Studies to assess use of the prevalence of schistosomiasisas an indirect indicator of poverty andpoverty-related diseases.• Studies to prevent the southward spread of S.mansoni.• Studies towards eliminating urinary schistosomiasisin most, if not all, of Egypt.• Monitoring of drug resistance to praziquanteland development of alternative strategies tocontain the spread of drug resistance. Egypt has36 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

used praziquantel as the mainstay of its masschemotherapy strategy for the last decade; thisstrategy has been effective and has contributedto the dramatic decrease in prevalence of thedisease. However, the global decrease in priceof praziquantel is encouraging use of the drugthrough mass chemotherapy for longer thannecessary, thereby increasing the risk of drugresistance.• Prospective randomized trials of the impact ofrepeated mass chemotherapy on susceptibility toviral and bacterial infections.• Continued development of a schistosomiasis vaccineand building of associated research capacity,as well as studies for the development of noninvasiveimmunological tools for detecting schistosomeantigens in urine and stool.• Trials to develop molluscicides of plant origininstead of the currently used chemical molluscicides,to conserve the environment.ONGOING PROGRAMMESAdditional activities for the NSCP involve integratingthe control of schistosomiasis with the control ofintestinal parasitic infection and anaemia in schoolagechildren. This is an extension of the pilot schoolhealth programme implemented for the past sixyears in Behera Governorate, and originally plannedto cover four bordering governorates (Kafr El-Shiekh, Gharbiya, Menoufia and rural Alexandria)selected on the basis of epidemiological and operationalcriteria. After one year of implementationit was decided to expand the scope of the activitiesto cover all the Nile Delta and selected UpperEgypt governorates. The expansion programme is ajoint initiative (involving MOHP, WHO, and ItalianCooperation) to control morbidity related to schistosomiasisand intestinal helminths among school-agechildren (6–12 years), both enrolled and not enrolledin school.The general objective of the expansion programmeis to improve the health and nutritional status ofschool-age children (6–12 years old) through reductionin prevalence and morbidity due to schistosomiasis,fascioliasis and soil-transmitted helminthinfections, strengthening, at the same time, the monitoringsystem of the Schistosomiasis and IntestinalParasites Control Department.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0737

WORKING PAPER 3.Implementation strategiesfor schistosomiasiscontrol in Uganda,and research needsunder the programmeNarcis B Kabatereine,* Simon Brooker,**Artemis Koukounari,*** Fiona Fleming,***Edridah M. Tukahebwa,* Francis Kazibwe,*Yaobi Zhang,*** and Alan Fenwick**** Vector Control Division, Ministry of Health,Kampala, PO Box 1661, Uganda.** Department of Infectious and Tropical Diseases,London School of Hygiene and Tropical Medicine,Keppel Street, London WC1E 7HT, UK.*** Schistosomiasis Control Initiative, Departmentof Infectious Disease Epidemiology, Faculty ofMedicine, Imperial College, Norfolk Place, LondonW2 1PG, UK.INTRODUCTIONInternational effort is currently focused on conditionsthat cause high mortality, for instance HIV/AIDS, tuberculosis, malaria and vaccine preventablediseases. Meanwhile parasitic diseases suchas schistosomiasis and soil transmitted helminths(STH), that lead to significant morbidity especiallyin poor, remote communities, are almost ignored(Savioli et al., 2004). Although their mortality rate islow, the neglected diseases inflict severe disabilitieson almost one billion people around the world especiallyamong the poorest populations in developingcountries (Hunt, 2006). In addition to physical harm,these diseases impose enormous economic burdenson the affected communities due to lost productivity.For example, the combined disability-adjustedlife years (DALY) for schistosomiasis and soil transmittedhelminths (hookworms, Ascaris lumbricoides,Trichuris trichiura) is 43.5 million, second only totuberculosis (46.5 million) and well ahead of malaria(35.7 million) and measles (34.1 million) (Mascie-Taylor and Karim, 2003; WHO, 2002; Chan, 1997).Unless the neglected diseases receive sufficientattention, the Millennium Development Goals forhealth will not be achieved by 2015.Schistosomiasis itself infects about 200 million people,of whom 85% live in sub-Saharan Africa; while652 million people in 76 countries are at risk of gettingthe infection (Chitsulo, 2000). In Uganda, schistosomiasismansoni, the most widespread of thetwo schistosome species parasitic in man, occurs in38 of the 56 districts, while S. haematobium is foundin only 2 f the 38 districts. It is estimated that 16.7million people are at risk of getting infected whileabout 4 million are already infected (Kabatereine etal., 2004). Hookworm is prevalent throughout thecountry, but A. lumbricoides and T. trichiura are geographicallyrestricted to the southwest (Kabatereineet al., 2005). Nearly every child in Uganda is infectedwith at least one of the above helminth species, or isat risk of being infected. Helminth infections are amajor health problem in the country, particularlyfor those living in close proximity to lakes, large rivers,dams and irrigation schemes; they cause severemorbidity that requires urgent intervention.In light of this, a national schistosomiasis and wormcontrol programme was initiated in Uganda in 2003with support from the Schistosomiasis ControlInitiative (SCI). The strategy is to control morbiditythrough mass annual deworming targeted at schoolagechildren and high-risk groups in the endemicareas. Preventive measures focus on raising awarenessabout schistosomiasis and STH infectionsthrough health education, primarily in schools butalso in the wider community. By combining healtheducation and treatment, the aim is that beneficiariesshould experience improvements in health, socreating a demand for treatment and, subsequently,increasing sustainability of the campaign. Duringthe pilot phase in 2003, a total of 437 500 people fromone sub-county in each of the 18 most affected districtsparticipated in the mass treatment campaign(Kabatereine et al., 2006). Approximately 1.3 millionand 3 million people were treated in 2004 and 2005respectively. After this attack phase, which was supportedby SCI funding, it was hoped that infectionlevels would have decreased to an extent where theMinistry of Health and the districts would be able tosustain the programme.Experience gained during the pilot phase has alreadybeen reported (Kabatereine et al., 2006). During evaluationit was felt that the financial records of the programmeshould be analysed to assess the financialcosts of the programme; this will also be reported.The present article aims to describe the organization,management and implementation strategyof the programme in order to identify which districtsare performing well and where programmeperformance requires improvement. The paper willalso facilitate replication of the control interventionin other highly endemic areas. The political will andcommitment of the districts to the programme, andthe perceptions of those implementing the activitiesand receiving the treatment, will be reported. TheMinistry of Health recommends synergy between38 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

different disease control programmes such as lymphaticfilariasis, onchocerciasis, schistosomiasisand STH in order to improve cost–effectiveness andreduce duplications of effort in health care deliverywithin communities where the diseases overlap;progress in this area is also reported. The healthimpact and costs of the programme will be presentedelsewhere.METHODOLOGYIdentification of target populationThe first stage in starting the national control programmewas to use geographical information systems(GIS) to map out the parasitological data thathad been accumulated between 1997 and 2002(Kabatereine et al., 2004). These data were from23 627 people distributed in 271 schools or communitiesacross the country. The derived map showeda wide spread of helminthiasis in the country. Thesecond stage was to overlay this map with environmentaldata to identify the ecological limits oftransmission. Since no transmission occurs in areaswhere the total annual rainfall is less than 900 mmand the altitude is more than 1400 m (Kabatereineet al., 2004), these areas were set aside without needfor further surveys. In the third stage, high spatialresolution landsat satellite data were used to definelakes and rivers. It was shown that prevalence consistentlyexceeded 50% in areas within 5 km oflakes Victoria, Kyoga, and Albert, and the AlbertNile. Thus it was decided that annual mass treatmentwould be provided to the whole populationsin these areas. In communities where the prevalencewas 20% to 50%, only school-age children were toreceive annual mass treatment, and where prevalencewas below 20%, health facility based treatmentwas encouraged and health education intensified.The procedure was such that every person whoreceived praziquantel also received albendazole.To gain experience, control activities in 2003 werelimited to a total of approximately 450 000 peopledistributed in one sub-county of each of the 18 mostaffected districts (Kabatereine et al., 2006). Thereafter,activities in each of the 18 districts were scaled up toinclude two or three more sub-counties and to targetabout 1.5 million people. The final scaling up wascompleted in April 2005, when all the endemic areasin the country in 23 districts implemented the programme,targeting 3.5 million people. Since healthcare delivery in Uganda is devolved to district level,implementation was based at this level. Each districtis divided into health sub-districts headed by amedical officer. There is also a smaller health facilityin most parishes headed by a clinical officer ornurse. All these people participated in implementationof the programme.Programme managementCoordination of the programme was based at theVector Control Division (VCD) of the Ministry ofHealth (MOH), Kampala. The coordination teamworked closely with other relevant departmentsin the MOH, especially the health promotion andeducation divisions, and collaborated with otherministries, particularly of education and local government.Administration of funds and personnel atthe district level were headed by the chief administrativeofficer (CAO). Implementation of the programmewas however overseen by the districtdirector of health services (DDHS), who heads thehealth department at district level. The DDHS wasassisted by his/her staff, mainly the district vectorcontrol officer (DVCO) and the district health educator(DHE). As at national level, the district healthteam collaborated with the education department inimplementation. At the sub-county level, implementationwas managed by the district team assisted bysub-county executive members, community leaders,elders, teachers, community drug distributors(CDDs) and local health workers. Treatment inschools was carried out by class teachers and in communitiesby CDDs who were selected by the concernedcommunities and trained by district trainers(Kabatereine et al., 2006). Supervision was the dutyof the district health team assisted by the nationalcoordinating team.EvaluationRigorous evaluation of the impact of control isessential (Brooker et al., 2004). Determination ofhealth impact was focused on infection levels (prevalenceand intensity) and morbidity (Kabatereine etal., 2006). Detection by microscopy and counting ofS. mansoni eggs in faeces were used to determinethe yearly prevalence and intensity of infection in arandomly selected cohort. Reversibility of morbiditywas monitored in this cohort using a questionnaireadministered by teachers. Morbidity was alsoassessed by ultrasound examination following theNiamey protocol (Richter et al., 2000) and by palpationof liver and spleen according to Vennerwald etal. (2005). Height, weight and other anthropometricmeasurements were used to assess growth in schoolagechildren. The effect of treatment on anaemia wasassessed through measurement of haemoglobin in adrop of blood using a haemoglobinometer.An annual evaluation is carried out to assess programmeperformance (provision, utilization, coverage).All districts were visited; the multistageReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0739

sampling technique was used to select the particularsub-county, schools and communities to be visitedin each district, where specifically designed questionnaireswere administered to the CAO, DDHSand DVCO, and information was collected fromregisters. At sub-county and village levels, only thetop leadership participated, while in schools andcommunities, the random sampling technique wasused to select teachers, CDDs and others to receivetreatment.RESULTS AND ACHIEVEMENTSThe results are shown in tables 1–2 and figures 1–4.Table 1. Number in millions treated annually/biannually, and coverage under the National Bilharzia and Worm ControlProgramme and the Child Health Days Plus programme, 2003–2005NBWCPPZQ+ALBCHD+ (ALB +other treatments)2003 2004 2005May Nov May Nov May NovTreated % Treated % Treated % Treated % Treated % Treated %0.43 79 - - 1.23 88 - - 2.99 87.6 - -- - 7.10 86.5 4.90 40.06 7.6 62.5 8.05 66.0 9.61 77.5NBWCP = National Bilharzia and Worm Control ProgrammeCHD+ = Child Health Days Plus – the NBCWP contributed albendazole for these days and is now working towards full integrationPZQ = praziquantelALB = albendazoleFigure 1. The distribution of S. mansoni at baseline in 2003 and after two years of the annual mass treatment campaign. Notethat the 2006 map was derived from a rapid mapping approach (Brooker et al., 2005)Standard parasitological surveyLot quality assurance sampling parasitological survey (rapid mapping)40 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Figure 2. Effect of two treatments on the prevalence of S. mansoni at differentintensities of infection in children (Kabatereine et al., 2006) Figure 3. Effect of two treatments on the prevalence of hookworm at differentintensities of infection in children (Kabatereine et al., 2006) two years of follow-up (Kabatereine et al., 2006) Figure 4. Changes in ultrasound pattern in S. mansoni infection at baseline and after Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0741

Table 2. Health characteristics (longitudinal data) of children successfully followed up for two years (2003–2005)(Kabatereine et al., 2006)Parameter 2003 2004 2005% infected with S. mansoni (n = 1704) 42.4 (40.0–44.7) 26.8 (24.7–28.9) 17.9 (16.1–19.7)% infected with hookworm (n = 1704) 50.9 (48.6–53.3) 24.1 (22.1–26.2) 10.7 (9.3–12.2)Mean S. mansoni intensity (epg [eggs per gram offaeces])219.6 (191.8–247.4) 73.3 (58.6–88.0) 37.4 (27.4–47.5)Mean hookworm intensity (epg) 309.4 (232.4–386.3) 76.8 (62.9–90.7) 21.9 (13.7–30.1)Mean haemoglobin (g/dL) 11.4 (11.3–11.5) 11.7 (11.6–11.7) 12.0 (11.9–12.1)% anaemic (n = 1852) 51.6 (49.3–53.8) 45.5 (43.3–47.8) 36.2 (34.0–38.4)Ultrasound examination results% with liver grading B (n = 180) 39.4 (32.3–46.6) 9.4 (5.2–13.7) 1.7 (0.0–3.5)% with liver grading in category ‘other’ (n = 180) 1.7 (0.0–3.5) 0.6 (0.0–1.6) 0% with portal vein score 0: ‘normal’ (n = 180) 82.2 (76.6–87.8) 98.0 (95.6–99.9) 96.7 (94.0–99.3)% with portal vein score 4: ‘dilatation’ (n = 180) 17.8 (12.2–23.4) 2.2 (0.1–4.4) 3.3 (0.7–6.0)% with portal vein score 6: ‘marked dilatation’(n=180)0 0 0% with collaterals detected (n = 156) 0 64.5 (57.0–72.0) 0% with ascites detected (n = 156) 0 64.7 (57.2–72.2) 0% with PSL score 0: not enlarged (n = 180) 45.6 (38.3–52.8) 40.0 (32.8–47.2) 47.2 (39.9–54.5)% with PSL score 1: enlarged (n = 180) 41.7 (34.5–48.9) 48.3 (41.0–55.6) 40.0 (32.8–47.2)% with PSL score 2: much enlarged (n = 180) 12.8 (7.9–17.7) 11.7 (7.0–16.4) 12.8 (7.9–17.7)Clinical examination resultsLiverMedian (range) in cm (n = 368)Consistency (n = 366)MSLMCL% Normal% Soft% Firm% Hard0 (0–12)2 (0–5)16.1 (12.4–19.9)20.5 (16.4–24.6)62.5 (57.6–67.5)0.8 (0.0–1.7)0 (0–14)2 (0–5)70.5 (65.8–75.2)26.2 (21.7–30.7)3.2 (1.5–5.1)00 (0–14)0 (0–6)73.7 (69.3–78.3)25.4 (20.9–29.9)0.8 (0.0–1.7)0Irregularity % (n = 367) 0 0 NATender % (n = 358) 2.0 (0.5–3.4) 1.1 (0.0–2.2) 0SpleenMedian (range) in cm MCL (n = 368)MAL (n = 367)Consistency(n = 368)% Normal% Soft% Firm% Hard3 (0–10)0 (0–5)26.1 (21.6–30.6)12.2 (8.9–15.6)58.4 (53.4–63.5)3.2 (1.5–5.1)0 (0–11)0 (0–6)63.3 (58.4–68.2)22.6 (18.3–26.8)14.1 (10.6–17.7)0PSL = longitudinal parasternal line scores; MSL = mid-sternal line; MCL = mid-clavicular line scores; MAL = mid axillary line scores0 (0–10)0 (0–5)NAProgramme achievements• Schistosomiasis and soil transmitted helminthcontrol has been included in the Health sector strategicplan 2006–2011 of the Ministry of Health.• The number of pharmaceutical companies registeredto supply praziquantel increased from onein 2003 to six by 2005.• The price of praziquantel per tablet hasdecreased considerably, from US$ 0.15 in 2003 toUS$ 0.07 in 2005.• Praziquantel has been included on the Ministryof Health’s Essential Drugs list and can now bepurchased on credit by the districts if necessary.• Deworming has become popular and all districtscarry out biannual deworming under the ChildHealth Days programme.42 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

RESEARCH NEEDS• Lack of knowledge, and the poor attitudeand practices of most people in schistosomiasisendemic areas, promote the persistenceof schistosomiasis transmission despite massiveintervention measures. Advocacy for leaders,intensive health education for concernedcommunities, and social mobilization are vitalfor successful disease control, but in order todeliver this package it is important to assess people’sperception of schistosomiasis, their traditionalresponses to the disease, and how thesetraditional responses might affect interventionmeasures. It is important to determine people’sknowledge, attitudes and practices concerningthe causes/transmission, manifestations, treatmentand other interventions before designingappropriate health education messages. Theimpact of such messages should be regularlyevaluated to assess their clarity for the targetpopulation.• Research to consider cultural influences onhealth-seeking behaviour, focusing on individuals’interpretations of their own experiences andthe impact of external influences, if any, is vital.• The Ministry of Health, Uganda, has recommendedsynergy between different disease controlprogrammes such as lymphatic filariasis,onchocerciasis, schistosomiasis, and STH, inorder to improve the cost–effectiveness of healthcare delivery in communities where these diseasesoverlap. To facilitate this approach, it isimportant to provide policy-makers with informationon geographical overlap of the diseasesby collecting existing parasitological data intoa common GIS. This will help to estimate theat-risk populations and determine the rates ofmultiple infection. Studies to ascertain the infrastructureavailable as well as the knowledgeand willingness of the community to take multipledrugs, and of drug distributors to undertakethe distribution of multiple drugs, are vital.Furthermore, drug combinations, the efficacy ofthe various combinations and their safety, shouldbe investigated.• Uganda, like many malaria endemic countries,is currently adopting artemisinin-based combinationdrugs for first-line treatment. Most likelythis will impact on schistosomiasis control sinceartemether is known to affect juvenile schistosomestages while praziquantel affects the adultparasite. It seems however that not much isknown about whether the two drugs should begiven simultaneously and whether there are anypharmacological interactions, or about the sideeffects and cure rates of combination vs. singledrugs. Furthermore, it is important to examinethe protective impact of artemether, either aloneor in combination with praziquantel, on the reinfectionrate.• Community-directed mass treatment ofonchocerciasis and soil-transmitted helminthswith ivermectin and albendazole respectivelyhas been shown to be cost effective in poorremote African communities with inadequatetrained health personnel (Ndyomugyenyi andKabatereine, 2003). The method involves the concernedcommunities as lead stakeholders in solvingtheir own health problems. This approachcontrasts with community-based interventionswhere health workers are the lead agents of theintervention. The community-directed treatmentstrategy is built on the experience of communitymembers and enhances their decision-makingand problem-solving capacity. The communityplans the drug distribution, decides on themethod of distribution acceptable to them (e.g.central place or household), and when to distribute.This enhances treatment coverage andpromotes the chances of sustainability. Such astrategy should be tested regarding the distributionof praziquantel.• Assessment of the costs and impact of large-scalecontrol programmes is vital, not only to demonstratethe health benefits but also to assessthe cost–effectiveness and show that limitedresources have been adequately utilized. Costanalysis might also be used to identify possiblefinancial barriers and opportunities importantto long-term sustainability of the programme.Comparisons of the cost–effectiveness of schistosomiasiscontrol implemented alone vs. whenit is integrated with other disease control programmesare vital for decision-makers.• Although several well controlled clinical trialshave demonstrated that praziquantel treatmentreduces morbidity related infections (Frenzel etal., 1999; Richter, 2003; Vennervald et al., 2005),it is not known if the results from such clinicaltrials can be replicated under a large-scale controlprogramme. Previous evaluations of mostreported large-scale interventions were usuallymade on the basis of infection indicators ratherthan morbidity indicators (Brinkmann et al.,1988; Engels et al., 1994). Research efforts to demonstratethe health benefit and performance (coverage)of large-scale community-directed masstreatment campaigns are therefore important(Brooker et al., 2004).• WHO has recently adopted a policy of usingpraziquantel in pregnant women (Allen et al.,2002). However, the efficacy of the drug inpregnancy has not been tested. Earlier studiesReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0743

showed that successful elimination of the parasitesrequires an interplay between praziquanteland the host immune system (Brindley and Sher,1987), and yet pregnancy is known to impairprotective responses, e.g. pregnancy promoteschanges from TH1 to TH2 regulatory cells (Sasakiet al., 2004). The impact of such immune changes,especially on the efficacy of the drug in expectantmothers, should be investigated.• Rapid and accurate identification of the communitiesat highest risk of morbidity from schistosomiasisis key to sustainable control (Brooker etal., 2005). Although a school questionnaire caneffectively and inexpensively identify communitieswith a high prevalence of S. haematobium(Lengeler, Utzinger and Tanner, 2002), parasitologicalscreening remains the preferred optionfor S. mansoni. To reduce screening costs andtime, reliable data need to be collected as rapidlyand cheaply as possible. Lot quality assurancesampling, which is increasingly being usedto monitor other health interventions e.g. vaccinationcoverage (Tawfik et al., 2001), and to estimateprevalence e.g. of HTLV-1 (Houinato et al.,2002) and sleeping sickness (Hutin et al., 2004),might play such a role. Recent work has demonstratedthe validity, applicability and cost–effectivenessof this method for monitoring S. mansoniinfections in Uganda (Brooker et al., 2005), andfurther work is recommended to investigate themethod in different settings.• The majority of studies on schistosomiasis prevalence,intensity, and associated disease burdenbefore and after treatment focus on adults and/or school-age children (Vennervald et al., 2005;Kabatereine et al., 2003). Surprisingly little attentionhas been given to pre-school children, particularlyinfants of 3 years or less. Large-scalemass treatment campaigns usually ignore thisage group (Kabatereine et al., 2005), and eventhe WHO treatment tablet pole does not caterfor them (Montresor et al., 2005). Schistosomeinfections in this very young age group are generallythought to be rare, and have frequentlybeen overlooked based on the reasoning thattheir water contact frequency is highly negligible(Jordan and Webbe, 1993). While this maygenerally be true, passive water contact of thisage group originating from the behaviour ofthe mothers is sometimes high. This age groupshould in future be included in epidemiologicaland morbidity studies and should be consideredin mass treatment campaigns in communitiesfound to be at high risk.ReferencesAllen H et al. New policies for using antihelmintics inhigh risk groups. Trends in Parasitology, 2002, 18:381-382.Brindley PJ, Sher A. The chemotherapeutic effect ofpraziquantel against Schistosoma mansoni is dependenton host antibody response. Journal of Immunology,1987, 139:215–220.Brinkmann UK et al. An evaluation of sampling methodswithin communities and the validity of parasitologicalexamination techniques in the field. TropicalMedicine and Parasitology, 1988, 39(2):162–166.Brooker S, et al. Evaluating the epidemiologicalimpact of national control programmes for helminths.Trends in Parasitology, 2004, 20:537–545.Brooker S et al. Rapid assessment of Schistosoma mansoni:the validity, applicability and cost-effectivenessof the Lot Quality Assurance Sampling methodin Uganda. Tropical Medicine and International Health,2005, 10:647–658.Chan MS. The global burden of intestinal nematodeinfections – fifty years on. Parasitology Today, 1997,13:438–443.Chitsulo L et al. The global status of schistosomiasisand its control. Acta Tropica, 2000, 77(1):41-51.Engels D et al. Control of Schistosoma mansoni andintestinal helminths: 8-year follow-up of an urbanschool programme in Bujumbura, Burundi. ActaTropica, 1994, 58(2):127–140.Frenzel K et al. Evidence for a long-term effect of asingle dose of praziquantel on Schistosoma mansoni-inducedhepatosplenic lesions in northern Uganda.American Journal of Tropical Medicine and Hygiene, 1999,60:927–931.Houinato D et al. Interest of LQAS method in the surveyof HTLV-1 infection in Benin (West Africa). Journalof Clinical Epidemiology, 2002, 55:192–196.Hunt Paul. Report of the Special Rapporteur on the rightof everyone to the enjoyment of the highest attainablestandard of physical and mental health: mission to Uganda.United Nations, 19 January 2006 (E/CN.4/2006/48/Add.2).Hutin YJ et al. Trypanosoma brucei gambiensetrypanosomiasis in Terego county, Northern Uganda,1996. A lot quality assurance sampling survey.American Journal of Tropical Medicine and Hygiene, 2004,70:390–394.Jordan P, Webbe, G. Epidemiology. In: Jordan P,Webbe G, Sturrock R, eds. Human schistosomiasis.Cambridge, CAB International, 1993:87–138.44 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Kabatereine NB et al. Progress towards countrywidecontrol of schistosomiasis and soil-transmittedhelminthiasis in Uganda. Transactions of the RoyalSociety of Tropical Medicine and Hygiene, 2006, 100:208–215.Kabatereine NB et al. Soil-transmitted helminthiasisin Uganda: epidemiology and cost of control. TropicalMedicine and International Health, 2005, 10:1-3.Kabatereine NB et al. Epidemiology and geography ofSchistosoma mansoni in Uganda: implications for planningcontrol. Tropical Medicine and International Health,2004, 9:372–380.Kabatereine NB et al. Efficacy and side effectsof praziquantel treatment in a highly endemicSchistosoma mansoni focus at lake Albert, Uganda.Transactions of the Royal Society of Tropical Medicine andHygiene, 2003, 97:599–603.Lengeler C, Utzinger J, Tanner M. Questionnaires forrapid screening of schistosomiasis in sub-SaharanAfrica. Bulletin of the World Health Organization, 2002,80:235–242.Mascie-Taylor CG, Karim E. The burden of chronicdisease. Science, 2003, 302:1921-1922.Monstresor A et al. The WHO dose pole for theadministration of praziquantel is also accurate in nonAfrican populations. Transactions of the Royal Society ofTropical Medicine and Hygiene, 2005, 99:78–81.Ndyomugyenyi R, Kabatereine NB. Integrated community-directedtreatment for the control of onchocerciasis,schistosomiasis and intestinal helminthinfections in Uganda: advantages and disadvantages.Tropical Medicine and International Health, 2003, 8:997–1004.Richter J. The impact of chemotherapy on morbiditydue to schistosomiasis. Acta Tropica, 2003, 86:161-183.Richter J et al. Ultrasound in schistosomiasis. A practicalguide to the standardized use of ultrasonography for theassessment of schistosomiasis-related morbidity. Geneva,World Health Organization, 2000 (TDR/STR/SCH00.1).Sasaki Y et al. Decidual and peripheral bloodCD4+CD25+ regulatory T cells in early pregnancysubjects and spontaneous abortion cases. MolecularHuman Reproduction, 2004, 10(5):347–353.Savioli L et al. Progress in the intervention and controlof schistosomiasis and soil-transmitted helminthiasis.Parasitology International, 2004, 53:103–113.Tawfik Y, Hoque S, Siddiqi M. Using lot quality assurancesampling to improve immunization coverage inBangladesh. Bulletin of the World Health Organization,2001, 79(6):501-505.Vennervald BJ et al. Regression of hepatosplenomegalyin Kenyan school-aged children after praziquanteltreatment and three years of greatly reduced exposureto Schistosoma mansoni. Transactions of the RoyalSociety of Tropical Medicine and Hygiene, 2005, 99:150–160.World Health Organization. Prevention and Controlof Schistosomiasis and Soil-Transmitted Helminthiasis.Report of a WHO Expert Committee. Geneva, WorldHealth Organization, 2002 (WHO Technical ReportSeries, No. 912).Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0745

WORKING PAPER 4.Quantification ofdisease burden dueto schistosomiasisCharles H. KingCenter for Global Health and Diseases, Case WesternReserve University School of Medicine, Cleveland, OhioUSA.INTRODUCTIONAt the close of 2005, schistosomiasis remains highlyprevalent in large parts of the world, representing acontinuing challenge to health planners in affectedcountries ranging from Africa to the Middle East,the Philippines, mainland Asia, the Caribbean states,and South America. Over time, the relative impactof schistosomiasis on the world health burden hasbeen intensely debated by proponents of differenthealth agendas. In the past fifty years, schistosomiasishas been variously categorized as the least to thevery worst of infectious disease burdens in affectedareas. 1,2To those unfamiliar with the field, this issue appearsunresolved, and the global priority for schistosomiasiscontrol remains in question. As assessed criticallyby Farooq over 50 years ago: “… this insidious andchronic disease [schistosomiasis] lacks the dramausually associated with other spectacular infectionsin the affected areas, and does not attract the attentionthat it deserves”. 2Since the last meeting of the Schistosomiasis WorkingGroup, wide-ranging efforts have been made to betterquantify the global burden of disease that isattributable to schistosomiasis. The approach hasbeen based on systematic examination of the availableevidence on infection prevalence and individualdisease impact, 3–6 in combination with the planningof focused data acquisition during the course ofnewly introduced, large-scale national and regionalcontrol programmes. 7,8 The purpose of these jointefforts has been to provide better evidence-basedestimates of schistosomiasis-associated morbidityand mortality in order to inform and facilitate ourpublic health deliberations.In this context, it is important to decide how to speakof schistosomiasis – is it the infection per se that weare considering in our policy decisions? Or is it thedisease, that is ultimately caused by presence of theinfection? It is apparent that any level of schistosomeinfection is associated with significant inflammationin the human host, leading to non-trivial subclinicalmorbidity in many persons, clinical morbidity insome, and premature mortality among a small proportionof those infected.The range of symptoms and physical findingsassociated with chronic schistosomiasis due toS. haematobium, S. mansoni, or S. japonicum is welldescribed in published literature. 9–12 However, thedisabling effects of the clinical events are not welldefined when viewed in terms of their net impacton a patient’s physical and social performance.Considering the WHO definition of health as a‘state of complete physical, mental and social wellbeing’,there is concern that earlier ‘objective’ assessmentsof schistosomiasis-related health burden mayhave undervalued its importance to public health.Infection outcomes without immediate health caredemands have been discounted, 13 although, from apersonal and societal perspective, many of the schistosomiasis-relatedphysical effects have significantsocial and economic impact. Where it has provendifficult to disaggregate the contribution of schistosomiasisto disease states such as anaemia andundernutrition in the face of multiple infections ordisease processes, the analytic approach has oftenbeen to pass over these conditions as ‘not clearlyattributable’ to schistosomiasis alone.From the policy standpoint, allocation of scarcehealth resources is felt to require an objective comparisonof the relative impact of different healthconditions, with the need to allocate these resourcesas efficiently as possible in order to effect overallimprovements in health. In this type of analysis, thetime frame and analytic perspective of the analysiscan strongly influence the decisions made aboutthe value of intervention. For this reason, a carefulreassessment of schistosomiasis-associated diseaseburden, taken from multiple perspectives, becomesvery appropriate.WHY A VALID QUANTIFICATION OFDISEASE BURDEN IS IMPORTANTThe growing commitment to monitoring health levelsand to rational allocation of health resourceshas led to a proliferation of techniques to evaluatehealth and health outcomes among individuals andwithin populations. 14 The quality-adjusted life year(QALY) and disability-adjusted life year (DALY)assessments are time-based approaches that seekto quantify the aggregate lifelong impacts of differenthealth states or diseases on overall health orhealth burden. They provide a framework for utilitariananalysis of resource allocation whereby overallhealth can be ‘maximized’ per dollar spent across46 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

a population or a given treatment programme. The1990–1996 evolution of the Global Burden of DiseaseProject, 15 jointly sponsored by WHO and the WorldBank, has led to widespread adoption of the DALYas a metric in many sectors of international healthplanning.This approach is not without controversy; 16–19 detractorspoint out that health-adjusted life year measures,while attempting to be objective, ‘…fail to givepriority to those who are worst off, …discriminateagainst people with limited treatment potential,…and they fail to account for qualitative differencesin treatment outcomes (e.g. life-saving versus healthimproving)’. 14 There is inherent age-bias in the calculationof both QALYs and DALYs, which is moreexplicit in the age-weighting scheme used in calculatingDALYs. 15 The abstraction of disease-specificdisability weights, without reference to social,cultural, or environmental context, has been seenas leading to significant underestimation of diseaseburden in disadvantaged populations. 18Nevertheless, it is important now to review andrevise approaches to the estimation of disease burdensbecause of the de facto prioritization of publichealth efforts based on perceived cost-effectivenessof interventions. The goal of the DALY initiativewas to ‘decouple epidemiological assessment fromadvocacy so that estimates of the mortality or disabilityfrom a condition are developed as objectivelyas possible’. 15 Yet as the senior investigator states,‘Paradoxically, if a measure is used, it will influencepolicy debate, permeate the thinking of decisionmakersand become part of the culture of the subject….DALYsare [now] used normatively, and thusbecome [the] normative measures’.In their 1996 estimates of the global burden of disease,15 the WHO and World Bank published agespecificdisability weights for schistosomiasis thatranged from 0.005–0.006, on a par for disability withthe mildly stigmatizing disease of facial vitiligo.These disability weights were derived by a deliberativepanel, convened in Geneva in 1995, using aperson-trade-off protocol (PTO) to compare a widearray of disabling conditions. 15 While that processhad reproducibility in terms of ordering the severityof disability caused by different infectious and noninfectiousconditions, the magnitude of the weightsfor schistosomiasis and other helminthic infectionsderived in this ‘Delphi’ (or expert-based) methodseemed exceptionally low to many workers in thefield of parasitic infectious diseases. A lack of familiarityof the panel with the physical consequencesof schistosomiasis may have led them to seriouslyunderestimate the disabling impact of human schistosomiasis.As Murray has noted, ‘Knowledge of ahealth state has a profound effect on preference evaluations.… knowledge leads to lower utility weights(death is zero)….’. 15In their summary analysis, the conveners of theDALY programme agreed that: ‘The [Global Burdenof Disease] and the calculation of DALYs linkedwith it must be viewed as an ongoing process withmethods, data and results in steady evolution’. 15 It isfor this reason that the DALYs assigned to schistosomiasisnow deserve reassessment.HOW SHOULD WE CAPTURE THE‘BURDEN OF DISEASE’?Quality of life involves physical, social, emotional,and cognitive spheres, as well as presence or absenceof pain or discomfort, vitality, and one’s overallsense of well-being. Assessment of the impact ofdisease from the patient’s perspective is not alwayswell correlated with ‘objective’ findings measuredon a clinical basis. Standardized interview tools formeasuring disease impact on health-related qualityof life have been developed in North Americaand Western Europe. However, there are major hurdlesin applying these findings to other cultures.‘The notion of quality of life is, itself, a cultural construct…It cannot be assumed to have universal relevanceor meaning’. 20Case descriptions and case series can form the initialempiric basis for disease description, but theydo not determine the actual population-based burdenof disease. Older, unstructured reviews and diseaseburden estimates were often swayed by theextremes of disease that had been reported in the literature.Severe, but rare complications of a commondisease will actually contribute a very small incrementto the community burden of disease, whereasa common complication of a common disease willhave a substantial effect on determining aggregatecommunity disease burden.If cost–utility analysis and comparisons across multipledisease conditions are to be valid, it is importantto have a good, evidence-based picture of the prevalenceof disease, as well as the disease burden for the‘average’ person having the condition under study. 14Current epidemiological investigation into schistosomiasisdisease burden focuses on refiningestimates of the key components of this burden estimation.For DALY estimation, the necessary componentsof the equation are:DALY = YLL + YLDReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0747

where YLL is the years of life in a population lostto premature mortality attributable to schistosomiasis,and YLD is the healthy years of life lost due todisability attributable to schistosomiasis. 15,18 YLD, inturn, is estimated by:YLD = D x Lwhere L is the duration of the disability and D is anassigned disability weight for the ‘average person’with schistosomiasis. (In the standard DALY analysis,adjustments are also made to this product on thebasis of age at onset, and the discounting of futuredisability states 15 ).From this standpoint, it is essential to have accurateestimates of schistosomiasis prevalence on aregional and global basis, and of cause-specific mortalityrelated to schistosome infection. In addition,it is necessary to have accurate estimates of the disablingeffect of schistosomiasis, and of the averageduration of infection. The latter has been assessedby one of three basic approaches described below.Observer-based estimates of disease burdenIn the past, much population-based field researchhas been focused on measuring easily quantifiableoutcomes, e.g. infection prevalence and intensity,along with liver size, splenomegaly, haematuria,ultrasound abnormalities, etc. For the latter outcomes,there was the implicit assumption that these‘objective’ abnormalities implied disability. Somemeasures, such as hepatosplenomegaly and haematuria,were seen to be more common with heavyinfection, and infection intensity was then taken asa proxy for morbidity risk in formulating diseasecontrolstrategies. 21,22 Yet we, and others, have cometo observe that infection proxies do not necessarilymap one-to-one with morbidity states (see e.g. 23 ),and these do not necessarily map one-to-one withdisability outcomes. 24Subjective estimates of disease burdenIt is apparent that some schistosomiasis-relatedoutcomes are not intensity related, some have athreshold effect, and some are so ubiquitous that‘uninfecteds’ in a population are the abnormal. Theimpact of infection on an individual’s quality of lifemay be hard to assess due to the long chronicity ofinfection and adaptation to the presence of disease.Parasitic reinfection is frequently so common that anindividual at risk spends half his or her life infected.Without treatment, or personal reference to the benefitsof the infection-free state, it may be difficultfor the affected person to define the impact of infectionon his or her health status. There may be ceilingeffects for the impact of therapy due to the presenceof co-morbidities, and cultural differences in theinterpretation of illness. In addition, US/Europeantechniques for estimating economic impact may notreadily transfer to the setting where subjects surviveon subsistence agriculture supplemented by onlyoccasional cash income. Thus ‘subjective’ patientpreferenceinstruments may not fully capture theimpact of infection on disease burden.Expert estimation of disease burdenThe Global Burden of Disease (GBD) programmehas attempted to derive disability weights throughthe deliberations of a series of expert panels whocompared hundreds of disease states to 22 benchmarkdisease states that had been previously rankedby consensus. 15 In this ranking, schistosomiasis wasjudged to be on a par with the least disabling benchmark,vitiligo, with a median disability weight of0.005. This weight was meant to incorporate anassessment of both the physical state of the infectedindividual and society’s responses (preferences) tothe disease state. 15 The practical implication for economicanalysis is that the panel considered the averageperson with schistosomiasis to be one-half ofone per cent disabled by his or her infection. Theassigned weight was substantially less than theweight for malnutrition (0.02), watery diarrhoea(0.045), or moderate/severe anaemia (0.011 to 0.09).Although schistosomiasis had been known to becausative in the formation of these disease states,their contribution to schistosomiasis-related disabilityestimates appears to have been overlooked in thefinal schistosomiasis disability weight estimate.In an alternative type of expert-based approach,Kirigia 25 polled schistosomiasis experts using structuredquestionnaires to derive estimates of theannual probability of progressing from minimalto severe schistosomiasis-associated disease in theendemic setting. Subsequent life-path analysis, comparedto available statistics on the prevalence ofmild, moderate, and severe schistosomiasis-associatedstates, indicated that these expert estimates,although based on long familiarity with the consequencesof schistosomiasis, were substantially toohigh.Therefore, there are limitations to all of theseapproaches to disability estimation. It has beenpersuasively argued that if cost–utility analysis isto be taken from the societal perspective, in alignmentwith the WHO definition of health, then theimpact of infection should be based on the subjective,or patient-preference, approach to assessing theimpact of disease. 26 Given a review of the available48 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

data, most would agree that there is measurable detrimentdue to schistosome infection, and significantreduction in quality of life among infected populationsdue to its physical and social impact. In thissense, the context of morbidity may be as importantas the nature and extent of the physical processinvolved.Currently, there are limitations to using eitherexpert-based or the alternative ‘objective’ or ‘subjective’approaches to estimating disease burden due toschistosomiasis. However, it is likely that our workingestimates can be improved through structuredreconsideration of established and emerging epidemiologicaldata, and through integrated assessmentof the objective, subjective, and societal factors thatare determinants of disability in schistosomiasis.REASSESSING THE BURDEN OFDISEASE DUE TO SCHISTOSOMIASISGlobal estimates for the burden of disease due toschistosomiasis are critically tied to:• Prevalence of the infection• Duration of the infection• Years of life lost to the infection• The age at which the condition is assessed• The disability attributed to the ‘average’ personwith the disease state being considered.In order to avoid some of the limitations of the previousGBD assessment, it is important to maintainan appreciation of the differences between acute,infection-related morbidity and chronic, cumulativemorbidity. The assessment should include an estimationof the schistosomiasis-attributable fractionof important chronic morbidity states – chronic diarrhoea,abdominal pain, anaemia, undernutrition,and cognitive impairment – that were previouslydisaggregated from their underlying causes in theGBD assessment.Where there has often been overvaluation of themortality effect (which is more easily measured asa ‘hard’ endpoint), there is often undervaluationof chronic morbidity, in light of individual adaptationto chronic disease. There is need to appreciatethe time-lag in expression of severe schistosomiasis-relateddisease. If age-weighting is used, itshould incorporate an appreciation that the disabilityimpact between the ages of 20 and 30 yearsis a delayed consequence of earlier infection statusbetween the ages of 10 and 20 years.REASSESSMENT OF THEPREVALENCE OF INFECTION ANDOF SCHISTOSOMIASIS-RELATEDCLINICAL OUTCOMESNew work has extended WHO’s worldwide andcountry-specific schistosomiasis prevalence estimatespublished by Chitsulo and colleagues in2000. 27 Their estimates, which indicated 193 millioncases worldwide, with 652 individuals at riskfor infection in 1995, have been recast for mid-2003,indicating at least 779 million now at risk and 207million now infected. 28 A careful review commissionedby the WHO Expert Committee (performedby van der Werf and colleagues 6 ) of published andunpublished data for sub-Saharan Africa, the regioncontaining > 85% of all global schistosomiasis cases,indicates an estimated 112 million cases of S. haematobiumand 54 million cases of S. mansoni in thisregion. Where possible, infection prevalence wasthen linked to the concurrent risk of schistosomiasisassociatedsigns and symptoms, i.e. as morbidity outcomes.This was based on observed links betweenprevalence, its association with the observed distributionof infection intensity, and the associationbetween intensity and risk for clinical disease, withadjustment for the heterogeneity of infection acrosslarger reporting units.From these projections, 70 million persons were estimatedto have haematuria in the last two weeks dueto S. haematobium, with 88 million and 18 millionhaving minor or major bladder pathology, respectively.For S. mansoni, 4.4 million were estimated tohave had associated blood in the stool, while 8.5 millionhad associated hepatomegaly.For other outcomes, including schistosomiasisattributablemortality, reliable estimates could notbe provided due to the divergence or scarcity of theavailable data. 6A recent, independent disease burden assessment,contrasting the findings of the GBD 15 and the WHOExpert Committee initiatives, 6 indicated that theirseparate estimates of infection prevalence were infact consistent. However, their estimates of schistosomiasis-attributablemortality varied by a factorof more than 10, reflecting a large degree of uncertaintyin this area. 4 It was also noted that ‘There is noagreement regarding the list of sequelae that shouldbe included in morbidity assessments. The limitedavailability of empirical evidence about the populationdistribution and duration of different non-fatalhealth outcomes… remains a strong limiting factorin the final selection of sequelae [that are to be consideredin morbidity burden assessment]’.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0749

Table 1. Disability-associated outcomes significantly linked with schistosomiasis in meta-analysis 3Significantly associated with schistosomeinfectionSignificantly greater with higherintensity infectionPossibly associated, but insufficientdata for meta-analysis, or mixedmethodologies used across studiesAnaemia Anaemia Decreased religious activityWeight-for-height deficit Skin-fold thickness deficit Decreased personal careLimited exercise duration Diarrhoea Increased health care visitsDiarrhoeaDecreased cognitionHistory of abdominal or pelvic painDecreased work yieldExercise intoleranceCurrently, the Schistosomiasis Control Initiativehas initiated schistosomiasis control programmesin Uganda, Tanzania, Zambia, Burkina Faso, Niger,and Mali. Additional population-based programmeshave been started in Zanzibar and Cameroon. Theuse of standard operating procedures among programmesis expected to yield extensive data oninfectious burden and associated morbidity in thevarious countries, as well as greater detail on theimpact of long-term treatment on morbidity outcomes,including ‘indirect morbidities’ such as malnutrition,anaemia and school performance. 7,8META-ANALYSIS OF DISABILITY-RELATED OUTCOMES INSCHISTOSOMIASISAlthough the abovementioned analyses providemore precise data on the world burden of infectionand infection-associated clinical findings, it must beconsidered that there is not necessarily a direct associationbetween the presence of a physical deficit orabnormality and a related disability or handicap.Much of the impact of disease depends on the individual’sadaptation to the morbidity, 15 the presenceor absence of co-morbidities, the social context andpotential for stigmatization, and the availability ofsupport resources. 18With this in mind, a separate meta-analysis of availableevidence has been performed for schistosomiasis-relatedoutcomes viewed to be closely related todisability risk among affected populations. 3 Afterextensive structured review of the published andavailable unpublished literature from 1921–2002,135 papers with data linked to individual performanceoutcomes were abstracted and compared. Theoutcomes of interest included exercise intolerance,exercise/play deficit, work yield deficit, houseworkdeficit, personal care deficit, religious activitydeficit, school attendance deficit, school performancedeficit, cognition deficit, increased health careneeds. In addition, studies that quantified the prevalenceor severity of disability-linked morbidities, i.e.abdominal pain, diarrhoea, dysuria, infertility, oxygenuptake (VO 2 max.) deficit, anaemia, malnutrition(including deficits in weight, height, weight forheight, skin fold thickness, per cent body fat, andserum protein), were compared and integrated forsummary estimates of infection impact on personalperformance or conditions previously linked to poorperformance.Results indicated a significant association betweenthe presence of schistosomiasis infection and anaemia,chronic pain, exercise intolerance, and undernutrition,as compared to local comparison groups(table 1). Based on the summary effect size for haemoglobinreduction and the weighted odds-ratioestimates for categorical outcomes, a proxy schistosomiasis-attributabledisability weight couldbe derived. In place of the 0.005 disability weightapplied to schistosomiasis by the Global Burden ofDisease programme, a 2–15% disability was suggestedin the various functional dimensions of theaverage person with schistosomiasis.IMPLICATIONS OF REVISINGPREVALENCE ESTIMATES ANDDISABILITY WEIGHTSThe foregoing estimates yield a significant differencein the quantitative assessment of disease burdendue to schistosomiasis. If we are to continueto work within the DALY system, despite its recognizedlimitations, then it is appropriate to utilizethese newer, evidence-based estimates to impute amore sophisticated estimate of disease burden whenperforming cost-utility analysis.The improved, upwardly revised area and countryspecificestimates of infection prevalence increaseDALY estimates directly. The suggested 4 to 30-foldincrease in schistosomiasis-related disability weightalso proportionately increases DALY estimates in adirect manner.50 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

As noted earlier, there is controversy as to whetherage-weighting of DALY outcomes is appropriate inschistosomiasis, given the chronicity of infection andthe long delay between peak infection and the onsetof the more severe forms of morbidity. Eliminationof the controversial DALY age-weighting system,which was debated in the GBD programme, 15 willfurther increase the DALY estimates for schistosomiasisdue to the higher prevalence of infectionamong children.In terms of global health burden, the resulting netchange in DALY estimates for schistosomiasis willnot likely change its ranking behind malaria and TBin overall impact. 4,29 However, the change in disabilityweighting does significantly decrease the cost ofintervention per DALY prevented, reducing the estimatefrom USD 22 to USD 1–6 per DALY averted.This compares favourably with the ExpandedProgramme for Immunization (EPI, USD 12–17 perDALY averted) and with other health initiatives interms of cost for disability prevented.UNANSWERED QUESTIONS ANDRESEARCH PRIORITIESAs the number of large-scale schistosomiasis controlprogrammes in sub-Saharan Africa increases,a better definition of basic epidemiology and treatmentbenefits will emerge for this area. Formal analysis7 should allow comparison to treatment benefitsin more developed areas such as Egypt, Brazil andChina, 30,31 where control programmes have been inplace for a number of decades. It is expected thatextended analysis of programme outcomes will providebetter insight into the impact of similar treatmentstrategies in different settings, and their specificimpact on ‘indirect morbidities’ such as nutritionand school performance. 4 New areas for extendedstudy should include schistosomiasis effects on cognition,maternal and fetal survival, human sexualperformance, and fertility. Given the strong socialstigma attached to infertility, more information isneeded on this aspect of infection-associated morbidity.Further, given the important linkage betweenschistosomiasis risk and socioeconomic status, thereis need to better define the levels of individual, family,and community impact of treatment.It is important to know what socially importantspheres of personal function are actually affectedby schistosomiasis infection. A better definition isneeded of subjective perceptions of schistosomiasis-associatedacute and chronic outcomes. 24 In particular,we need to gauge the differences in patients’own perceptions about schistosomiasis and theirpreferences before and after therapy.Miguel and Kremer 32 have emphasized the potentialindirect benefits or ‘externalities’ of mass treatmentstrategies for schistosomiasis and soil-transmittedhelminths. Their analysis indicates that helminthtreatment programmes can generate communitybenefits beyond individual response to treatment.These can include reductions in community transmissionand improved school attendance. In assessingwillingness to pay, it is not clear whether effectivecommunity treatment will lead to a demand for furthertreatment. 8 Past experience in hookworm eradicationprogrammes in poor rural areas of the USsuggests that deworming may be associated withultimate improvement in local levels of educationand income. 33 Well-designed studies documentingsuch an effect in developing countries would be apowerful argument towards the ultimate ‘sustainability’of parasite control.Finally, the question remains whether the DALY isthe appropriate metric of schistosomiasis disability.Does common ignorance of the disease and its complicationsperpetuate its status as a neglected diseaseof underserved populations? Is the age-weightingsystem used for DALY calculations appropriatefor a chronic condition that may persist for halfan expected lifetime, with significant lags betweenprevalence and the development of advanced infection-associateddisease?References1. Forsyth DM. A longitudinal study of endemic urinaryschistosomiasis in a small East African community.Bulletin of the World Health Organization,1969, 40:771-783.2. Farooq M. Medical and economic importance ofschistosomiasis. Journal of Tropical Medicine andHygiene, 1964, 67:105–112.3. King CH, Dickman K, Tisch DJ. Reassessment ofthe cost of chronic helmintic infection: a metaanalysisof disability-related outcomes in endemicschistosomiasis. Lancet, 2005, 365:1561-1569.4. Michaud CA, Gordon WS, Reich MR. The globalburden of disease due to schistosomiasis. HarvardCenter for Population and Development Studies,Working Paper Series 2004, 14(1).5. van der Werf MJ et al. Associating communityprevalence of Schistosoma mansoni infection withprevalence of signs and symptoms. Acta Tropica,2002, 82(2):127–137.6. van der Werf MJ et al. Quantification of clinicalmorbidity associated with schistosome infectionin sub-Saharan Africa. Acta Tropica, 2003,86(2–3):125–139.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0751

7. Brooker S et al. Evaluating the epidemiologicalimpact of national control programmes forhelminths. Trends in Parasitology, 2004, 20(11):537–545.8. Southgate VR et al. Towards control of schistosomiasisin sub-Saharan Africa. Journal ofHelminthology, 2005, 79(3):181-185.9. Olveda RM. Disease in schistosomiasis japonica.In: Mahmoud AAF, ed. Schistosomiasis. London,Imperial College Press, 2001:361-390.10. Ouma JH et al. Disease in schistosomiasis mansoniin Africa. In: Mahmoud AAF, ed. Schistosomiasis.London, Imperial College Press, 2001:333–360.11. Prata A. Disease in schistosomiasis mansoni inBrazil. In: Mahmoud AAF, ed. Schistosomiasis.London, Imperial College Press, 2001:297–332.12. King CH. Disease in schistosomiasis haematobia.In: Mahmoud AAF, ed. Schistosomiasis. London,Imperial College Press, 2001:265–296.13. Gryseels B. The relevance of schistosomiasis forpublic health. Tropical Medicine and Parasitology,1989, 40(2):134–142.14. Gold MR, Stevenson D, Fryback DG. HALYS andQALYS and DALYS, oh my: similarities and differencesin summary measures of population health.Annual Review of Public Health, 2002, 23:115–134.15. Murray CJL, Lopez AD, eds. The Global Burdenof Disease: a comprehensive assessment of mortalityand disability from diseases, injuries, and risk factorsin 1990 and projected to 2020. Cambridge MA,Harvard School of Public Health, 1996.16. Anand S, Hanson K. Disability-adjusted life years:a critical review. Journal of Health Economics, 1997,16(6):685–702.17. Arnesen T, Nord E. The value of DALY life:problems with ethics and validity of disabilityadjusted life years. British Medical Journal, 1999,319(7222):1423–1425.18. Reidpath DD et al. Measuring health in a vacuum:examining the disability weight of the DALY.Health Policy and Planning, 2003, 18(4):351-356.19. Schwappach DL. Resource allocation, social valuesand the QALY: a review of the debate and empiricalevidence. Health Expectations, 2002, 5(3):210–222.20. Hunt SM. Cross-cultural issues in the use of qualityof life measures in randomized controlled trials.In: Staquet MJ, Hays RD, Fayers PM, eds. Qualityof life assessment in clinical trials: methods and practice.Oxford, Oxford University Press, 1998:51–67.21. Warren KS et al. Quantification of infection withSchistosoma haematobium in relation to epidemiologyand selective population chemotherapy. I.Minimal number of daily egg counts in urine necessaryto establish intensity of infection. Journal ofInfectious Diseases, 1978, 138:849–855.22. Warren KS. Selective primary health care: strategiesfor control of disease in the developing world.I. Schistosomiasis. Reviews of Infectious Diseases,1982, 4(3):715–726.23. Wamachi AN et al. Increased ratio of tumornecrosis factor-alpha to interleukin-10 productionis associated with Schistosoma haematobium-inducedurinary-tract morbidity. Journal ofInfectious Diseases, 2004, 190(11):2020–2030.24. Kirigia JM. Economic evaluation in schistosomiasis:valuation of health states preferences. Aresearch note. Health Economics, 1998, 7(6):551–556.25. Kirigia JM. Economic evaluation in schistosomiasis:using the delphi technique to assess effectiveness.Acta Tropica, 1997, 64:175–190.26. Gold MR et al. Cost-effectiveness in health and medicine.New York, Oxford University Press, 1996.27. Chitsulo L et al. The global status of schistosomiasisand its control. Acta Tropica, 2000, 77(1):41–51.28. Steinmann P et al. Schistosomiasis and waterresources development: systematic review, metaanalysis,and estimates of people at risk. LancetInfect Diseases, 2006 6(7):411–425.29. Bergquist NR, Leonardo LR, Mitchell GF. Vaccinelinkedchemotherapy: can schistosomiasis controlbenefit from an integrated approach? Trends inParasitology, 2005, 21(3):112–117.30. Zhou XN et al. An economic evaluation of thenational schistosomiasis control programme inChina from 1992 to 2000. Acta Tropica, 2005, 96(2–3):255–265.31. Talaat M, Evans DB. The costs and coverage ofa strategy to control schistosomiasis morbidityin non-enrolled school-age children in Egypt.Transactions of the Royal Society of Tropical MedicineHygiene, 2000, 94(4):449–454.32. Miguel E, Kremer M. Worms: identifying impactson education and health in the presence of treatmentexternalities. Econometrica, 2004, 72:159–217.33. Bleakley H. Disease and development: evidencefrom the American south. Journal of the EuropeanEconomic Association, 2003, 1:376–386.52 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

WORKING PAPER 5.Schistosomiasis in womenof childbearing age,including in pregnancyG. Richard OldsThe Linda and John Mellowes Professor and Chairman,Department of Medicine, Medical College of Wisconsin,Milwaukee, Wisconsin, USA.The last quarter century has brought significantchange to the field of schistosomiasis. 1–3 Prior to1980, the only available treatment for this helminthinfection was toxic and required injections. Withthe introduction of praziquantel (PZQ), single-doseoral treatment became a reality but the high initialprice (2–3 US$ per dose) limited its broad applicationin endemic countries. Today, PZQ remains safeand highly effective and has been used effectivelyagainst all human schistosome species. The fall inprice of PZQ (to around US cents 3 a tablet) has leadto growth in national control programmes based onperiodic mass applications to targeted populations. 2The use of PZQ in this way has reduced, but clearlynot eliminated, morbidity induced by this parasite.It has also lead to a marked reduction in intensityof infection, and modest reductions in prevalenceof infection, but to little impact on transmission.Effective control programmes in Asia and SouthAmerica, combined with the rapid development ofwater resources in Africa (irrigation schemes anddams), has changed the worldwide distribution ofschistosome induced morbidity, which is now primarilyfocused in sub-Saharan Africa. 2Our thinking about morbidity induced by schistosomiasishas also undergone significant change overthe last quarter century. 4–5 Most research prior to the1980s focused on the end organ fibrotic changes inthe liver and urinary bladder, unique to infectionwith this parasite. In general, these morbid sequelaetake years to develop and have been significantlyimpacted by periodic treatment of populations withPZQ. This type of thinking, however, has lead to asignificant underestimation of the true impact thatschistosomiasis has on infected populations. Thisunderestimation of DALYs has recently been outlinedby King et al. 6 More subtle morbidity inducedby the parasite affects a much larger percentage ofthe infected population and persists despite periodictreatment; this includes anaemia, growth stunting,cognitive impairment, and decreases in functionalwork capacity. 6–10 Because many infectious pathogensas well as micronutrient deficiencies contributeto these problems, the unique role that schistosomiasisplays in them can only be analysed through double-blindplacebo-controlled trials. 10,11 Through theseand other studies, we now appreciate that the burdenof disease is far greater than was originallysuspected. In addition, we recognize particularlyvulnerable groups who are at high risk for the morbideffects, including growing children, all womenof childbearing age, and individuals with an irondeficient or nutritionally poor diet. Other high riskgroups include individuals who are already malnourished,and those of low social and economicstatus.With this as a background, it is disturbing that theissue of treatment of pregnant women with PZQremains unresolved. 12,13 Despite no in vitro or animalevidence for an adverse effect on either thepregnant mother or her unborn child, praziquantelwas released as a category B drug, assumedsafe in animals but not tested in humans. This hasalmost universally been interpreted by national controlprogrammes as a reason to withhold treatmentfrom pregnant women until after delivery. In someextreme cases, this issue has lead to deworming programmesbeing limited to pre-menarche ages forwomen. This is a particularly disturbing result sincemost women in schistosomiasis endemic countriesare at high risk for anaemia. 14,15At least one attempt was made during the last decadeto perform an appropriate double-blind placebo-controlledtrial to resolve this issue, but it wasblocked by ministry of health officials. A secondtrial has recently been funded by the US NationalInstitutes of Health but has not received in-countryinstitutional review board approval (Kurtis, personalcommunication). The issue was identifiedas high priority by the last WHO expert committeewhich published its recommendations in 2002. 2Based on these recommendations, a WHO informalconsultation on the use of PZQ during pregnancy/lactation was convened and its recommendationspublished the same year. Despite these efforts, manynational control programmes continue to withholdtreatment for pregnant women. Below I will attemptto outline what is currently known about womenof childbearing age as a high risk group for schistosomeinduced morbidity, including the unique riskthey have during pregnancy. I will then review thepotential impact of infection on the unborn child. Iwill build on the arguments outlined in an articlecommissioned for the WHO informal consultation 12and published in 2003. 13Women historically have been thought to be at lowerrisk for schistosomiasis induced end organ morbiditybecause, epidemiologically, the prevalence andReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0753

intensity of schistosome infection was observedto be lower in women than in men. This was moststriking with S. haematobium and least obvious inpopulations exposed to S. japonicum. Despite thesefacts, women of childbearing age in Africa continueto undergo significant exposure to schistosomiasis.With the introduction of national control programmes,many women of childbearing age werenot treated or had treatment delayed due to thepregnancy/lactation issue. In a study from thePhilippines, 30% of infected women between the16, 13ages of 16 and 30 went untreated over this issue.In a survey from Tanzania, 15 less than 10% of theinfected women had been offered treatment in thelast year while many had never been treated.In addition, the introduction of school-based treatmentprogrammes has introduced school enrolmentas a potential barrier to treatment. In many countrieswomen are underrepresented among primaryand secondary school attendees. Even when programmesare in place to find and treat non-enrolledstudents, coverage is likely to be less for those whoare not enrolled. In all of these settings, womenmay be suffering the classical end organ morbidityinduced by infection at a higher frequency.When we examine populations for schistosomeinduced subtle morbidity, women are clearly atsignificant risk for the development of anaemiacompared to their male counterparts. 17 This is compoundedin communities that are also endemicfor other diseases in which anaemia is a commonsequela, such as hookworm or malaria. 15 In countrieswith marginal nutritional resources, womenmay also be at greater risk for other forms of subtlemorbidity including growth stunting, impairedcognitive development and decreased functionalwork capacity. Recently several new studies havestarted to examine this issue specifically as it relatesto women.Anaemia is the number one health problem ofwomen throughout the world. 17 It is estimated thatthere are over two billion people in the world withanaemia, most of whom are iron deficient. There areanother 1.6 billion people who are iron deficient butnot yet anaemic. In developing countries almost halfthe women are iron deficient. Anaemic women havedecreased work capacity and increased absenteeism.Anaemic pregnant women are more likely tobecome septic and to haemorrhage, while anaemia isa major cause of maternal mortality. Maternal anaemiais a major cause of low birth weight and malnutritionin infants. Anaemic children have impairedintellectual and physical development.Anaemia is caused by a variety of factors. The associationbetween anaemia and schistosomiasis has beenstrongly suggested by several cross-sectional studiesand is most marked in areas in which the overallprevalence of anaemia is high and dietary iron islow. 15,18,19 Anaemia due to schistosomiasis is uniquein that at least part of the anaemia is induced bychronic inflammation. 14 As a result, in the two double-bindplacebo-controlled trials using PZQ, curinga patient with schistosomiasis not only arrested thefall in haemoglobin but actually resulted in a rise inthat value, even without iron supplementation. 10,11Interestingly, treatment of hookworm infection inone of these trials did not affect serum haemoglobins.10 In addition, a positive effect of PZQ treatmentwas observed, even in individuals who werethought to be free of infection based on two stoolexaminations. 10 The authors concluded that treatmentof even very light schistosome infections canbe beneficial to the patient’s haemoglobin.Pregnancy is particularly likely to negatively impactthe nutritional status of the mother and to exacerbateanaemia. Over half the pregnant women indeveloping countries are anaemic, and many areseverely so. 17 In a recent study in Tanzania, 15 SimonBrooker and his colleagues examined almost a thousandwomen 15–45 years of age attending a prenatalclinic in an area endemic for Schistosoma mansoni,hookworm and malaria. In this cross sectional study,S. mansoni prevalence was 64%, and hookworm 56%,while 31% had dual infections. Sixteen women hadpositive smears for falciparum malaria. The prevalenceof anaemia was 66%, with an increasing prevalenceoccurring during the course of pregnancy (72%for women in their last trimester). Haemoglobinconcentration decreased (p = 0.02) with increasingintensity of schistosome infection. Hookworm infectionwas statistically unrelated to haemoglobin levels.Women with positive malaria smears had lowerabsolute haemoglobin levels but this difference didnot reach statistical significance. A table of the oddsratios of the risk of anaemia in this population isshown below (table 1).In an ongoing study of pregnant women infectedwith schistosomiasis (unpublished data), Friedmanand Kurtis report that pregnant women infectedwith S. japonicum have significantly higher transferrinreceptor levels and significantly lower ferritinlevels at 32 weeks gestation than uninfected pregnantcontrols. They have concluded that pregnantwomen infected with schistosomiasis have both irondeficiency and anaemia of chronic disease.It has been particularly hard to find studies on schistosomiasisand pregnancy that look at the potential54 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

negative impact of schistosomiasis on the unbornchild. In the 1990s, it was shown that mice infectedwith schistosomiasis had a decreased number of viablelitters, increased maternal deaths, and increasedspontaneous abortions. Offspring born to infectedmothers were stunted. In a study in Ghana, S. haematobiuminfection during pregnancy was associatedwith increased risk of premature birth and low birthweight. Five other studies have reported negativebirth outcomes attributable to schistosomiasis. In anunpublished ongoing study, Friedman and Kurtishave found, in the first 97 pregnant women studied,a 460-gram decrease in birth weight of infantsborn to moderately infected women as compared tolightly or uninfected women.Table 1. Multivariate logistic regression model of significantvariables associated with the risk of anaemiaamong pregnant women in north-western Tanzania*VariableAdjusted oddsratios (95% CI) aP valuesS. mansoni infection0–99 epg 1.0100–399 epg 1.04 (0.73–1.48) 0.827>400 epg 1.87 (1.07–3.27) 0.026Age group30 years 0.47 (0.29–0.74) 0.002TrimesterFirst 1.0Second 2.81 (1.79–4.42)

This is particularly important as it relates to anaemiaand work capacity. Anaemia is an enormousproblem in the developing world, but iron supplementationhas many limitations. Aggressive chemotherapyof schistosomiasis will likely significantlyimprove anaemia in any country endemic for thisdisease. In addition, female children, who carry asignificant lifetime risk for anaemia, should alsobe targets for aggressive deworming programmes,both before and after menarche. The situation withpregnant women and schistosomiasis is a particularlysensitive issue. I feel this issue can only beaddressed by a careful placebo-controlled trial whichneeds to be performed now, across all three speciesand in different environmental settings. Although Iam reasonably confident that schistosomiasis is badfor both mother and child, the impact of treatmenton the morbid parameters is less clear. It is likelythat treatment will significantly benefit the motherat any time during pregnancy. Despite the fact thatI feel PZQ is completely safe for the unborn infant,recent studies on the relationship between maternalinflammation and birth outcomes suggest thata careful study needs to be performed to assess thetrue impact of treatment on schistosomiasis of theunborn child.References1. Ross AGP et al. Schistosomiasis: a clinical perspective.New England Journal of Medicine, 2002,346(16):1212–1220.2. Prevention and control of schistosomiasis and soiltransmittedhelminthiasis. Report of a WHO expertcommittee. Geneva, World Health Organization,2002 (WHO Technical Report Series, No. 912).3. Olds GR, Dasarathy S. Recent advances in schistosomiasis.Current Infectious Disease Reports, 2001,3(1):59–67.4. Olds GR et al. Immunity and morbidity in schistosomiasisjaponicum infection. American Journal ofTropical Medicine and Hygiene, 1996, 55(5):121–126.5. Olds GR, Dasarathy S. Schistosomiasis. CurrentTreatment Options in Infectious Diseases, 2000, 2:88–99.6. King CH, Dickman K, Tisch D. Reassessment ofthe cost of chronic helmintic infection: a metaanalysisof disability-related outcomes in endemicschistosomiasis. The Lancet, 2005, 365:1561–1569.7. Ezeamama A et al. Functional significance oflow intensity polyparasite helminth infectionsin anemia. Journal of Infectious Diseases, 2005,192(12):2160–2170.8. Nokes K et al. Evidence for an improvementin cognitive function following treatment ofSchistosoma japonicum infection in Chinese primaryschool children. American Journal of TropicalMedicine and Hygiene, 1999, 60(4):556–565.9. Stephenson LS. The impact of schistosomiasis onhuman nutrition. Parasitology, 1993, 107:S107–S123.10. Olds GR et al. Double-blind placebo-controlledstudy of concurrent administration of albendazoleand praziquantel in schoolchildren withschistosomiasis. Journal of Infectious Diseases, 1999,179:996–1003.11. McGarvey ST et al. Schistosomiasis japonica andchildhood nutritional status in northeastern Leyte,The Philippines: A randomized trial of praziquantelversus placebo. American Journal of TropicalMedicine and Hygiene, 1996, 54(5):498–502.12. Report of the WHO informal consultation on the useof praziquantel during pregnancy/lactation and albendazole/mebendazolein children under 24 months.Geneva, World Health Organization, 2002 (WHO/CDS/CPE/PVC/2002.4).13. Olds GR. Administration of praziquantel to pregnantand lactating women. Acta Tropica, 2003, 86(2–3):185–195.14. Friedman JF, Kanzaria HK, McGarvey ST. Humanschistosomiasis and anemia: the relationship andpotential mechanisms. Trends in Parasitology, 2005,21(8):386–392.15. Ajanga A et al. Schistosoma mansoni in pregnancyand associations with anaemia in northwestTanzania. Transactions of the Royal Society of TropicalMedicine and Hygiene, 2006, 100(1):59–63.16. Olveda RM et al. Schistosomiasis japonica in thePhilippines: the long-term impact of populationbasedchemotherapy on infection, transmission,and morbidity. Journal of Infectious Diseases, 1996,174:163–172.17. The world health report. Geneva, World HealthOrganization, 2004.18. Kanzaria HK et al. Schistosoma japonicum andoccult blood loss in endemic villages in Leyte, thePhilippines. American Journal of Tropical Medicineand Hygiene, 2005, 72(2):115–118.19. Sturrock RF et al. Schistosomiasis mansoni inKenya: relationship between infection and anaemiain schoolchildren at the community level.Transactions of the Royal Society of Tropical Medicineand Hygiene, 1996, 90(1):48–54.56 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

WORKING PAPER 6.MeasuringschistosomiasismorbidityBirgitte J. Vennervald 1 and David W. Dunne 21DBL, Institute for Health, Research and Development,Charlottenlund, Denmark2Department of Pathology, University of Cambridge, UKINTRODUCTIONThe World Health Assembly recognition of the publichealth problems caused by schistosome infectionspromotes efforts towards schistosomiasis morbiditycontrol. The control strategy recommended byWHO is aimed at reducing the morbidity caused byschistosomiasis.In order to make headway in the control of morbiditywe must try to answer the following questions:what do we define as schistosomiasis related morbidity,how do we measure it, what is the impactof the detected morbidity on the health of affectedcommunities, what other factors might influence thelevel of morbidity in an endemic setting, and howcan we measure the impact of treatment or interventionon morbidity?Another important question is what implicationsthe ‘direct morbidity’ has at the community leveland whether we are measuring anything relevant tothe health and well-being of the population. It is ofinterest to know if people feel sick and unwell and ifthere is a direct relation between what we can measureand the well-being of people. In other words canwe assess the ‘feeling sick’?In order to control morbidity we need tools whichcan assist in monitoring the effect of an interventionon the level of morbidity. Preferably this shouldwork both on a short-term and a long-term basisand be simple, non-invasive and non-expensive. Itwould be an added advantage if the risk of re-developingsevere morbidity after an intervention couldbe predicted.Morbidity assessment tools are essential in controlbut it is important to keep in mind that they are alsoneeded as research tools. We need new tools thatcan tell us more about the pathogenesis of schistosomiasisincluding the mechanisms of both developmentand regression of morbidity in order to deliverchemotherapy and other interventions in the mostrational, effective and safe way and to develop newtools for control.ASSESSMENT OF MORBIDITYUltrasonography has proven its value as a safe,rapid and non-invasive technique for morbidityassessment in schistosomiasis. The technique hasthe invaluable advantage of directly visualizing theorgan-specific schistosomiasis-associated changesseen in the liver and urinary bladder, as well asadditional disease complications such as portalhypertension and hydronephrosis (Richter, 2003;Hatz, 2001; Richter et al., 2003). Furthermore, WHOsponsored expert meetings have produced valuablestandardized ultrasound protocols for the quantificationof morbidity in S. haematobium and S. mansoniinfections, and the development of standardizedprotocols for evaluation of Asian schistosomiasismorbidity is in progress (Richter et al., 2003; NiameyWorking Group, WHO, 2000).Urinary schistosomiasis, caused by S. haematobium,affects the genitourinary tract with egg depositionin the urinary bladder wall although the reproductiveorgans may also be involved. Late-stage consequencesmay include hydronephrosis and possiblepredisposition to urinary bladder cancer. Studiesfrom different S. haematobium endemic settings inKenya, Tanzania, Ghana and Niger using the standardizedprotocol have shown that reversal of urinarytract morbidity occurs within six months of treatment,and that the rate of reappearance of urinarytract morbidity depends on the level of re-infection(Kahama et al., 1999; Hatz et al., 1998; Wagatsuma etal., 1999; Campagne et al., 2001).Though classical autopsy studies in Brazil unequivocallylinked the development of S. mansoni hepatosplenicschistosomiasis (HS), portal hypertensionand its severe sequelae with gross periportal fibrosis,recent ultrasound and clinical studies in Africasuggest that HS can also be found in S. mansoniinfectedchildren in the absence of gross hepaticfibrosis (Vennervald et al., 2004). Many of the childrenpresented with evidence of increased portalpressure, but none had ultrasound detectable periportalfibrosis. This combination does not currentlyfeature in the diagnostic algorithm given by WHO(Niamey Working Group, WHO, 2000).Other studies have also reported evidence of portalhypertension in the absence of ultrasound detectableperi-fibrosis. In a study from Kenya and Egyptinvolving ultrasound examination of 3954 individualsand using the Niamey height-indexed criteria(Niamey Working Group, WHO, 2000) forReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0757

portal vein enlargement, King et al. (2003) foundthat 14% of Kenyans with a normal liver texture patternmet the criteria for portal vein enlargement. InMadagascar, ultrasonographic observations typicalfor portal hypertension but without any observableliver texture abnormalities or measurable peri-portalthickening were made in 37 individuals, representing4.3% of the study cohort (Boisier et al., 2001). Incontrast to the study by King et al. (2003), Boisier etal. (2001) used height adjusted reference values forportal vein diameter obtained from a Malagasy population.Together, these observations suggest thatthe current WHO guidelines may need revision.The main problems concerning the use of ultrasonographyin control programmes are the relativelyhigh cost of the equipment, the need for welltrained examiners preferably with a medical, radiographyor similar qualification, and the need foradequate quality control procedures.There is still a need for simple and inexpensivetools for morbidity assessment. One way of assessingmorbidity may be simply to ask subjects aboutthe presence of signs and symptoms of morbidityassociated with schistosomiasis. Generally thisworks very well for haematuria associated with S.haematobium infection among schoolchildren, but ina Tanzanian study that examined schistosomiasisrelatedperceptions, attitudes and treatment-seekingpractices, it was found that the perceived causes andsymptoms were incongruous with the biomedicalperspective. In this study, a number of respondentsreported schistosomiasis to be a shameful disease(Mwanga et al., 2004), an attitude that may leadto underreporting of symptoms. This approach ofdirectly questioning subjects is more problematicfor intestinal schistosomiasis, where symptoms suchas diarrhoea and blood in the stool are often alsoassociated with conditions other than schistosomiasis(Kabatereine et al., 2004[a]; van der Werf et al.,2004).Enlargement of the liver and/or spleen is commonlydetected with schistosomiasis mansoni (Kabatereineet al., 2004[a]), and has recently been reported tooccur even in the absence of periportal fibrosis(Vennervald et al., 2004). Assessment of the degreeof organ enlargement by simple clinical examinationmay be a useful tool. A standardized method of clinicalscoring that takes organ consistency into accounthas recently been described (Vennervald et al., 2004)and has proven useful in post-treatment assessmentof regression of organ enlargement (Vennervald etal., 2005).Genital schistosomiasis in women is now viewedas a disease with important individual and publichealth consequences (Leutscher et al., 1997), while S.haematobium eggs can be detected in semen samplesfrom men with S. haematobium infection indicatingthat the genitals are a common site of egg deposition(Leutscher et al., 2000). Genital schistosomiasisis receiving increased attention because it is potentiallya risk factor for a number of sexually transmitteddiseases including HIV (Lawn, 2004). Genitalschistosomiasis poses a problem for proper diagnosisand it is worth noting that urine examination isnot very valid since egg excretion in urine is oftenvery low or absent in adults with genital schistosomiasis(Poggensee et al., 2000).In S. haematobium infection, detection of eosinophilcationic protein (ECP) in urine has proven to be avaluable marker for urinary bladder inflammationwith the potential to reveal signs of early inflammationand morbidity (Reimert et al., 2000). ECP hasbeen evaluated as a morbidity marker for femalegenital schistosomiasis (FGS); increased levels ofECP were detected in vaginal lavage samples fromwomen with FGS compared to endemic controls.However, the sensitivity of this diagnostic methodwas reported to be low (Midzi et al., 2003). Studiesthat assessed ECP in faecal samples as a markerof intestinal morbidity in S. mansoni infectionhave yielded promising preliminary results (C.M.Reimert, personal communication).FACTORS INFLUENCING THE LEVELOF MORBIDITYWhen measuring the level of morbidity, it is importantto know to what extent the results can be generalizedwithin the community as well as to a largergeographical area, since a number of factors such asdegree and length of exposure (Booth et al., 2004[a]),intensity of infection (Kabatereine et al., 2004[a]),and co-infections with malaria (Booth et al., 2004[b]),may influence both the development and the levelof morbidity in an exposed population.Geographic information system (GIS) technology isincreasingly being applied to the study of schistosomiasis.This powerful tool for mapping the spatialdistribution of infection and disease is nowstarting to generate important data for use in bothbasic morbidity research and the development ofmore effective and efficient national control programmes(Kabatereine et al., 2004[b]; Handzel et al.,2003; Clennon et al., 2004), and can provide valuableinformation about risk of exposure and co-infectionon a micro-geographical scale. This is importantin view of the very focal nature of schistosomiasisinfection and disease.58 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Malaria and schistosomiasis are often geographicallyco-endemic in sub-Saharan Africa, and co-infectionswith these parasites are common in school-agechildren, the main target group for schistosomiasiscontrol programmes. Both infections may causeenlargement of the liver and/or spleen, and an exacerbatingeffect of relatively high exposure to bothmalaria and S. mansoni infections on splenomegalyhas been demonstrated in a study in which GISspatial analysis was combined with detailed clinicaland ultrasound examination (Booth et al., 2004[b]).IgG3 responses to malaria schizont antigen, a proxyfor exposure to malaria, were higher in Kenyan childrenwith S. mansoni infection and hepatosplenomegalycompared with infected controls (Mwatha etal., 2003), and results from a study in Kenya indicatethat the benefits of treating hepatosplenomegalywith praziquantel (PZQ) will depend on thelevel of exposure to malaria (Booth et al., 2004[c]).POST-INTERVENTION ASSESSMENTThe key tool in schistosomiasis morbidity control istreatment with PZQ, and, with the major ongoingcontrol initiatives (Fenwick et al., 2003), this drugwill be used extensively in many schistosomiasisendemic countries in the coming years. In a comprehensivereview, Utzinger and Keiser (Utzingerand Keiser, 2004) described the current drugs availablefor morbidity control and covered aspects oftherapeutic efficacy and adverse events in clinicalschistosomiasis.Several studies have examined the effect of treatmenton S. mansoni related organomegaly, periportalfibrosis and other ultrasound detectable parameters(Boisier et al., 1998; Doehring-Schwerdtfeger etal.,1992; Frenzel et al., 1999), and one study hascompared ultrasonography and detailed clinicalexamination in measuring morbidity regression(Vennervald et al., 2005). In this study a steadydecrease of the organomegaly among children withHS was demonstrated up to three years after treatmentwith PZQ. There was however a significantdifference in the rate of organ regression betweenchildren who became egg negative after treatmentas compared to children who remained egg positive,but where intensity of infection decreased markedly(own unpublished results).Most previous studies have assessed the effect oftreatment over a relatively short follow-up periodand often among children only. It is therefore importantto assess the long-term effect of PZQ treatmentwith follow-up studies more than five years aftertreatment among populations living in areas ofintense transmission in order to assess the impact ofPZQ on the severe consequences of schistosomiasismansoni such as portal hypertension and oesophagealvarices.CONCLUSIONSThe increased focus on conditions such as malaria,AIDS and tuberculosis, that cause either severe acutedisease or high levels of mortality, has resulted inrelative neglect of infections such as schistosomiasis.With the Schistosomiasis Control Initiative, focushas been redirected towards schistosomiasis control.However, control strategies should be evidencebasedand field research is necessary to determinethe impact of an intervention on the morbidity level.Scientific evidence that allows accurate evaluationof what works, what does not work, and the reasonswhy, is crucial for the development of efficient andcost-effective strategies to ensure long-term reductionin disease levels in target populations.Significant advances have been achieved in ourunderstanding of the epidemiology of schistosomiasisand the various factors that may influence themorbidity level. However, there is need for greaterunderstanding of the morbidity mechanisms and forbetter tools for morbidity assessment. Good researchis vital to sustainable disease control, and advancesin the laboratory, even if not immediately applicableto control efforts, are needed to improve our understandingof the disease and develop new tools formorbidity assessment and control.It is also important to strengthen research capacityin endemic countries and to support the many goodscientists from these countries. One of the advancesin morbidity assessment has been the increase innumber of ultrasonographers from endemic countriestrained in assessment of schistosomiasis morbidity.It is vital for the sustainability of controlefforts that local capacity is created, and that thiscapacity participates in the control programmes andassists in the training of new people. Any supportfor further training and exchange between ultrasonographersfrom endemic areas would be veryvaluable.MAIN POINTS AND CONCLUSIONS• The absence of gross or ultrasound detectablefibrosis does not exclude the possible presence ofsevere morbidity in S. mansoni infected patients.• Chronic co-exposure to schistosomiasis mansoniand malaria may influence both the level of morbidityand the measurement of morbidity:– by affecting the severity of HS morbidityReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0759

– by affecting the regression of morbidity afterPZQ treatment– by confounding the assessment of morbidity.• There is geographical variation (at the macroand micro-geographical levels) in the severity ofschistosomiasis associated morbidity, and it islikely that many external environmental factorshave important roles in determining the severityof morbidity associated with schistosomiasis.• Inflammatory markers may prove to be importantparameters for the assessment of a variety ofschistosomiasis associated morbidities.• Ultrasonography is useful as a tool for morbidityassessment of several different schistosomiasis-associatedconditions. However, the capacityto apply this technique locally in schistosomiasisendemic countries needs to be developed as apriority in order to make full use of its potential.• Other types of pathology may be of significancein populations living in endemic areas, e.g. intestinalmorbidity associated with schistosomiasismansoni and japonicum remains almost completelyunstudied and is likely to be of significance,particularly in situations where otherfactors such as co-exposure to intestinal parasitesand/or malnutrition are present.ReferencesBoisier P et al. Geographic differences in hepatospleniccomplications of schistosomiasis mansoniand explanatory factors of morbidity. Tropical Medicineand International Health, 2001, 6:699–706.Boisier P, et al. Reversibility of Schistosoma mansoniassociatedmorbidity after yearly mass praziquanteltherapy: ultrasonographic assessment. Transactions ofthe Royal Society of Tropical Medicine and Hygiene, 1998,92(4):451–453.Booth M et al. Hepatosplenic morbidity in two neighbouringcommunities in Uganda with high levels ofSchistosoma mansoni infection but very different durationsof residence. Transactions of the Royal Society ofTropical Medicine and Hygiene, 2004[a], 98:125–136.Booth M et al. Micro-geographical variation in exposureto Schistosoma mansoni and malaria, and exacerbationof splenomegaly in Kenyan school-agedchildren. BMC Infectious Diseases, 2004[b], 4:13.Booth M et al. Exposure to malaria affects the regressionof hepatosplenomegaly after treatment forSchistosoma mansoni infection in Kenyan children.BMC Medicine, 2004[c], 2:36.Campagne G et al. Continued ultrasonic follow-up ofchildren infected with Schistosoma haematobium aftertreatment with praziquantel. Tropical Medicine andInternational Health, 2001, 6:24–30.Clennon JA et al. Spatial patterns of urinary schistosomiasisinfection in a highly endemic area of coastalKenya. American Journal of Tropical Medicine andHygiene, 2004, 70:443–448.Doehring-Schwerdtfeger E et al. Ultrasound versusclinical examination as indication for Schistosoma mansoniassociated morbidity in children. Tropical Medicineand Parasitology, 1992, 43(4):245–248.Fenwick A et al. Drugs for the control of parasitic diseases:current status and development in schistosomiasis.Trends in Parasitology, 2003, 19:509–515.Frenzel K, et al. Evidence for a long-term effect of asingle dose of praziquantel on Schistosoma mansoniinducedhepatosplenic lesions in northern Uganda.American Journal of Tropical Medicine and Hygiene, 1999,60(6):927–931.Handzel T et al. Geographic distribution of schistosomiasisand soil-transmitted helminths in WesternKenya: implications for anthelminthic mass treatment.American Journal of Tropical Medicine and Hygiene, 2003,69:318–323.Hatz CF et al. Evolution of Schistosoma haematobiumrelatedpathology over 24 months after treatment withpraziquantel among school children in southeasternTanzania. American Journal of Tropical Medicine andHygiene, 1998, 59:775–781.Hatz CFR. The use of ultrasound in schistosomiasis.Advances in Parasitology, 2001, 48:225–284.Kabatereine NB et al. Epidemiology and morbidityof Schistosoma mansoni infection in a fishing communityalong Lake Albert in Uganda. Transactions of theRoyal Society of Tropical Medicine and Hygiene, 2004[a],98:711–718.Kabatereine NB et al. Epidemiology and geography ofSchistosoma mansoni in Uganda: implications for planningcontrol. Tropical Medicine and International Health,2004[b], 9:372–380.Kahama AI et al. Urine circulating soluble egg antigenin relation to egg counts, hematuria, and urinarytract pathology before and after treatment in childreninfected with Schistosoma haematobium in Kenya.American Journal of Tropical Medicine and Hygiene, 1999,61:215–219.60 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

King C H et al. Measuring morbidity in schistosomiasismansoni: relationship between image pattern,portal vein diameter and portal branch thickness inlarge-scale surveys using new WHO coding guidelinesfor ultrasound in schistosomiasis. TropicalMedicine and International Health, 2003, 8:109–117.Lawn SD. AIDS in Africa: the impact of coinfectionson the pathogenesis of HIV-1 infection. Journal ofInfection, 2004, 48:1–12.Leutscher P et al. Clinical findings in female genitalschistosomiasis in Madagascar. Tropical Medicine andInternational Health, 1997, 3:327–332.Leutscher P et al. Community-based study of genitalschistosomiasis in men from Madagascar. Lancet, 2000,355(9198):117–118.Midzi N et al. Assessment of eosinophil cationic proteinas a possible diagnostic marker for female genitalschistosomiasis in women living in a Schistosomahaematobium endemic area. Parasite Immunology, 2003,25:581–588.Mwanga JR et al. Schistosomiasis-related perceptions,attitudes and treatment-seeking practices in Magudistrict, Tanzania: public health implications. Journal ofBiosocial Science, 2004, 36:63–81.Mwatha JK et al. Associations between anti-Schistosoma mansoni and anti-Plasmodium falciparumantibody responses and hepatosplenomegaly, inKenyan schoolchildren. Journal of Infectious Diseases,2003, 187:1337–1341.Niamey Working Group. Ultrasound in schistosomiasis:a practical guide to the standardized use of ultrasonographyfor the assessment of schistosomiasis-related morbidity.Geneva, World Health Organization, 2000 (TDR/STR/SCH/00.1; www.who.int/tdr/publications/publications/ultrasound.htm)Poggensee G et al. Female genital schistosomiasis ofthe lower genital tract: prevalence and disease-associatedmorbidity in Northern Tanzania. Journal ofInfectious Diseases, 2000, 181:1210–1213.Reimert CM et al. Quantitative assessment of eosinophiluriain Schistosoma haematobium infections: anew marker of infections and bladder morbidity.American Journal of Tropical Medicine and Hygiene, 2000,62:19–28.Richter J. The impact of chemotherapy on morbiditydue to schistosomiasis. Acta Tropica, 2003, 86:161–183.Richter J, Hatz C, Haussinger D. Ultrasound in tropicaland parasitic diseases. The Lancet, 2003, 362:900–902.Utzinger J, Keiser J. Schistosomiasis and soil-transmittedhelminthiasis: common drugs for treatmentand control. Expert Opinion on Pharmacotherapy, 2004,5:263–285.van der Werf MJ et al. Measuring schistosomiasiscase management of the health services in Ghana andMali. Tropical Medicine and International Health, 2004,9(1):149–157.Vennervald BJ et al. Detailed clinical and ultrasoundexamination of children and adolescents in aSchistosoma mansoni endemic area in Kenya: hepatosplenicdisease in the absence of portal fibrosis.Tropical Medicine and International Health, 2004, 9:461–470.Vennervald BJ et al. Regression of hepatosplenomegalyin Kenyan school-aged children after praziquanteltreatment and in the absence of re-infection bySchistosoma mansoni. Transactions of the Royal Society ofTropical Medicine and Hygiene, 2005, 99:150–160.Wagatsuma Y et al. Resolution and resurgence ofSchistosoma haematobium-induced pathology after community-basedchemotherapy in Ghana as detectedby ultrasound. Journal of Infectious Diseases, 1999,179:1515–1522.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0761

WORKING PAPER 7.Clinical schistosomiasisJosé Roberto LambertucciUniversidade Federal de Minas Gerais, Estudos deMedicina Experimental, Núcleo de Estudos SobreEsquistos, Belo Horizonte, Brazil• Definition or development of a serologic test fordiagnosis.• Definition of a histologic pattern of granulomain the liver characteristic of the acute phase ofschistosomiasis.• Definition of the best approach to treatment(schistosomicides plus steroids).The clinical aspects of Schistosoma mansoni infectionin humans are outlined in table 1.THE STAGE OF INVASIONThe stage of invasion starts with cercarial dermatitisand evolves with the migration and development ofthe schistosomes. Symptoms may commence withfever as early as two or three days after infection.Pulmonary involvement may be heralded by coughand pulmonary infiltrates in chest X-ray. Wheezing,myalgia, abdominal pain, eosinophilia and moderatesplenomegaly may compose the clinical picture.The diagnosis of schistosomiasis at this stage is quitedifficult. Experimental work in mice suggests thateither praziquantel or oxamniquine, when givenduring the first week of infection in the usual doses,is efficient in aborting development of the worms.Research needs• Earlier diagnosis and treatment:– presumptive diagnosis followed by treatmentof cercarial dermatitis in endemic areas withpraziquantel, or with artesunate after the secondweek.ACUTE SCHISTOSOMIASISThe acute phase of schistosomiasis is usually asymptomaticbut clinical signs of varying intensity mayoccur. Those living in endemic areas may developthe syndrome after having contact for the first timewith water contaminated by S. mansoni cercariae.The most common manifestations are fever, chills,weakness, weight loss, headache, nausea, vomiting,diarrhoea, hepatomegaly, splenomegaly, andmarked eosinophilia (table 2). In patients with acuteschistosomiasis admitted to hospital because ofintensity of symptoms, treatment should be startedwith corticosteroids, followed by schistosomicides.Research needs• Recognition of the importance of acute schistosomiasisin endemic areas.Table 1. Clinical classification of schistosomiasis mansoniStage of invasionAcute schistosomiasis (apparent and non-apparent)Chronic schistosomiasis• Hepatointestinal• HepatosplenicComplications• Pulmonary hypertension• Neuroschistosomiasis• Association with bacteria (Salmonella, Staphylococcus aureus)• Glomerulonephritis• Schistosomiasis in the immunocompromised host• Ectopic schistosomiasisTable 2. Clinical and laboratory findings in acuteschistosomiasis mansoni• A history of contact with stream waters in endemic areas in thelast 60 days• Fever, diarrhoea, hepatosplenomegaly, dry cough, urticaria• Similar clinical picture in other members of the group whobathed together• Eosinophilia• Ultrasound: hepatosplenomegaly, periportal lymph nodes• Computed tomography (CT) scan of the lungs: micronodules inboth lungs• Eggs of S. mansoni in the stools• Liver biopsy: huge necrotic-exudative granulomas in portal tracts• Serology (enzyme-linked immunosorbent assay [ELISA] usingkeyhole limpet haemocyanin [KLH] antigen)INTESTINAL/HEPATOINTESTINALSCHISTOSOMIASISAfter the acute phase manifestations recede, theinfection progresses to the chronic phase. This is thestage of infection usually observed in endemic areas,but most individuals are asymptomatic. Intermittentdiarrhoea is the most common symptom in patientswith intestinal/hepatointestinal schistosomiasiswithout polyps. Episodes of diarrhoea alternate withperiods of normal bowel movement or constipation,and faeces may contain blood and mucus. On palpation,the abdomen may be tender, particularly alongthe descending colon and sigmoid. The liver may beenlarged and hardened but hepatic function tests areinvariably normal. Sigmoidoscopy may show areasof granular inflammation with hyperaemic pinpointelevations, and shallow ulcerations or small haem-62 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

orrhages. Colonic polyposis, rarely seen in Brazil, isa common complication of intestinal schistosomiasisin Egyptian farmers.Research needs• A clinical and ultrasonographic definition ofhepatointestinal schistosomiasis.HEPATOSPLENIC SCHISTOSOMIASISIt is not difficult to identify and confirm a diagnosis ofadvanced hepatosplenic schistosomiasis in patientsadmitted to a reference hospital (see tables 3 and 4),although it can be difficult to disclose individualswith hepatosplenic schistosomiasis in field-basedstudies. These individuals can be distinguished fromothers with hepatointestinal schistosomiasis basicallyby the presence of splenomegaly, and this has beenattempted by abdominal palpation. In areas endemicfor malaria and visceral leishmaniasis, or in the presenceof other diseases which evolve with splenomegaly(mononucleosis-like syndromes, for example), apalpable spleen may not help in the identification ofpatients with hepatosplenic schistosomiasis.In Brazil, hepatosplenic schistosomiasis was foundmore frequently in white people than in black peoplewith similar levels of infection.With portable ultrasound, it is possible to improvethe accuracy of clinical examination. A combinedclinical and ultrasonographic classification of schistosomiasisin endemic areas has been proposed:(1) Palpable spleen, severe periportal thickeningand portal hypertension (a group usually foundin general hospitals – see table 3).(2) Severe periportal thickening, portal hypertensionand a non palpable spleen (hepaticschistosomiasis).(3) Palpable spleen with light to moderate periportalthickening.(4) Palpable spleen with a normal liver on ultrasound.The meaning and importance of groups 3 and 4 inthe natural history of schistosomiasis remain to beappraised.Research needs• A clinical and ultrasonographic definition ofhepatosplenic schistosomiasis.• Definition of the best surgical approach tovariceal bleeding in patients with hepatosplenicschistosomiasis.• Comparison of the serum markers of fibrosiswith histology of the liver, and with imagingtechniques.Table 3. Characteristics of compensated hepatosplenicschistosomiasis mansoniClinical findingsHigher prevalence in the age range 10–30 yearsGeneral aspect: goodHepatosplenomegaly (exclude other causes)Variceal bleedingNo signs or symptoms of liver failureSomatic underdevelopment in the youngBiochemical and haematologic findingsNormal liver function tests (alanine aminotransferase [ALT],alkaline phosphatase, gamma-glutamyltransferase [GGT],bilirubin, albumin, prothrombin time)Hypergammaglobulinaemia (increase of the IgG fraction)Anaemia, leukopenia, thrombocytopeniaHaemodynamic aspectsNormal liver sinusoidal pressurePortal and splenic hypertensionPeculiar alterations of the intra-hepatic vasculatureNormal liver flowUltrasoundCharacteristic periportal thickeningGall bladder wall thickening in the absence of calculous cholecystitisIncreased left liver lobeIncreased diameter of the splenic and portal veinsIdentification of portal collateral veins (e.g. left gastric vein)Magnetic resonance imagingIncrease in the intensity of signal in portal tractsSplenomegalyEasy identification of portal and collateral vesselsPathologic aspectsModerate inflammatory activityIntense Symmers’ fibrosisLiver cells preservedLobular structure of the liver preservedTable 4. Characteristics of decompensated hepatosplenicschistosomiasis> 30 years of ageLiver atrophy when compared to the compensated form ofhepatosplenic schistosomiasisCo-morbidities: hepatitis B, hepatitis C, alcohol abuse, a history ofprevious variceal bleedingAbdominal scar (post-splenectomy)Signs and symptoms of liver failure: ascites, jaundice, vascularspiders, mental confusion, slurred speech, coma, gynecomastiaPoor general appearance, muscle wastingBiochemical alterations: hypoalbuminemia, hyperbilirubinemia,hyperammonemiaPortal thrombosis is commonly describedReduced hepatic flowPeriportal fibrosis and proliferation of biliary ductsFocal post-necrotic cirrhosisReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0763

ULTRASOUND vs. MAGNETICRESONANCE IMAGING IN THEDIAGNOSIS OF PERIPORTALFIBROSISLately, periportal thickening on ultrasound hasbeen considered as evidence of Symmers’ fibrosis.In a recent study in Brazil comparing ultrasound(US) with magnetic resonance imaging (MRI), ina group of 20 patients with periportal thickeningdiagnosed by US and assumed to have liver fibrosiscaused by S. mansoni infection, 20% where foundby MRI to have fat infiltration of the portal tracts ofthe liver. If these findings are confirmed, a limit forthe use of ultrasound in schistosomiasis should beestablished.Research needs• Studies addressing the value of MRI in evaluationof periportal thickening in schistosomiasis.PULMONARY HYPERTENSIONClinical and radiological findings are similar tothose associated with other causes of pulmonaryhypertension. Symptoms are fatigue, palpitations,dyspnea on exertion, cough with occasional haemoptysis,signs of right ventricular hypertrophy, anddilation of the pulmonary artery. Echocardiographyhelps the diagnosis, but cardiac catheterization ismore informative: pulmonary hypertension ispresent when a pulmonary pressure of 20 mm Hgor higher is registered. The patient may ultimatelyprogress to decompensation with congestive heartfailure. Sudden death with cardiovascular collapsehas been reported.Pulmonary hypertension has been described in13% of patients with advanced hepatosplenic schistosomiasis,and cor pulmonale in 2.1%. Standardtreatment of patients with pulmonary arterial hypertension(PAH) includes anticoagulant therapy withwarfarin (anticoagulant agent) and a diuretic such asfurosemide for fluid retention caused by right-sidedheart failure. In selected patients, a calcium-channelblocking agent may be helpful. Some patients withPAH in whom medical management has failed haveundergone lung transplantation.In a recent randomized clinical trial, 277 patientswith symptomatic PAH were randomized to placeboor sildenafil orally three times daily for 12 weeks.The authors conclude that sildenafil in doses of 20mg three times a day is effective for treatment ofpulmonary arterial hypertension. The drug has beenapproved by the US Food and Drug Administration(FDA) for this indication under the trade nameRevatio.Sildenafil inhibits phosphodiesterase type 5, themain phosphodiesterase in the pulmonary vasculature;inhibiting it maintains high levels of cGMP,which promotes the vasodilation effects of endogenousnitric oxide. The drug may also have an antiproliferativeeffect on pulmonary artery smoothmuscle cells.In a preliminary study on the course of hepatosplenicschistosomiasis in 13 patients with pulmonaryhypertension in Brazil, sildenafil showedpromising results.Research needs• Well designed studies using sildenafil are necessaryto confirm these data.NEUROSCHISTOSOMIASISSchistosomal myeloradiculopathy (SMR) is the mostcommon neurological form of S. mansoni infection.In 2004, a study in Brazil found that 5.6% of inflammatorymyelopathies seen at a tertiary Brazilianhospital were due to SMR. In a hospital in Tanzania,a prevalence of 6% has been estimated.Ninety five per cent of untreated patients die or donot show any improvement. Frequently, physiciansare not aware of the existence of schistosomal myeloradiculopathy,and when they are, they do nothave the means to investigate schistosomiasis and toexclude other diseases.The clinical picture includes: lumbar and/or lowerlimb pain, lower limb hypoesthesia/anesthesia,lower limb paresthesias, lower limb weakness, urinarydysfunction, intestinal dysfunction, sexualdysfunction. Diagnosis of SMR is based on the followingcriteria: evidence of low spinal cord lesion,demonstration of exposure to schistosomal infectionby microscopic or serological techniques, and exclusionof other causes of transverse myelitis. MRI ofthe spine should be used in all cases. Biopsy of thespinal cord should be considered in special cases.Cerebrospinal fluid (CSF) examination will add toinformation on diagnosis when it shows the presenceof eosinophils, hyperproteinorraquia, lymphocytosis,and, in some cases, a positive immunologicaltest for schistosomiasis in the spinal fluid.Exclusion of other diseases of the spinal cord shouldbe performed routinely; these include: tumours (pri-64 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

mary or metastatic), extrinsic compression of thespinal cord, B12 deficiency, diabetes, systemic lupuserythemathosus, anti-phospholipid syndrome,syphilis, HIV and HTLV-1 infection, auto-immunevasculitis, herpes simplex myelitis, tuberculosis,hepatitis B and C, multiple sclerosis, neurocysticercosis,syringomyelitis.Treatment includes the use of ivermectin to treatstrongyloidiasis, followed by praziquantel (60 mg/kg body weight, single dose) and high doses ofmethylprednisolone (15 mg/kg a day, iv; maximumdose, 1 g a day) for 5 days, followed by prednisone(1 mg/kg a day per os) for 6 months.Epidemiological surveillance includes: a) trainingof health personnel to develop a high index of suspicionfor schistosomal myeloradiculopathy (forexample, the clinical triad of low back pain, lowerlimb weakness and urinary dysfunction should alertthe local physician that this patient needs furtherinvestigation); b) notification of a regional referencecentre and provision of neurological examination;c) stool examination for S. mansoni eggs, lumbar tapwith CSF examination, and radiological examination.Any obstacle to the above procedures should becommunicated to the state health authorities, whowill provide alternatives to support those patients inneed of more sophisticated investigation.Research needs• Recognition of the importance of neuroschistosomiasisin endemic areas.• Definition of parameters for diagnosis and treatment(when, how and for how long).ASSOCIATION WITH BACTERIAThe association of schistosomiasis with Salmonellaand other gram-negative organisms is well documented.The most common characteristics of theclinical syndrome are: 1) a long history (from severalweeks to a few years) of febrile disease; 2) bacteraemiawith one of many species of the genus Salmonellaor other gram-negatives; 3) chronic active schistosomiasis.The number of cases reported in Brazil forthis association has decreased during the last tenyears, which has been attributed to mass chemotherapywith schistosomicides.The association of schistosomiasis and Staphylococcusaureus causing pyogenic liver abscesses has beendescribed in Brazil in the murine model of schistosomiasisand in humans. The development of liverabscesses in experimental schistosomiasis in micehas been confirmed in Egypt.Research needs• Studies in endemic areas on the association ofschistosomiasis with gram-negative bacteria:– what is the prevalence in endemic areas?– definition of treatment.GLOMERULONEPHRITISChronic glomerulonephritis appears in 12%–15% ofpatients with hepatosplenic schistosomiasis mansoniadmitted to general hospitals in Brazil. Thenephrotic syndrome is the most frequent form ofclinical presentation of schistosomal nephropathy.There is evidence that renal manifestations developslowly, perhaps ten or more years after the onset ofhepatosplenic disease.The outcome of treatment of the nephrotic syndromeassociated with hepatosplenic schistosomiasis withantischistosomal drugs, corticosteroids and immunodepressorshas been disappointing. Some authorshave shown that when patients present with nephroticsyndrome, the disease is too far advanced andis therefore irreversible.Research needs• Recognition of glomerulonephritis as a severecomplication of hepatosplenic schistosomiasis:– definition of the prevalence in endemic areas.– research on treatment.SCHISTOSOMIASIS IN THEIMMUNOCOMPROMISED HOSTThe number of people immunosuppressed by drugs(cytotoxic chemotherapy or other immunosuppressiveagents including steroids and irradiation), oraffected by diseases that cause immunodepression(AIDS, neoplasia, malnutrition, chronic renal failure),is growing fast. In the immunocompromisedhost there have been changes in the clinical presentation,pathological aspects and therapeutic approachto most associated infectious diseases.Data on the behaviour of schistosomiasis mansoniin the immunosuppressed host are scarce. Even so,it is possible to draw out some areas of clinical interestconcerning this particular scenario:• Depression of cell-mediated immune responsein the host diminishes granulomatous responseto S. mansoni eggs. Without granuloma formation,destruction of hepatic cells is to beexpected, causing varying degrees of hepatitis(depending on the worm load and the level ofimmunosuppression).Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0765

• Egg output decreases sharply in mice experimentallyinfected with S. mansoni and immunosuppressedby drugs or thymectomy. A well formedgranuloma facilitates the migration of eggs in thehost tissues. Without granuloma formation, S.mansoni eggs do not reach (or reach only in smallnumbers) the gut lumen. Diagnosis of schistosomiasisbased on parasitological stool examinationshould be re-evaluated in this context.• The efficacy of schistosomicides is alsoexpected to decrease in such cases, since theaction of oxamniquine and praziquantel isimmunodependent.• Schistosomal infection is expected to interferewith the course of diseases responsible for immunosuppression.For instance, in patients withacquired immunodeficiency syndrome, schistosomiasismay aggravate the clinical picture bydecreasing the T CD4+ cell count thus carryingan increased risk for concomitant infection withbacteria (e.g. Salmonella), viruses or fungi.Research needs• Definition of the role of schistosomiasis in thenatural history of acquired immunodeficiencysyndrome.• Definition of the behaviour of schistosomiasis inthe immunocompromised host.ECTOPIC SCHISTOSOMIASISMANSONIWhen periovular granulomas form outside the portaland pulmonary circulations, it is considered tobe ectopic schistosomiasis. Most of the time this representsa curiosity. Periovular granulomas can befound in such strange sites as the thyroid, kidneys,pancreas, testicles, ovary, uterus, adrenals, lymphnodes, heart, prostate and central nervous system.Ectopic cutaneous lesions usually affect the perinealarea or trunk, but involvement of other areas of theskin has also been reported. Rarely is ectopic eggdeposition sufficient to suggest a clinical syndrome.TREATMENT OF SCHISTOSOMIASISAlthough schistosomiasis chemotherapy primarilyrelies on praziquantel, the present arsenal alsoincludes oxamniquine and artemisinin derivatives.Research needs• Development of novel antischistosomal agents.• Development of combinations of schistosomicides(praziquantel and oxamniquine; praziquanteland artesunate).• Studies on increasing the dosage of praziquantelin use today.• Studies on repeat treatment with praziquantelonce every 2 to 4 weeks for periods of up to 6months.References on which this text is basedThe Medical Letters. Sildenafil for pulmonary arterialhypertension. The Medical Letter on Drugs andTherapeutics, 2005, 47:65–67.Lambertucci JR et al. Schistosoma mansoni: assessmentof morbidity before and after control. Acta Tropica,2000, 77:101–109.Silva LCS et al. Treatment of schistosomal myeloradiculopathywith praziquantel and corticosteroids andevaluation by magnetic resonance imaging: a longitudinalstudy. Clinical Infectious Disease, 2004, 39:1618–1624.Utzinger J et al. Combination chemotherapy ofschistosomiasis in laboratory and clinical trials.Antimicrobial Agents and Chemotherapy, 2003, 47:1487–1495.Research needs• Studies on ectopic lesions in endemic areas.66 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

WORKING PAPER 8.Progress towardsthe detection ofschistosomiasisAna Rabello and Martin EnkCentro de Pesquisas René Rachou, Fiocruz,Belo Horizonte, BrazilWhat progress has been made and what are thecurrent priorities in research towards the detectionof schistosome infections? Any comprehensiveapproach to address this matter requires a framework:diagnosing schistosomiasis to do what, where,to/by whom?SOCIO-POLITICO-ECONOMICREQUIREMENTS FOR MORBIDITYCONTROLIn the context of Goal 1 of the Millenium DevelopmentGoals, which is to eradicate extreme poverty andhunger, the 54th World Health Assembly (in 2001)recognized that tools are available to treat parasiticinfections that deprive the poorest of the poorof their health and well-being, slow economicprogress, and contribute to social marginalization.A resolution was put forward to start to seriouslytackle worm infections, specifically soil-transmittedhelminths and schistosomiasis. Accordingly, theWorld Health Organization launched the Partnersfor Parasitic Control (PPC) initiative, the global targetof which is to treat at least 75% of all school-agechildren who are at risk of morbidity from soil-transmittedparasites and schistosomiasis by the year2010 (Resolution WHA54.19. WHO, 2001).Because schistosomiasis has focal distribution,and in order to ensure the safe, efficient and economicuse of praziquantel, tools are required thatwill allow simple, rapid and inexpensive identificationof communities at highest risk of morbidity.The PPC calls for a diagnostic method that targetsreduction of morbidity. More than 80% of individualsinfected with schistosomes live in sub-SaharanAfrica (Chistulo et al., 2000), where 106 millionpresent with bladder wall pathology and 14.8 millionwith liver/spleen enlargement (van der Werf,2003), and where more than 800 million are at riskof infection. In this context it is worth mentioningthat, in least developed countries, people in exposedpopulations live on less than US$ 2 a day (UnitedNations Statistics Division, 2005**) and have verylimited access to health care and schooling.The current strategy to achieve this PPC goal is toinvolve governments and the public health sectorin implementing community-based programmesfor school-age populations. This activity shouldideally be part of integrated programmes requiringthe engagement of local, often poorly trained,health care workers who deal with the differentchallenges on a minimum budget. A useful guidefor planners and programme managers providesdirection for collecting baseline parasitological data(Montresor et al., 2002) through questionnaire surveysfor urinary schistosomiasis in all schools and,in areas likely to be endemic for urinary or intestinalschistosomiasis, urine and stool surveys in a randomsample of schools. The Kato-Katz method isrecommended for stool examination, and a filtrationtechnique (or reagent strip) for detection of eggs (orblood) in urine. Is the scientific community capableof offering simpler and more effective diagnostictools to the deworming programme than those presentlyavailable? Is there any progress? Is anythingcoming out of the pipeline?Questionnaires and reagent stripsWhen urgent intervention is required to preventdeath and liver or bladder damage, often in an environmentof civil unrest or man-made or naturaldisaster, any extra labour and costs needed are problematic.Although no new alternative, simple, fastscreening method has been produced, during thelast decade, scientific efforts have validated the usefulnessof the questionnaire and the reagent stripas simple tools to estimate Schistosoma haematobiuminfection. Consistently in studies performed in differentgeographic areas, strong positive associationhas been found between reported haematuria,micro-haematuria and eggs in urine (Ansell et al.,1999; Stothard et al., 2002; van der Werf, Borsboomand de Vlas, 2003; van der Werf and de Vlas, 2004).Therefore a simple questionnaire asking “Did youhave blood in urine during the last month?” and“Did you suffer from schistosomiasis during the lastmonth?” is a validated tool that allows for a decisionto be taken – the decision to treat all school-agechildren when 30% of them report gross haematuria,indicating that 50% have detectable eggs inurine (Guyatt et al., 1999). Lower predictive valuesare observed for the entire population, especiallyfor women of childbearing age due to confound-* World Health Assembly Resolution WHA 54.19. Schistosomiasis and soil-transmitted helminth infections. Geneva, World Heath Organization, 2001.** http://unstats.un.org/unsd/default.htm – accessed 23 October 2005.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0767

ing conditions such as menstruation, pregnancy andgenitourinary infections (Utzinger et al., 1998). Thisaspect must be taken into consideration when planningthe complementary strategy of the dewormingprogramme which is based on community actionand treatment of groups at high risk of infection. Amatter of concern is that the efficiency of the questionnaireand strip test decreases as the prevalenceand intensity of infection decrease.The situation is far more difficult regarding thedetection of S. mansoni and S. japonicum eggs in stoolbecause using questionnaires for intestinal symptomshas proved less promising. Repeated andextensive studies aimed at developing and validatinga questionnaire for rapid screening of S. mansoniinfection have addressed a variety of possiblespecific symptoms. The questions “Did you haveblood in stool during the last month?” and “Didyou have bloody diarrhoea during the last month?”were significantly associated with the prevalence ofS. mansoni infection, but the diagnostic performanceof these symptoms was only moderate. In differentdistricts of sub-Saharan countries, the sensitivity ofinformation on the perception of blood in stools variedfrom 47% to 88.2%, the specificity varied from57.7% to 76%, the positive predictive values variedfrom 66% to 73.2%, and the negative predictive valuesfrom 60% to 78.9% (Utzinger et al., 1998, 2002).Less information is available on the efficiency of thequestionnaire in estimating S. japonicum infection.In China, a six-question (on episodes of diarrhoea,frequency of water contact, school grade attained,weakness, past history of S. japonicum infection,and previous treatment for schistosomiasis, if any)form showed sensitivity of 93.7% and specificity of91.9% (Zhou et al., 1998). The use of multi-questionquestionnaires and their analysis by logistic regressionresulted in an area below the receiver-operatingcharacteristic curve of 0.90 (Tan et al., 2004), butthese are complex approaches that require skilledpersonnel.Egg detectionOne of the drawbacks of the questionnaire andurinary strip test is that neither provides baselineinformation on the intensity of infection. There isno need to re-confirm that the urine filtration andKato-Katz stool examination methods offer goodsensitivity in highly endemic areas; these are highlystudied methods and their usefulness for morbiditycontrol is well defined. Urine is easily collectedbut, due to the circadian pattern of egg excretion,specimens should ideally be collected between 10am and 2 pm. Parasitological methods (urine filtrationor Kato-Katz) cost about 10 US cents; althoughthese relatively cheap and simple methods havebeen available for decades, electricity, microscopesand trained microscopists may be very few or notavailable.In this case again, the best scientific contributionsand progress over the last decades have resulted notin the development of new methods but in betterunderstanding of the advantages, limitations andutility of available methods. A recent example isthe use of computer simulation to investigate thevalidity and cost-effectiveness of different screeningand control strategies for S. mansoni infection inUganda. In identifying schools with a prevalence ofS. mansoni higher or equal to 50%, a sampling computerizedmethod provided sensitivity and specificityof >90% at sample sizes of less than 20 children(Brooker et al., 2005).THE SCIENTIFIC ANDTECHNOLOGICAL REQUIREMENTSFOR TRANSMISSION CONTROLIn many countries such as Saudi Arabia, ThePhilippines, Morocco, China, Venezuela, and inregions of Egypt and Brazil, significant progress inthe control of schistosomiasis and other diseases hasbeen achieved by the national control programmesdue to considerable increases in resource capabilities,health educational activities, and environmentalsanitation. Use of large-scale chemotherapy hasallowed prevalence to decrease dramatically and bekept at low levels.In this strikingly diverse framework, in which reliableand accurate diagnostic tools are needed as a keyelement for schistosomiasis elimination, the healthservices are generally prepared and resources,though limited, are on hand. However, the windowof opportunity to switch from morbidity control totransmission control in these areas is only partiallyopened because of the lack of diagnostic tools forreliable, simple and inexpensive identification ofthe relatively small number of individuals who harbourjust a few worms. Can the scientific communityoffer more effective diagnostics tools than thosepresently available? Is there any progress?Unfortunately, the results of research on improveddiagnostic techniques are still unsatisfactory bearingin mind the ideal technique and the financial andinfrastructural difficulties of most endemic countries.Repeated parasitological examinations of urineor stool associated with different methods of antibodydetection remain the validated instruments. Toovercome the lack of sensitivity in situations of low68 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

worm burden (as found in low prevalence areas)and in evaluation after treatment, it is necessary toincrease the number of stool samples. This approachreduces the operational advantages of the techniqueby increasing the costs, hampering the screen-andtreatoperations, and reducing compliance. In monitoringthe control programmes, parasitological datamust be considered with caution since treatmentmay reduce the egg elimination rate by 90% in thosepatients who remain infected.Antibody detectionAlthough the efficiency of antibody detection variesaccording to the antigen system or method, thetechniques usually present high sensitivity but lowspecificity. Most commonly used is the enzymelinkedimmunosorbent assay (ELISA). The searchfor antigens of higher specificity than the solublecrude egg (SEA) or worm antigens (SWAP) resultedin purified preparations such as cathionic fraction6 (CEF6) (Doenhoff et al., 1993), adult microsomalantigen for S. mansoni, japonicum and haematobium(MAMA, JAMA, HAMA) (Tsang et al., 1983), gutassociated antigen 31/32 (Klinkert et al., 1991), andthe alkaline phosphatase immunocapture assay(Pujol and Cesari et al., 1990). Variable results withthese purified preparations were observed in differentsettings. They may be useful in specific situations(Doenhoff et al., 2004), but in general, theantibody-based methods offer low specificity, persistenceafter chemotherapy, cross reactivity, poorcorrelation with egg output, complex handling, andhigh costs.Although some progress has been reported in theresearch and development of rapid tests for antibodydetection, no validated resilient novel tool isavailable. Rapid tests for antibody detection in newassay formats have been reported for S. japonicum:the dot immunogold filtration assay (Wen et al.,2005), and the silver-enhanced colloidal gold metalloimmunoassay(Chu et al., 2005). A western blotassay has also been evaluated for anti-S. mansoniantibody detection (Sulahian et al., 2005). These newformats use crude antigens and still need to be validatedin large-scale field trials.Antigen detectionSimilarly, a number of assays to detect circulatingantigen have been described. Most experience hasbeen obtained with the detection of anodic (CAA)and cathodic (CCA) schistosome antigens in serumand urine using the ELISA or dipstick platforms,and antigen capture with monoclonal antibodies.The main advantages are high specificity, positivecorrelation with worm burden, and the possibilityfor estimation of infection intensity. Moreover, circulatingschistosome antigens disappear rapidly aftertreatment and can therefore be used for assessmentof cure. However, the sensitivity of antigen detectionvaries from 55% to 100%, being low in low endemicareas (van Lieshout, 2000) with no advantage overstool and urine examination.DNA detectionRecently, a DNA detection assay was developedand evaluated in a pilot field study. The polymerasechain reaction (PCR) indicated a prevalence of 38.1%,while triple Kato-Katz testing indicated 30.9% prevalencein the same samples (Pontes et al., 2003). TheDNA amplification assay may constitute an alternativeto available diagnostic techniques for the detectionof S. mansoni infection, but still needs furthervalidation. The PCR may, in particular, constitute atool for the diagnosis of Schistosoma sp. infection inspecial situations when high sensitivity and specificityare required and where infrastructure, financialresources and skilled personnel are available.Combined approachAs long as there is no simple diagnostic test for massscreening in areas of low prevalence, one strategy isto combine different methods to identify the smallnumber of infected people. One possibility is to useantibody detection, and to confirm actual infectionwith multiple parasitological examinations.The goal of this approach is to reduce the chancesof under-diagnosis and at the same time to reduceunnecessary treatment. The implementation of aschistosomiasis surveillance system, run by localpublic health centres and based on geographicaldistribution, water contact patterns, and the mappingand registration of individual cases, can help todefine the target population. Here again, inter andtrans-disciplinary (bio-science, mathematics, epidemiology,programme management) research isneeded in order to provide the basis for decisions onthe most cost-effective approach.Various control strategies have been defined by differentnational control programmes. Unequivocalbenefits are expected in the above-mentioned highmorbidity areas as praziquantel is a safe drug evenduring pregnancy and breastfeeding (Adam et al.,2005). The same strategy may not be proper in lowendemic areas, where severe morbidity is rare, butthe lack of a useful and simple diagnostics methodcombined with the low price of chemotherapeuticintervention has shifted the control strategy fromindividual diagnosis and treatment to selective populationmass drug distribution. In an endemic areawhere less than 10% of children present with eggs inReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0769

stool or urine, the targeted treatment of all schoolagechildren twice during their school years is recommended(Montresor et al., 2002). Expressing thisapproach in numbers, in a community with 1000school-age children and an estimated prevalence of8%, the drug will unnecessarily be administered toapproximately 900 students.This policy has potential implications:1) The risk of increasing drug resistance.2) The possible high costs and difficult sustainabilitywhen compared to individual diagnosisand treatment integrated into the primaryhealth care system. The cost of a strategy basedon ‘passive chemotherapy’ and health educationproved to be about half that of mass drug distributionin two villages in China, with 11% and12.3% prevalence of S. mansoni infection, withsimilar treatment coverage (Guo et al., 2005).On the other hand, in Ghana and Mali, onlyhalf of the patients reporting blood in stool orurine would receive treatment in a passive casedetection health care system (van der Werf etal., 2004). The different experiences are certainlythe result of health education and a strengthenedprimary health care service in China. Sucha comprehensive approach brings benefits thatgo far beyond the targeted disease.3) The ethical aspects. In respect to individualautonomy, whenever a drug is to be administeredunnecessarily to a person, he/she must beinformed of the risks and benefits, and the alternativeapproaches must be debated. Moreover,residents in endemic areas must have the rightto refuse to take the drug in the absence of anindividual positive diagnosis.The lack of notable developmentIn conclusion, this review reflects the limited investmentof both public and private sectors in researchand product development for diagnostics for schistosomeinfections. Despite the fact that research hasyielded breakthroughs in molecular biology, chemistryand engineering, no advances have been takenup by industry and applied to diagnostics developmentfor a growing range of illnesses and conditionsincluding schistosomiasis. There is urgent needfor an extended public-private partnership modelto target research and development from genomesequencing to regulatory approval, including makingavailable newly registered products to the publicsector at affordable prices.For the two scenarios discussed above (morbiditycontrol and transmission control), it is clear that thepriorities are to develop tests for rapid assessmentof intestinal schistosomiasis in areas of high endemicityand to develop more sensitive and specificdiagnostic tools for use in areas of low transmission,as was defined by TDR in 2001.*** In addition,improved diagnostics tools are needed to assist inchemotherapy, in the monitoring and evaluation ofcontrol programmes and of drug resistance, and inclinical trials of vaccine candidates and new drugs.Importantly, the diminishing focus on schistosomiasishas reduced the number of involved researchgroups. The decline in funding for schistosomiasisand diagnostics has led to this lack of notableadvances. As a final note, and most importantly, disease-endemiccountries’ research capacity and localautonomy are essential in carrying out and maintainingrealistic, collaborative and self-sustainedcontrol programmes.ReferencesAdam I, Elwasila E, Homeida M. Praziquantel for thetreatment of schistosomiasis mansoni during pregnancy.Annals of Tropical Medicine and Parasitology, 2005,99:37–40.Ansell J et al. The reliability of self-reported blood inurine and schistosomiasis as indicators of Schistosomahaematobium infection in school children: a studyin Muheza District, Tanzania. Tropical Medicine andInternational Health, 1997, 2:1180–1189.Brooker S et al. Rapid assessment of Schistosoma mansoni:the validity, applicability and cost-effectivenessof the Lot Quality Assurance Sampling methodin Uganda. Tropical Medicine and International Health,2005, 10:647–658.Chitsulo L et al. The global status of schistosomiasisand its control. Acta Tropica, 2000, 77:41–51.Chu X et al. Silver-enhanced colloidal gold metalloimmunoassayfor Schistosoma japonicum antibody detection.Journal of Immunological Methods, 2005, 301:77–88.Doenhoff MJ et al. Seroepidemiology and serodiagnosisof schistosomiasis in Kenya using crude and purifiedegg antigens of Schistosoma mansoni in ELISA.Transactions of the Royal Society of Tropical Medicine andHygiene, 1993, 87:42–48.*** http://www.who.int/tdr/diseases/schisto/direction.htm70 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Doenhoff MJ, Chiodini PL, Hamilton JV. Specific andsensitive diagnosis of schistosome infection: can itbe done with antibodies? Trends in Parasitology, 2004,20:35–39.Guo JG et al. The role of ‘passive chemotherapy’ plushealth education for schistosomiasis control in Chinaduring maintenance and consolidation phase. ActaTropica, 2005, 96:177–183.Guyatt H et al. The performance of school-basedquestionnaires of reported blood in urine in diagnosingSchistosoma haematobium infection: patterns byage and sex. Tropical Medicine and International Health,1999, 4:751–757.Klinkert MQ et al. Immunological analysis of clonedSchistosoma mansoni antigens Sm31 and Sm32 withsera of schistosomiasis patients. Tropical Medicine andParasitology, 1991, 42:319–324.Montresor A et al. Helminth control in school-agechildren. A guide for managers of control programmes.Geneva, World heath Organization, 2002.Pontes LA et al. Comparison of a polymerase chainreaction and the Kato-Katz technique for diagnosinginfection with Schistosoma mansoni. American Journal ofTropical Medicine and Hygiene, 2003, 68:652–656.Pujol FH, Cesari IM. Antigenicity of adult Schistosomamansoni alkaline phosphatase. Parasite Immunology,1990, 12:189–198.Stothard JR et al. Urinary schistosomiasis in schoolchildrenon Zanzibar Island (Unguja), Tanzania: a parasitologicalsurvey supplemented with questionnaires.Transactions of the Royal Society of Tropical Medicine andHygiene, 2002, 96:507–514.Sulahian A et al. Development and evaluation ofa Western blot kit for diagnosis of schistosomiasis.Clinical and Diagnostic Laboratory Immunology, 2005,12:548–551.Tan H et al. Rapid screening method for Schistosomajaponicum infection using questionnaires in flood areaof the People’s Republic of China. Acta Tropica, 2004,90:1–9.Tsang VC et al. Schistosoma mansoni adult microsomalantigens, a serologic reagent. II. Specificity of antibodyresponses to the S. mansoni microsomal antigen(MAMA). Journal of Immunology, 1983, 130:1366–1370.Utzinger J et al. Schistosoma mansoni, intestinal parasitesand perceived morbidity indicators in schoolchildrenin a rural endemic area of western Cote d’Ivoire.Tropical Medicine and International Health, 1998, 3:711–720.Utzinger J, Tanner M. Screening for schistosomiasiswith questionnaires. Trends in Parasitology, 2002,18:375–377.van der Werf MJ, Borsboom GJ, de Vlas SJ. No effectof recall period length on prevalence of self-reportedhaematuria in Schistosoma haematobium-endemic areas.Transactions of the Royal Society of Tropical Medicine andHygiene, 2003, 97:373–374.van der Werf MJ et al. Quantification of clinical morbidityassociated with schistosome infection in sub-Saharan Africa. Acta Tropica, 2003, 86:125–139.van der Werf MJ et al. Measuring schistosomiasiscase management of the health services in Ghana andMali. Tropical Medicine and International Health, 2004,9:149–157.van der Werf MJ, de Vlas SJ. Diagnosis of urinaryschistosomiasis: a novel approach to compare bladderpathology measured by ultrasound and threemethods for hematuria detection. American Journal ofTropical Medicine and Hygiene, 2004, 71:98–106.van Lieshout L, Polderman AM, Deelder AM.Immunodiagnosis of schistosomiasis by determinationof the circulating antigens CAA and CCA, in particularin individuals with recent or light infections.Acta Tropica, 2000, 77:69–80.Wen LY et al. Evaluation on the applied value of thedot immunogold filtration assay (DIGFA) for rapiddetection of anti-Schistosoma japonicum antibody. ActaTropica, 2005, 96:142–147.Zhou H et al. Diagnosis of schistosomiasis japonica inChinese schoolchildren by administration of a questionnaire.Transactions of the Royal Society of TropicalMedicine and Hygiene, 1998, 92:245–250.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0771

WORKING PAPER 9. Researchtowards new treatmentsfor schistosomiasisDonato CioliInstitute of Cell Biology, National Research Council(CNR), ItalyA single drug, praziquantel (PZQ), is currentlyavailable for the treatment of infections due toSchistosoma haematobium (the most frequent species),S. japonicum, S. mekongi, S. intercalatum and the socalledminor schistosomes. For S. mansoni infections,oxamniquine is still commercially available but itsprice discourages use and procurement is often difficult.Thus, PZQ is practically the only drug availablefor an infection that concerns 200 million people.It is clear that we are living dangerously, since theoryand experience strongly suggest that drug resistanceis a virtually unavoidable phenomenon for any antiinfectivecompound; if resistance were to underminethe usefulness of PZQ, it could take severalyears to develop an adequate substitute. In view ofthe fact that several million PZQ doses are administeredevery year and the number is going to rise inthe immediate future – increasing the risk of developmentof resistance – it should be apparent that itis now time to start looking for new drugs againstschistosomiasis.PRAZIQUANTELPZQ has proved to be a excellent drug, but is farfrom perfect. Its main asset is efficacy, which canbe roughly summarized in the notion that a singleoral dose usually gives cure rates of 70%–90%and reductions in egg excretion of 85%–95%. Theother important feature, as already mentioned, isthe wide spectrum of efficacy, encompassing allknown human schistosomes as well as other trematodesand cestodes. Side effects are rarely seriousand are usually of short duration, so that treatmentscan be administered without direct medical supervision.1 The widespread use has promoted large-scaleproduction and commercial competition, which hasresulted in very reasonable prices (about US$ 0.24per average treatment).The main problem with PZQ is that it is practicallyinactive against immature schistosomes, its fullactivity being displayed only 6–8 weeks after infection.This is the cause of many treatment ‘failures’and a serious limitation to the overall drug efficacy.The problem is particularly serious in high transmissionareas, where the probability of recent infectionsat the time of treatment is relatively high. 2Another problem is the existence of schistosomesthat show decreased sensitivity to PZQ. The fact thatdifferent PZQ susceptibilities exist has been documentedboth in field and laboratory-derived schistosomes,but the relevance of these differences mustbe evaluated quite carefully. Differences are invariablysmall (about 3x in terms of the median effectivedose [ED 50 ]) and do not increase upon exposureof repeated parasite generations to drug pressure. 3Some technical details of the ED 50 determination(i.e. the time of treatment after infection) may contributeto overestimation of PZQ refractoriness. Arecent report from an area of Egypt where schistosomeswith decreased PZQ susceptibility had beenisolated ten years ago, showed no indication of drugresistance in the population. 4 Thus, it is likely thatthe limited variability of PZQ efficacy observed sofar reflects, as with any drug, a certain genetic heterogeneityof schistosome populations, but is unlikelyto represent, as of today, a serious problem in termsof public health. This should be taken as an incentiveto exert continuous monitoring of PZQ efficacy,since the risk is still pending that serious and rapidlyspreading drug failure may appear in the future.As administered today, PZQ is a 50/50 racemic mixtureof two stereoisomers, one of which is totallyinactive as a schistosomicide but is contributing toproduce side effects. This goes against the increasingdemand of drug regulatory agencies to develop single-enantiomercompounds for all modern drugs. 5Finally, the mechanism of action of PZQ has notbeen unequivocally established, which is an obstacleto any rational development of better analoguesand an impediment to interpreting phenomena ofdecreased drug sensitivity.It is apparent from the above that several areas ofresearch could be directed towards better use ofPZQ. To begin with, drug efficacy is usually measuredby counting parasite eggs at follow-up, butthe timing of examination after treatment is highlyvariable and this prevents meaningful comparisonsbetween different treatments. The optimal timingof follow-up should be determined in such a waythat full deployment of drug effects is allowed whileminimizing ‘false failures’ due to reinfection or tomaturation of immature worms. Also, laboratorydetermination of PZQ ED 50 s in the mouse shouldbe adapted to take into account the possibility thatsome schistosome isolates may reach full maturation,and full drug sensitivity, at very late times afterinfection.72 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

An experimentally standardized protocol of PZQadministration has still to be adopted. The 40 mg/kgvs. 60 mg/kg choice is likely to depend on the localparasite characteristics, but parameters e.g. the associationwith food or drinks could probably be standardized.Combinations with other drugs may havethe goal of prolonging the bioavailability of PZQ insome special circumstances (e.g. using cimetidine) orof increasing the effectiveness of PZQ by associatingit with compounds with different antischistosomalmodes of action. In principle, a combination of PZQand artemisinin derivatives sounds extremely attractivesince the latter compounds are especially activeagainst immature schistosomes, but a number ofproblems need to be tackled experimentally (as discussedbelow). For S. mansoni infections, a combinationwith oxamniquine has been tested with mixedresults; it doesn’t seem very promising since bothdrugs are ineffective against immature worms. 6Efforts should be made to produce PZQ consistingonly of the active stereoisomer. Incidentally, thiswould also reduce by half the size of the PZQ tabletsthat are often difficult to swallow, especially forchildren.Continuous monitoring of PZQ effectiveness shouldbe established for early detection of any possibleappearance of drug resistance. Large chemotherapyprogrammes should include follow-up examinationsperformed at least on samples of the treatedpopulation, and any repeated, widespread or suspiciousfailures should be followed by parasiteisolation and laboratory determination of drug sensitivityin experimental animals.Operational research is needed to examine currentPZQ delivery systems, and to determine how PZQtreatment and delivery can significantly reduceschistosomiasis morbidity and enhance sustainabilityof control. For example, the frequency oftreatment campaigns is a key element in the optimizationof economic resources in relation to morbidityreduction in the population. Association of PZQwith anthelminthic drugs targeted at different parasitesis quite common in the case of albendazole,and additional combinations may be investigated.As already mentioned, elucidation of the mechanismof action of PZQ would be of paramountimportance. An attractive hypothesis has been putforward which implicates the beta subunit of voltage-gatedcalcium channels as a key molecule in theobserved massive calcium influx in the parasite andin the subsequent tegumental alterations caused byPZQ. 7 The evidence collected so far is quite convincingbut is mainly based on the expression of schistosomegenes in heterologous systems and needsdirect confirmation in the parasite. Also, a comprehensivedescription of schistosome calcium channelsis still lacking and no attempt has been madeto fit the insensitivity of immature worms into themodel.OXAMNIQUINEIn over thirty years of intensive use, mainly on theAmerican continent, oxamniquine has proved to bea very safe and effective drug for S. mansoni infection.It would be an absolute loss if commercial reasonswere to cause its disappearance. Every effortshould be made to keep it on the market, as it is theonly valid, albeit partial, alternative to PZQ.The major drawback of oxamniquine (limited spectrumof activity) is somewhat counterbalanced bythe existence of a reasonable model regarding itsmechanism of action. It has been shown that oxamniquineacts like a pro-drug, being transformedinto the active compound by a schistosome enzymethat catalyses its conversion to a reactive ester. Theoxamniquine ester spontaneously dissociates givingrise to an alkylating agent capable of formingcovalent bonds with parasite DNA and other macromolecules.Lack of the esterifying enzyme – a sulfotransferase– leads to drug inactivity. 8 Since S.japonicum and S. haematobium appear to possess theenzyme, but presumably with critical changes in theoxamniquine binding site, it is in principle feasibleto determine the structure of their binding sites andthen to modify the oxamniquine molecule in such away that it could bind to the enzymes of the otherspecies. If successful, this would recuperate a preciousweapon for the armamentarium of antischistosomaldrugs.ARTEMISININ DERIVATIVESThese compounds, currently among the most potentantimalarials available, are also active against allmajor human schistosome species. 9 They are of specialinterest because their activity is exactly complementaryto the activity of PZQ, i.e. it is especiallydirected against immature worms, while adult schistosomesare only partially sensitive. Thus combinationtherapy would be in principle very attractive,but there are a number of practical issues that makethe proposition rather problematic. Artemisininderivatives have to be administered in multipledoses, are relatively expensive, and may interferewith antimalarial chemotherapy if used againstschistosomiasis in areas where both diseases arepresent. Artemisinins by themselves have been successfullyused as antischistosomals in some specialReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0773

circumstances, e.g. in people exposed to the infectionat a defined time because of a flood, but cannotbe considered as a possible alternative to PZQ dueto their limited activity against adult worms.RESEARCH ON NEWANTISCHISTOSOMAL DRUGSIn principle, new antischistosomals can be searchedout either by high throughput screening of largechemical collections or by focusing on existing leadsand more promising potential targets. The firstapproach is currently supported by TDR (throughits drug discovery unit), but screening for antischistosomalsin vitro or in vivo is a rather expensiveprocess and the funds available have not permitted,so far, the large-scale operation that is desirable. Asto the second approach, brief mention will be madehere of some examples of existing leads that mightbe the object of further exploration.Acridanone hydrazonesA series of acridine derivatives synthesized byHoffmann La Roche (among them Ro 15-5458) haveshown promising activity against the three majorhuman schistosomes and, most importantly, againstboth mature and immature stages. 10,11 A single oraldose gave practically complete cure in mice, rabbitsand primates. At least two members of the serieswere active even after epicutaneous application onthe skin of hairless mice. In addition, they are relativelysimple chemicals that could probably be synthesizedrather inexpensively. The major problemwith these acridine compounds is that they are typicalDNA-intercalating agents and may thereforepossess mutagenic and carcinogenic properties. Thebacterial tests performed so far have failed to showmutagenicity, but much more extensive toxicologicaltrials are clearly needed for this type of compound.BenzodiazepinesSeveral benzodiazepines have been shown to possessantischistosomal properties, among them theanticonvulsant clonazepam and its methyl derivativedesignated Ro 11-3128. 12 The latter compoundwas very effective in animals as well as in a preliminaryhuman study, but activity was confined to S.mansoni and S. haematobium, while S. japonicum wasnot affected. Immature schistosomes are also sensitiveto Ro 11-3128. The problem is that, not surprisinglyfor a benzodiazepine, the drug causes severeand long-lasting sedation, accompanied by ataxiaand muscle relaxation. This could be preventedby administering the benzodiazepine antagonistRo 15-1788, which does not block the antischistosomalactivity, but unfortunately the effect of theantagonist is of short duration compared to that ofRo 11-3128 so that repeated administrations wouldbe needed. 13 Further development of the drug wasabandoned, but some similarities with the mode ofaction of PZQ may be of interest: both compoundscause a rapid calcium influx, muscular contractionand tegument disruption; both display stereoselectiveactivities; both emerged from a screening ofcompounds active on the nervous system. It wasshown, however, that PZQ does not compete for thebinding site of Ro 11-3128.Plant derivativesA long list of plant-derived substances have beenshown to be more or less active against variousstages of the schistosome life cycle. Such substancesare often quite appealing for their ‘natural’ originand for their possibly inexpensive production inthe same areas where schistosomiasis is endemic.In many cases, however, these plant extracts arehardly acceptable mixtures of hundreds of undefinedcompounds, are quite variable in composition,and would require elaborate processes for isolationand identification of the active principle. Toxicityis often a problem that limits the use of such ‘natural’products. A systematic and rigorous study ofnatural substances, however, remains one of themost promising sources of new drugs, includingantischistosomals.Other potential drug targetsA large number of potential drug targets exist that,although not experimentally shown to be applicablein antischistosomal chemotherapy, are neverthelessattractive because they have been exploited inother systems or against different pathogens. Thisis a field of enormous interest, especially since theprogress of genomics is opening a number of schistosomemolecules to direct experimental testing.Last but not least, it is quite possible that new drugsagainst schistosomiasis may not come from effortsaimed directly at this specific goal, but may well bethe result of basic research on the biology of schistosomes.Needless to say, investments in this area arenever wasted.74 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

References1 Cioli D, Pica-Mattoccia L. Praziquantel.Parasitology Research, 2003, 90(Suppl 1):3–9.2 Gryseels B et al. Are poor responses to praziquantelfor the treatment of Schistosoma mansoni infectionsin Senegal due to resistance? An overviewof the evidence. Tropical Medicine and InternationalHealth, 2001, 6:864–873.3 Cioli D et al. Determination of ED50 values forpraziquantel in praziquantel-resistant and -susceptibleSchistosoma mansoni isolates. InternationalJournal of Parasitology, 2004, 34:979–987.4 Botros S et al. Current status of sensitivity to praziquantelin a focus of potential drug resistance inEgypt. International Journal of Parasitology, 2005,35:787–791.5 Triggle DJ. Stereoselectivity of drug action. DrugDiscovery Today, 1997, 2:138–147.6 Utzinger J et al. Combination chemotherapy ofschistosomiasis in laboratory studies and clinicaltrials. Antimicrobial Agents and Chemotherapy, 2003,47:1487–1495.7 Greenberg RM. Are Ca2+ channels targets of praziquantelaction? International Journal of Parasitology,2005, 35:1–9.8 Cioli et al. Antischistosomal drugs: past, present... and future? Pharmacology and Therapeutics, 1995,68:35–85.9 Xiao SH, Catto BA. In vitro and in vivo studiesof the effect of artemether on Schistosoma mansoni.Antimicrobial Agents and Chemotherapy, 1989,33:1557–1562.10 Coelho PM, Pereira LH. Schistosoma mansoni:preclinical studies with 9-Acridanone-hydrazonesin Cebus monkeys experimentally infected. Revistado Instituto de Medicina Tropical de São Paulo, 1991,33(1):50–57.11 Guirguis FR. Efficacy of praziquantel and Ro 15-5458, a 9-acridanone-hydrazone derivative, againstSchistosoma haematobium. Arzneimittel-Forschung,2003, 53(1):57–61.12 Stohler HR. Ro 11-3128, a novel schistosomicidalcompound. In: Siegenthaler W, Luethy R,eds. Current Chemotherapy, Proceedings of the10th International Congress of Chemotherapy,American Society of Microbiology, WashingtonDC, 1978:147–148.13 Hunkeler et al. Selective antagonists of benzodiazepines.Nature, 1981, 290:514–516.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0775

WORKING PAPER 10.The socioculturalcontext of schistosomiasiscontrol: currentknowledge and futureresearch needsBirgitte Bruun and Jens Aagaard-HansenDBL – Institute for Health Research and Development,Denmark, and Schistosomiasis Research Programme(SRP)INTRODUCTIONThe first initiatives to control schistosomiasis wereimplemented in Egypt around the First World Warand have continued in various countries around theworld ever since. Thus, for almost a hundred yearswe have accumulated knowledge about the controlof schistosomiasis. However, in spite of these efforts,the latest figures indicate that the number of infectedpeople has risen. Since the first estimation almost 60years ago of 114 million people infected (Stoll, 1947),today 200 million are thought to be infected (Engelset al., 2002; Chitsulo et al., 2000).This rise can be partly explained by populationgrowth in some of the endemic areas, but this factdoes not diminish the challenge to public health,particularly since the infection is increasingly foundin the poorest areas of the world where resources forcontrol are very limited. The challenge is of a technicalnature in terms of the need for improved diagnosticsand treatment regimens, but it is also verymuch of a social and political nature. The processof making treatment available to the infected and,indeed, of preventing people getting infected in thefirst place, is inextricably linked to specific sociocultural,behavioural, political and economic factorsand processes at local, national and internationallevels.The sociocultural factors and processes are many.At the level of local day-to-day activities, transmissiondynamics are influenced by changing patternsof water contact which are related to socioculturalexpressions of age, gender role and occupation.Cultural factors play a role in the identification ofsigns and symptoms, and when the severity of thedisease is negotiated among other pressing concernsin the household. These factors have implications forthe way people select and use possible alternativesto unsafe water contact and for the way health educationand treatment options should be developed.But vulnerability is not only a matter of individuals’risk behaviour. At the level of national and internationalsocioeconomic processes, endemic areasare ‘produced’ and maintained by water resourcesdevelopment, by the dynamics of population movement(e.g. migration and tourism), by unplannedurbanization, and also by the structures that marginalizecertain groups of people (e.g. women, certainethnic groups, refugees). These larger scalesocioeconomic processes contribute systematicallyto increased vulnerability (Saker et al., 2004).Activities to control the infection can also beregarded as a specific sub-set of social processes,which condition access to diagnosis and information,and involvement in decision-making regardinghealth programmes. These issues have become particularlyprominent since the global control strategyshifted from vector control to morbidity control andthe human definitive host became the focus of interventions.Control programmes do not operate in asociocultural or political vacuum, but interact withnational health systems that are influenced by a hostof sociocultural and economic factors, including theagendas set by the Millennium Development Goals(MDGs), sector-wide approaches (SWAps), decentralizationpolicies and poverty reduction strategies(PRS).As we move from a look at day-to-day activities,through the larger scale social dynamics that influencevulnerability, to the operations of control programmesand health systems, we gradually moveaway from a specific focus on schistosomiasistowards the underlying dynamics that determine(unequal) vulnerability to ill health. These dynamicsare formed by political, economic, social and culturalfactors, or ‘the social determinants of health’,which is an illuminating conceptual frameworkfor understanding and addressing disease, includingschistosomiasis. Research on the social determinantsoffers quantifiable insights into importantvariables, but also has the capacity to embrace analysesof social processes, which can illuminate howvulnerability emerges in interaction with shiftingpolicies and programmes for control (see workingpaper 11 of this publication on: The social determinantsof schistosomiasis).The social sciences can provide insight into the socialdynamics at local, national and international levelsthat influence transmission and control. Social scienceis an umbrella term for a host of very diversedisciplines, of which economics, political science,cultural geography, communication, education,sociology and anthropology have contributed specificallyto knowledge regarding schistosomiasis.76 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

This paper will mainly summarize selected researchfindings from the latter two disciplines regardingschistosomiasis control and point to future areas forresearch on control activities. The paper is basedon an ongoing comprehensive literature search,including English, French, Chinese and Portuguesearticles, on sociocultural aspects of both the transmissionand control of schistosomiasis. It is our aimto publish an annotated bibliography in 2006 underthe auspices of TDR. The compilation of the bibliographyis funded by the Schistosomiasis ResearchProgram (SRP) under the Schistosomiasis ControlInitiative (SCI) funded by the Bill and Melinda GatesFoundation.CURRENT KNOWLEDGE ANDTOPICS FOR FURTHER RESEARCHREGARDING THE SOCIOCULTURALASPECTS OF SCHISTOSOMIASISCONTROLAs mentioned above, social science has exploredtransmission dynamics at local, national, and internationallevels. This paper will, however, focus onstudies of schistosomiasis control, which can largelybe grouped into four main topics:• Diagnosis and case management• Health education• Community involvement• Schistosomiasis control in a broader health systemsperspective.The sections below will summarize selected findingsunder each topic and point to gaps in our knowledge.It should be emphasized that the findings andsuggested topics for future research listed beloware localized and may not account for all endemicareas.Diagnosis and case managementDiagnosis and case management are often seen aspurely technical enterprises, but they can also beperceived more broadly as ‘interfaces’ between theinfected individual, the afflicted community and thehealth care system represented by different types ofhealth service, health care worker and researcher.The literature related to schistosomiasis is verylimited in this field, but the following have beenobserved:• The acceptability of diagnostic tools and therebydata on prevalence levels can be influenced bysocial and cultural factors, including genderbiases and economic constraints of the poorestto join screenings and surveys. Only scarce dataare available on the links between acceptabilityof various diagnostic methods from the local per-spective, consequences for willingness to participatein surveys, ethics, and the validity of data(Goncalves et al., 2005; Hatz, 2001; Feldmeier etal., 1993:162).• Case detection and case management, which areimportant in passive control strategies, dependon health personnel skills, capacity and motivationas well as on the income generating possibilitiesof health facilities (Bian et al., 2004; deVlas et al., 2004; van der Werf et al., 2004; van derWerf et al., 2002; Sayed et al., 2000).• Although the existence of genital schistosomiasisin women has been known since the beginningof the 20th century, and much more recently hasalso become known in men, these forms of schistosomiasisappear to be seriously under-diagnosed(Talaat et al., 2004; Leutscher et al., 2000;Poggensee et al., 1999; Feldmeier et al., 1995). Theextent of genital schistosomiasis is of particularconcern since this form of schistosomiasis mayinteract with the spread of sexually transmittedinfections, including HIV (Leutscher et al., 2003;Poggensee et al., 2001).Since survey data have essential implicationsfor policy development and priority-setting, theobservations above invite scrutiny with regard tothe representativeness of data, specifically as towhether there is unbiased inclusion of marginalizedgroups. In this regard it should also be notedthat the unknown extent of genital schistosomiasismeans that its status as a public health issue remainsunclear (Poggensee et al., 1999).Topics for future research• How can the social aspects of diagnosis, such asunder-representation of women or the poorest,be addressed in screening and surveillance?• How can the need for ethically and individuallyacceptable methods of control that are also effectiveat the community level be addressed?• What are the social and technical barriers to betterdiagnosis of genital schistosomiasis in bothmen and women?Health educationIn schistosomiasis control, health education is seenas instrumental in improving awareness of the infectionand increasing knowledge about its transmission.It is also seen to motivate behaviour changeand to create an enabling environment where otherinterventions, such as treatment and the instalmentof water supply and sanitation, are accepted. Finally,health education is sometimes intended to maintainsustainability of programme results and to build citizenshipby engaging local stakeholders politicallyReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0777

in their local environment. The latter purpose is particularlyprominent in studies from Brazil (Massaraet al., 2004).In sociological and anthropological research relatedto schistosomiasis, studies on health education arethe most numerous. Such studies present varioushealth education models for different target groupsor they evaluate the impact of health education interventionson perceptions, behaviour and/or levels ofprevalence. Findings are often similar to health educationinitiatives for other ailments. Selected observationsare:• Health education does not work if people haveno (attractive) alternatives to unsafe water contact.This observation applies equally to domestic,occupational, religious and recreationalactivities (Ekeh et al., 1988).• Health education messages are often conveyed ina way that appears irrelevant to local stakeholders’experience, priorities and routines (Kloos,1995).• Many health education initiatives do have animpact on knowledge. However, improvedknowledge does not necessarily lead to changedpractice in order to avoid risk. In other words,there is no linear connection between knowledgeand behaviour (as is also well known from manyother diseases) (Kloos, 1995).• Health education is not a matter of pouringinformation into empty vessels. Health informationis always re-interpreted in the light ofprevious experience and translated into actiondepending on what is socially, economically andpractically possible and desirable for the individualand the household. Unfortunately, muchhealth education in control programmes does notreflect this insight (El Katsha et al., 1994).• Health education components of control programmesare rarely systematically evaluated forimpact, and the few impact studies there havebeen have produced varying results (Lucien etal., 2003; Sow et al., 2003; Lansdown et al., 2002;Nsowah-Nuamah et al., 2001; Garba et al., 2001;Guanghan et al., 2000).• The possibility of developing a standard scriptfor effective health education is doubtful due tolocal variations. So far, health education on schistosomiasishas taken a myriad forms, involvingmass media, theatre, posters and brochures, elaborateinteractive education projects in schools,and the animation of local educators. This complicatesany attempt to conduct comparativeanalyses of impact (Kloos, 1995).Many lessons about the more effective strategies forhealth education can be learned from HIV/AIDS andTB programmes, where active involvement of localpeople is often at the core of the work (but wheresuccess is rare in the lowest income countries). Thenext section will describe community involvement,but first, a few research needs specifically related tohealth education in schistosomiasis are:Topics for future research• What are the factors involved when men, womenand children actually do change behaviour toreduce the risk of schistosomiasis infection?• What is the experience when health educationcampaigns on schistosomiasis are combined withother health promoting campaigns?• How do people navigate between various perceivedhealth risks and how can knowledge ofthese strategies be incorporated into the designand indicators of control programmes?Community participationMany studies have looked at community participation.The literature observes that community participationor involvement is sometimes understoodas an intervention along with health education andsanitation, and more rarely it is understood as it wasoriginally intended: as an approach to planning,implementation and evaluation. It is a term witha very wide range of uses, from mere rhetorics inprogramme documents to actual partnerships andaction research (Espino et al., 2004; El Katsha et al.,1998). A critique observes how community participationis sometimes reduced to a matter of using volunteersto reduce expenses and using local leadersto ease acceptance of the programme. Furthermore,local representatives are rarely included in decisionmakingforums (Loureiro, 1989). However, it is amisconception to believe that community participationmakes programmes less demanding in termsof material and human resources (Kloos, 1995:1499).Furthermore, official representations of communityparticipation tend to down-play the ‘political’aspects of the process, but in practice any interventionis ‘political’, whether it is labelled participatoryor not. Especially studies from Brazil have highlightedthis particular aspect of schistosomiasis control(Acioli et al., 1998; Dias, 1998; Barbosa, 1995).Selected observations from studies on communityparticipation in relation to schistosomiasis include:• Many policy-makers and implementers agreethat communities can and should be involvedin various aspects of control (e.g. snail controland environmental management). However, thetranslation of involvement into action is sometimesreduced to an issue of making peoplecooperate, partly due to the institutional logic ofthe health sector, where mechanisms for involv-78 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

ing communities in planning and priority-settingare rare (Alves, 1998).• In many cases the term ‘community participation’has lost its original meaning. A new term,‘community-directed intervention’, has emergedin onchocerciasis control programmes in Nigeria(that are now integrated with schistosomiasisand other intestinal helminth control) to indicatea higher degree of community responsibility fordistribution of drugs and other aspects of control.Studies have shown how this approach out-performedmore conventional programme-designedsystems in effectiveness, acceptance, and coverage(Katabarwa et al., 2005).• Few studies in schistosomiasis control haveassessed the relationship between the type ofcommunity participation and the impact and/or sustainability of prevention and control measuresover time. Even fewer have looked into thesocial processes involved in community participationwith the aim of generating more generalconclusions about the dynamics of social change(Espino et al., 2004).• The concept of ‘community’ evokes the imageof a uniform organism with shared interests,but community representatives cannot alwaysbe taken to act in the interests of all communitymembers (women, the poorest, ethnic or politicalgroups, etc.). No community is completelyhomogeneous (Espino et al., 2004).• There are very few studies on how mobile populations,or communities cut through by social,economic and political divisions, can be involvedin control activities, if at all (Espino et al., 2004).• Women generally maintain a higher and moreconstant level of enthusiasm in surveys and controlprojects than men (Feldmeier et al., 1993:165).• There is no single, universal way to motivatecommunity participation. Success largelydepends on factors that differ from village to village,e.g. the authority of the village chief, theinternal cohesion of the village community, thegeneral economic situation and economic stratification(Hielscher and Sommerfeld, 1985:481).Topics for future research• What are the links between successful involvementof local stakeholders in planning, implementationand evaluation on the one hand andimproved sustainability in different endemic settingson the other hand?• How can we best address the fact that schistosomiasisis often found among the poorest andmost mobile groups who have the least resources(in terms of time, manpower and social relations)to contribute to control measures? What indicatorsof equity should be defined?• If women are more engaged in local controlactivities, what is their motivation? What wouldmake men become more engaged? How can weengage children both in and out of school?• What are the conducive and constraining factorsinvolved in letting local stakeholders takemore control of programmes? To what extent areprogrammers and health authorities at all levelsready to let go of control? What would theinstitutional implications be, also in sectors otherthan the health sector?• If capacity building is needed in this regard,how can we avoid it becoming another and moresophisticated way of vertical control with limitedsustainability?Schistosomiasis control in a broader healthsystems perspectiveThere is a growing sense that advances in drugs,vaccines and diagnostics are not enough to improvehealth on their own, but that the systems by whichthese means are distributed need scrutiny. In malariacontrol some voices claim that failure to control thedisease is not due to lack of tools but to failures at thesocietal and organizational levels (Heggenhougen etal., 2003). Does this observation perhaps apply toschistosomiasis control efforts as well?Apart from economic, political and governanceissues, there are also social and cultural aspects ofschistosomiasis control at this level. Very few studiesaddress these themes, but some of the observationsand issues raised are:• Understanding health-seeking behaviour andfactors influencing the decision to self-report isrelevant for health planners (Danso-Appiah et al.,2004:785). Whether people seek treatment is notonly a matter of their knowledge of the infection.Perceived quality of health care, the cost of medicine,and user fees are among the socioeconomicand cultural factors that influence whether peopleprioritize treatment (e.g. Uchoa et al., 2000)or seek alternatives within a pluralistic system(Muela et al., 2000).• The exact dynamics of social development (bettereducation, living conditions, sanitation, etc.)and schistosomiasis are unclear, but the infectiontends to appear among the poorest and mostunderprivileged (Watts, 2005; Dias, 1998; Liese,1986).• Health workers and facilities are, most often, neitherequipped nor motivated for passive controland case management (as mentioned above).Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0779

• User fees can skew case finding. If schistosomiasiscontrol structures are vertical and situatedin a health system that is in the process of introducinguser fees, there is a risk that “reducingthe prevalence and incidence of schistosomiasiswould be irrational behaviour from a shortand medium-term profit perspective” (Bian et al.,2004:91–92).• In relation to priority-setting, the measurementof burden of disease has been contested. The fewdisability measurements of cognitive development,working ability and income generation areeven more controversial (King, 2005; Michaud etal., 2004; Parker, 1992).• Even if there was consensus on the burden ofdisease related to schistosomiasis, it might notbe the only factor in priority-setting. The burstsof global attention paid to polio, malaria and TBwere not only the result of rational assessmentsof burden of disease and the availability of costeffectiveinterventions. Their emergence on theglobal health agenda was driven not only bythe risk they posed to the North, but also by thesymbols and emotionally engaging images of diseasethreats, and by the role that various actorsand technologies could have in combating them(Shiffman et al., 2002:231).The issues raised above are similar to many otherhealth concerns in developing countries and inextricablylinked to the lack of political understandingand commitment, and financial and humanresources. Thus, some of the proposed topics forfuture research below are not specific to schistosomiasiscontrol alone but could be part of a moregeneric research agenda.Topics for future research• How will user fees for diagnosis and treatmentaffect equity in access to relevant medical servicesin different local settings?• How can the measurement of burden of diseaseand disability related to schistosomiasis be furtherimproved to strengthen priority-setting inthe health sector?• What is the evidence for the effectiveness, efficiencyand sustainability of standardized controlprogrammes vs. programmes that adapt to localconcerns and conditions?• To what extent does the health sector havethe authority and capacity to explore innovativeapproaches and linkages to other healthpromoting activities that are made to fit localconditions?• What would be the optimal mix between horizontalimplementation and vertical technical orprogrammatic support in different settings? Howto create synergy between local control effortsand global initiatives?• What are the social and political barriers to thenecessary intersectoral collaboration and to public–privatepartnerships in schistosomiasis control,which are absolutely paramount in waterresources development and urbanization processes,not to mention general initiatives to reducepoverty?FUTURE DIRECTIONS FORSOCIAL SCIENCE RESEARCH ONSCHISTOSOMIASIS CONTROLThe history of schistosomiasis control has fluctuatedbetween control measures focused on one-dimensional,technical ‘quick-fix’ interventions on the onehand and the application of multiple approacheson the other hand. This fluctuation occurred as the‘quick fixes’ seemed not to work (Reich, 1988) andas new understanding of how the social dimensionsin disease causation interact with technical innovationsand changes in organizational/managerial setupsbecame available. There has been a tendency tofocus on biological rather than social factors in thetransmission of schistosomiasis, except for brief periodsin the 1930s and late 1960s (Sandbach, 1976:275).Today, for good reasons, treatment with praziquantelis the backbone of control interventions, withincreasingly refined ways of targeting populationsdue to increased attention to the cost–effectivenessof disease specific interventions. The long-term sustainabilityof this approach is, however, questionabledue to the costs of repeated treatment, the possibilitythat the parasite will develop drug resistance,and the many practical challenges that control programmesmeet during implementation in complexsociocultural settings involving a variety of healthand non-health stakeholders.If control efforts are to become more effective andsustainable, it is also necessary to work towardsbetter use of the available economic, technical andhuman resources – and this implies (behaviour)change not only for the people who live on thebanks of lakes, rivers and streams but also for programmersand policy-makers at national and internationallevels (e.g. Porter et al., 1999). Researchersneed to complement technical solutions with criticalinsights into the social and intervention managementdynamics at all levels in order to strengthenthe interventions. Further insight will be needed onmodes of delivering various combinations of interventionsand on how local stakeholders can best beinvolved in the processes of priority-setting. Such‘grounding’ of the process might point to ways80 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

that schistosomiasis control could ‘piggy-back’ onother interventions in the interests of local stakeholders,whose health needs are already integrated.Whether such a process could lead to more appropriatehealth service delivery if different control andprevention programme components were combinedin new ways should also be explored. The inclusionof social science perspectives will not make controlof schistosomiasis any simpler – but then again, itnever was simple, as is evident from the perpetuallyhigh global numbers of infected people.AcknowledgementsThe authors would like to thank the SchistosomiasisResearch Program (SRP) for funding the work forthe forthcoming bibliography on the Social-culturalcontext of schistosomiasis transmission and control.Furthermore, we thank the following people for valuablecomments to the draft versions of this paper:Dr Susan Watts, Senior Research Associate, SocialResearch Center, American University in Cairo,and Social Determinants of Health, WHO EasternMediterranean Regional Office, Cairo; Drs PascalMagnussen, Jens Byskov, and Niels Ornbjerg at theDBL – Institute of Health Research and Development,Denmark, and others.ReferencesAcioli MD, de Carvalho EF. [Discourses and practicesconcerning the social participation process in healtheducation activities: community mobilization in thePCDEN/PE. Programa de Controle das DoencasEndemicas do Nordeste/Pernambuco]. Cadernos deSaúde Pública, 1998, 14(Suppl 2):59–68.Alves PC et al. [Schistosomiasis and the challenge ofcommunity participation]. Cadernos de Saúde Pública,1998, 14(Suppl 2):79–90.Barbosa FS. Determination and control of schistosomiasis.Memórias do Instituto Oswaldo Cruz, 1995,90(2):155–159.Bian Y et al. Market reform: a challenge to publichealth – the case of schistosomiasis control inChina. The International Journal of Health Planning andManagement, 2004, 19(Suppl 1):S79–S94.Chitsulo L et al. The global status of schistosomiasisand its control. Acta Tropica, 2000, 77(1):41–51.Danso-Appiah A et al. Determinants of health-seekingbehaviour for schistosomiasis-related symptomsin the context of integrating schistosomiasis controlwithin the regular health services in Ghana. TropicalMedicine and International Health, 2004, 9(7):784–794.de Vlas SJ et al. Quantitative evaluation of integratedschistosomiasis control: the example of passive casefinding in Ghana. Tropical Medicine and InternationalHealth, 2004, 9(6):A16–A21.Dias JC. [Community participation and control ofendemic diseases in Brazil: problems and possibilities].Cadernos de Saúde Pública, 1998, 14(Suppl 2):19–37.Ekeh HE, Adeniyi JD. Health education strategies fortropical disease control in school children. The Journalof Tropical Medicine and Hygiene, 1988, 91(2):55–59.El Katsha S, Watts S. A model for health education.World Health Forum, 1994, 15(1):29–33.El Katsha S, Watts S. Schistosomiasis screening andhealth education for children: action research inNile delta villages. Tropical Medicine and InternationalHealth, 1998, 3(8):654–660.Engels D et al. The global epidemiological situationof schistosomiasis and new approaches to control andresearch. Acta Tropica, 2002, 82(2):139–146.Espino F, Koops V, Manderson L. Community participationand tropical disease control in resource-poor settings.Geneva, UNICEF/UNDP/World Bank/WHO SpecialProgramme for Research and Training in TropicalDiseases (TDR), 2004 (TDR/STR/SEB/ST/04.1 ).Feldmeier H, Poggensee G, Krantz I. A synopticinventory of needs for research on women and tropicalparasitic diseases. II. Gender-related biases in thediagnosis and morbidity assessment of schistosomiasisin women. Acta Tropica, 1993, 55(3):139–169.Feldmeier H, Krantz I. A synoptic inventory of needsfor research on women and tropical parasitic diseases.I. Application to urinary and intestinal schistosomiasis.Acta Tropica, 1993, 55(3):117–138.Feldmeier H et al. Female genital schistosomiasis.New challenges from a gender perspective. Tropicaland Geographical Medicine, 1995, 47(Suppl 2):S2–15.Garba A et al. [Impact of health education programson the control of urinary bilharziasis in Niger]. Santé,2001, 11(1):35–42.Goncalves MM et al. [Sociocultural and ethical factorsinvolved in the diagnosis of schistosomiasis mansoniin an area of low endemicity]. Cadernos de SaúdePública, 2005, 21(1):92–100.Guanghan H et al. The role of health education forschistosomiasis control in heavy endemic area ofPoyang Lake region, People’s Republic of China. TheSoutheast Asian Journal of Tropical Medicine and PublicHealth, 2000, 31(3):467–472.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0781

Hatz CFR. The application of ultrasonography inschistosomiasis. In: Baker JR, Muller R, Rollinson D,eds. Advances in Parasitology, 2001:256–263.Heggenhougen HK, Hackenthal V, Vivek P. The behaviouraland social aspects of malaria and its control: anintroduction and annotated bibliography. UNDP/WorldBank/WHO Special Programme for Research andTraining in Tropical Diseases (TDR), 2003 (TDR/STR/SEB/VOL/03.1).Hielscher S, Sommerfeld J. Concepts of illness and theutilization of health-care services in a rural Malian village.Social Science and Medicine, 1985, 21(4):469–481.Katabarwa MN et al. Community-directed interventionsstrategy enhances efficient and effective integrationof health care delivery and developmentactivities in rural disadvantaged communities ofUganda. Tropical Medicine and International Health,2005, 10(4):312–321.King CH, Dickman K, Tisch DJ. Reassessment of thecost of chronic helmintic infection: a meta-analysis ofdisability-related outcomes in endemic schistosomiasis.Lancet, 2005, 365(9470):1561–1569.Kloos H. Human behavior, health education andschistosomiasis control: a review. Social Science andMedicine, 1995, 40(11):1497–1511.Lansdown R et al. Schistosomiasis, helminth infectionand health education in Tanzania: achieving behaviourchange in primary schools. Health EducationResearch, 2002, 17(4):425–433.Leutsscher PD et al. Sexual behavior and sexuallytransmitted infections in men living in ruralMadagascar: implications for HIV transmission.Sexually Transmitted Diseases, 2003, 30(3):262–265.Leutsscher P et al. Community-based study of genitalschistosomiasis in men from Madagascar. Lancet, 2000,355(9198):117–118.Liese B. The Organization of schistosomiasis controlprogrammes. Parasitology Today, 1986, 2(12):339–345.Loureiro S. [Social aspects of the epidemiology andcontrol of schistosomiasis mansoni]. Memórias doInstituto Oswaldo Cruz, 1989, 84(Suppl 1):124–133.Lucien KF, Nkwelang G, Ejezie GC. Health educationstrategy in the control of urinary schistosomiasis.Clinical Laboratory Science, 2003, 16(3):137–141.Massara CL, Schall VT. A pedagogical approach toschistosomiasis – an experience in health educationin Minas Gerais, Brazil. Memórias do Instituto OswaldoCruz, 2004, 99(5 Suppl 1):113–119.Michaud CM, Scott WS, Reich MR. The global burdenof disease due to schistosomiasis. Harvard Schoolof Public Health, Harvard Center for Populationand Development Studies, Schistosomiasis ResearchProgram, Working Paper Series 14, no. 1, 2004.Muela SH, Mushi AK, Ribera JM. The paradox of thecost and affordability of traditional and governmenthealth services in Tanzania. Health Policy and Planning,2000, 15(3):296–302.Nsowah-Nuamah NN et al. Urinary schistosomiasisin southern Ghana: a logistic regression approachto data from a community-based integrated controlprogram. American Journal of Tropical Medicine andHygiene, 2001, 65(5):484–490.Parker M. Re-assessing disability: the impact of schistosomalinfection on daily activities among womenin Gezira Province, Sudan. Social Science and Medicine,1992, 35(7):877–890.Poggensee G, Feldmeier H, Krantz I. Schistosomiasisof the female genital tract: public health aspects.Parasitology Today, 1999, 15(9):378–381.Poggensee G, Feldmeier H. Female genital schistosomiasis:facts and hypotheses. Acta Tropica, 2001,79(3):193–210.Porter J, Ogden J, Pronyk P. Infectious disease policy:towards the production of health. Health Policy andPlanning, 1999, 14(4):322–328.Reich MR. Technical fixes and other problems in savinglives in the world’s poorest countries. Journal ofPublic Health Policy, 1988, 9(1):92–103.Saker L et al. Globalization and infectious diseases: areview of the linkages. Geneva, UNICEF/UNDP/WorldBank/WHO Special Programme for Research andTraining in Tropical Diseases (TDR), 2004 (TDR/STR/SEB/ST/04.2 ).Sandbach FR. The history of schistosomiasis researchand policy for its control. Medical History, 1976,20(3):259–275.Sayed HA et al. Assessment of the diagnostic systemof Schistosoma infection at rural health unit level,Egypt. Journal of the Egyptian Society of Parasitology,2000, 30(2):487–503.Shiffman J, Beer T, Wu Y. The emergence of global diseasecontrol priorities. Health Policy and Planning, 2002,17(3):225–234.Sow S et al. Low awareness of intestinal schistosomiasisin northern Senegal after 7 years of health educationas part of intense control and research activities.Tropical Medicine and International Health, 2003,8(8):744–749.82 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Stoll NR. This wormy world. 1947. Journal ofParasitology, 1999, 85(3):392–396.Talaat M et al. The social context of reproductivehealth in an Egyptian hamlet: a pilot study to identifyfemale genital schistosomiasis. Social Science andMedicine, 2004, 58(3):515–524.Uchoa E et al. The control of schistosomiasis in Brazil:an ethnoepidemiological study of the effectiveness ofa community mobilization program for health education.Social Science and Medicine, 2000, 51(10):1529–1541.van der Werf MJ et al. Evaluation of staff performanceand material resources for integrated schistosomiasiscontrol in northern Senegal. Tropical Medicine andInternational Health, 2002, 7(1):70–79.van der Werf MJ et al. Measuring schistosomiasiscase management of the health services in Ghana andMali. Tropical Medicine and International Health, 2004,9(1):149–157.Watts S. The social determinants of schistosomiasis.In: Scientific Working Group on Schistosomiasis: reportof a meeting 14–16 November 2005. Geneva, UNICEF/UNDP/World Bank/WHO Special Programme onResearch and Training for Tropical Diseases (TDR),Geneva, 2006 (TDR/SWG/07).Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0783

WORKING PAPER 11. Thesocial determinantsof schistosomiasisSusan WattsSocial Research Center, American University in Cairo,PO Box 2511, Cairo 11511, Egypt.The Commission on the Social Determinants ofHealth (SDH) was launched by WHO in March2005. Its mandate is to trace the pathways by whichsocial determinants affect health status and outcomes.Of these determinants, poverty is the key.The Commission is also to recommend policies totackle inequalities originating from the social determinants.The concern for inequalities, and for inequities,‘unfair and remediable inequality’ (Feachem,2000), is central to WHO’s mandate, harking backto the original definition of health in the WHOConstitution and in Health for All.The SDH approach goes beyond a biomedical understandingof schistosomiasis as it affects individualsto consider the social and behavioural settingwithin which the infection is transmitted and hasits impact. It encompasses every aspect of schistosomiasistransmission and control: diagnosis, treatmentand care, preventive activities such as healtheducation, vector control, and the provision of safewater and sanitation.In this paper, I will present a preliminary explorationof the current challenges social determinantspresent to schistosomiasis research, and how thesemay affect plans for future research and controlactivities in some of the poorest countries of theworld. These challenges can be explored by way ofthe knowledge networks WHO identified for theconsideration of the Commission. They include:measurement, health systems, employment conditions,globalization, early child development, urbansettings, priority public health conditions, genderand social exclusion (Lee, 2005; Marmot, 2005; formore information on SDH see CSDH 2005[a] and2005[b]).For the Commission, schistosomiasis is not likely tobe identified as a priority public health condition.However, some of the Commission’s concerns forpriority health conditions are relevant for schistosomiasis.These include the integration of SDH policiesand actions into general health programmes;equitable access to public services; intersectoralaction; and promoting equitable access to healthcare. It is essential that schistosomiasis be regardedas an equity issue, as the disease is most commonamong poor, marginal populations. Moreover, itis now recognized as being associated with nutritionaldeficiencies that are a major barrier to socialdevelopment.THE CHANGING EMPHASIS ONTHE SOCIAL DETERMINANTS OFSCHISTOSOMIASISThe importance of the social determinants of schistosomiasisfor researchers and policy-makers isreflected in the various constituent strategies ofcontrol programmes. These have changed with thedevelopment of new tools, new (measurable) objectives,and new perspectives on what it is possible toachieve through social action and public policies.In the era before praziquantel, the social context oftreatment was largely ignored in the mass treatmentprogrammes carried out by authoritarian colonialregimes and their successors. Research on the socialdeterminants of transmission focused on water contactbehaviour. With the introduction of praziquantelas an effective treatment in the 1980s, it becameimportant to identify social/demographic groupsto be targeted for treatment through the primaryhealth care system. Programme objectives focusedon the control of transmission, prioritizing, amongothers, school-age children, who experienced thelargest number of infections and shed the largestnumber of schistosomes.Currently however, the core strategy of providingtreatment with praziquantel has as its objectivethe control of morbidity. Risk groups have beenre-defined as those vulnerable to infection and/orless likely to receive treatment through routine primaryhealth care services. This approach echoesthe emphasis in the SDH on equity and reachingthose in society who are most vulnerable. Three riskgroups have been identified in the literature:1. Those engaging in certain occupations – especiallyfishing, and agricultural activities associatedwith irrigation.2. Women – during pregnancy, and exposure duringdomestic activities.3. Children of school age.This change in focus occurred when research identifiedpreviously hidden morbidity due to schistosomiasis.School-age children are of particularconcern, not only because of the high rates of reinfection,but mainly because of the associationbetween schistosomiasis and stunting, vitamin Adeficiency and developmental and cognitive problems.For pregnant women, deliberately omittedin earlier treatment programmes, treatment could84 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

also help to limit nutritional deficiencies which areexacerbated by schistosomiasis, especially iron deficiencyanaemia.Attention among researchers and public health specialistsis now shifting to sub-Saharan Africa, whereendemic countries are among the poorest in theworld. Here, schistosomiasis programmes will beoperating in very different social and political environmentsfrom countries such as Egypt, Morocco,Brazil, the Philippines and China, which recentlyclaimed to have achieved successful morbidity control.These last mentioned countries are consideredas being within the range of medium (rather thanlow) human development.SCHISTOSOMIASIS AS A DISEASE OFPOVERTYAs of 2005, 85% of all schistosomiasis infections arefound in sub-Saharan Africa, mostly among poorpeople who live in remote areas, without access tohealth services, safe water, sanitation, and education.We now need to give more attention to schistosomiasisas a disease of poverty. Indeed, becauseof the particular dynamics of schistosomiasis transmission,and the need for treatment, it is possibleto argue that the presence of schistosomiasis canbe used as an indicator of poverty. What differencedoes this recognition of the link between povertyand schistosomiasis make to our research agenda,and to the way we present our findings to thosewith the power to take action?The social determinants of schistosomiasis insub-Saharan AfricaAmong the characteristics of poor people and poorhouseholds relevant for schistosomiasis research insub-Saharan Africa are:• Lack of access to resources, especially healthservices, safe water and sanitation, andeducation.• Poor people suffer poorer health than those whoare better off. They need more health care, butoften get less. The poor are defined as ‘hard toreach’: care is more expensive and difficult todeliver.• Poor people are more likely to have an inadequatediet than the better off.• Many poor areas and individuals have limitedsocial capital, and limited access to social networksessential to obtain resources and overcomeperiodic domestic crises.The result of these accumulated disadvantages ismarginalization and social exclusion from the largersociety. Because of this, poverty is often hidden, andits extent underestimated.The UNDP Human Development Indicators (HDI)are generalized measures of well-being. These indicatorsare aggregated into a composite index andranked for each country. Those listed in table 1 arerelevant for the social determinants of schistosomiasis,and give an indication of the relative standingof various countries. However, because these figuresare averages, they do not identify the extent ofinequality in a country, the gap between the averageand those at the bottom of the heap. Intensity ofinfection, morbidity and disease risk are likely to behighest in the poorest sector.All countries in the Low Human Development categorylisted above are targeted for schistosomiasistreatment interventions. Except for Nigeria, themost populous country in Africa, they have recentlybeen added to the list of countries covered by theSchistosomiasis Control Initiative (SCI). The poorestcountry, Niger, is at the bottom of the human developmentleague, 177th of 177 countries for whichrecords are available.Many of these countries have inadequate health systems.It is difficult to provide meaningful figuresthat capture the many aspects of access to healthcare. The proportion of births attended by skilledhealth personnel has been shown to be related tochild and maternal survival. This indicator canalso stand as a proxy indicator for general access tohealth care. For these reasons it is used as a key indicatorfor the Millennium Development Goals. Datafor these countries on skilled birth attendants alsoshow a large discrepancy between top and bottomwealth quintiles, with at least one third fewer birthsattended by skilled personnel in the poorest 20%of households compared to the richest 20% (UNDP,2005:table 8).MEASURING THE SOCIALDETERMINANTSExploration of the social determinants of healthraises a number of methodological issues, chieflyrelated to measurement, that are not experienced inthe more quantitatively oriented discipline of epidemiology.Epidemiological studies can, often in amatter of weeks, measure the impact of treatmentby comparing the levels of infection before and aftertreatment. But it is likely to take much longer forthe impact of social determinants, be they changesin behaviour, in wealth status, or in access to waterand sanitation, to show up in SDH evaluation studies.Also the methods, definitions and scale of oper-Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0785

Table 1: Human Development IndicatorsMedium Human DevelopmentHDI Rank HDI index 1. 2. 3. 4. 5. 6.Ghana 138 0.520 21 42 26 45 59 44Uganda 144 0.508 44 59 39 na na 39Low Human DevelopmentNigeria 158 0.453 40 62 25 70 67 35Tanzania 164 0.418 27 54 44 20 82 36Zambia 166 0.394 45 55 47 64 68 43Mali 174 0.333 55 52 38 72 45 41Burkina Faso 175 0.317 49 88 34 45 36 31Niger 177 0.281 54 88 40 61 38 16Definitions:1. Percentage of population without access to improved water sources: Unimproved water sources include vendors, tanker trucks, and unprotected wells and springs.Reasonable access is defined as the availability of at least 20 litres a person per day from a source within one km of the dwelling. (A central issue here is affordability,whether buying from water vendors or from newly privatized water companies.)2. Percentage of the population without access to improved sanitation: Adequate excreta disposal facilities include connections to sewer or septic tank system, pour-flushlatrine, simple pit latrine, or VIP latrine. Facilities are considered adequate if they are private or shared (but not public), and if they can effectively prevent human,animal and insect contact with excreta.3. Under height for age: > 2 standard deviations below the median of the reference population; moderate and severe stunting (evidence of long-term nutritionaldeficiency).4. Percentage of population living on less than US 1$ a day.5. Net primary enrolment ratio: number of students enrolled as percentage of those of official school age for this level.6. Percentage of births attended by skilled health personnel.Source: UNDP, 2005, derived from tables 3, 6, 7 and 12.ation used in SDH research are distinct from thoseused in epidemiology.Community-based research is essential in SDHresearch to provide a view of schistosomiasis at thelocal level, in the setting in which interventions actuallyhave an impact on health. Concern for the socialdeterminants of schistosomiasis involves comingto an understanding not only of what local peopledo, but why. These ‘why’ questions illustrate ‘process’,linkages between behaviour and what localpeople consider is feasible and appropriate, giventheir knowledge, priorities and skills. Processes aredifficult to measure objectively, but the dynamicsof change can be analysed rigorously. Informationon topics such as water use and treatment-seekingbehaviour can be used for health messages and forplanning improvements in access to safe water andsanitation.In tropical Africa, detailed studies of handwashing,a critical hygiene behaviour in the preventionof diarrhoeal disease, have been carried out in ruralsettings with poor access to safe water and sanitation.These studies have been used to develophygiene education and rapid assessment protocolsfor use at the community level. Changes in dailywater use (relevant for schistosomiasis control) andhandwashing have a high likelihood of being sustainableonce established, as they are repeated ona daily basis; they become habitual activities thatare handed down to children during socialization(Curtis and Cairncross, 2003).In the context of local conditions, many terms usedin discussions of the social determinants of schistosomiasistake on specific significance. For example,with the recent emphasis on occupation andvulnerability to infection, survey questions need tobe re-evaluated. Many survey questions focus onthe major occupation. However, surveys shouldinclude a full range of work-related activities, bywomen and men, as these affect such things as thetime available to visit health centres for treatment,and exposure to infection during farming. Poor peopleneed to engage in a multiplicity of activities toensure household survival. Women’s activities areespecially likely to be missed as they occur in theinformal sector. They include preparing and sellingfood, looking after cattle and poultry, and workingalongside their husbands in the fields. Women’sdomestic roles can also be seen as contributing towork-related activities, as they support householdmembers engaged in income-generating activities.Domestic water management (collection, storage,use and disposal of water) can consume many hoursa day when there is no water, or no adequate drainagefor waste water within the house (Watts, 2004;El Katsha and Watts, 2002:22–28).* see also http://www.lshtm.ac.uk/dcvbu/staff/valspage.htm, accessed 5/15/2004.86 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Social capital, comprising social networks used toaccess resources, is a vital resource for people in allsocieties. Horizontal networks, mostly involving kinand neighbours, help people respond to domesticcrises, while vertical networks link them to thosewith more ‘social power’ and help them gain accessto education, health care, subsidized food, etc.Although people in poor communities often havelittle social capital, some have good social networks,which, because they operate informally, are outsidethe purview of official observers who belong to adifferent social class. These local variations must berecognized (Szreter and Woolcock, 2004).RESEARCH IMPLICATIONSResearching genderThe term ‘gender’ refers to the social roles, responsibilitiesand activities of males and females. Genderis socially determined, while the term ‘sex’ is biologicallydetermined; therefore it is not enough to simplyreplace the term ‘sex’ with the term ‘gender’ inepidemiological studies. The need to disaggregatedata according to gender is well known. Aspectsof gender relevant to schistosomiasis include: genderedtasks, gendered spaces, and gendered treatment-seekingbehavior (El Katsha and Watts, 2002:chapter 9).Current treatment strategies, which focus on vulnerablewomen, need to take a holistic view of thestatus of women, and their lack of social power,contrasted with the social and economic prioritygranted by the wider society to men. Pregnant andlactating women, neglected until recently in treatmentprogrammes, need treatment for schistosomiasisand nutritional deficiencies that affect their ownhealth and the health of their unborn children. Howcan such treatment reach those who need it most,and to what extent can it be combined with otherprogrammes that involve women and their youngchildren, such as nutritional supplements andvaccination?Community-based studies of female genital schistosomiasis(FGS) are needed. These require gendersensitivity in working with local populations,and health staff, as the infection has symptoms thatmimic sexually transmitted diseases (STDs). Theyalso require a detailed knowledge of local genderdynamics, and reaching out to men as well as towomen (Talaat et al., 2004). We need more communitystudies on FGS associated with S. haematobium;there are none as yet on FGS due to S. mansoni. Therehave been few community studies of male genitalschistosomiasis (Feldmeier et al., 1999; Leutscher etal., 2005).The impact of globalization onschistosomiasisGlobalization can be briefly defined as a longtermprocess of increasing global connectivity andchange. It is often associated with increasing poverty,as poor people are vulnerable to loss of employment(due to changing global market structures) andrights to health care (due to failing health systems,regulated by structural adjustment programmes).Globalization means, in most cases, that control ofthe financial affairs of a country resides beyond itsborders. (See also the TDR publication on globalizationand infectious diseases [Saker et al., 2003],which reviews the changes in disease distribution,transmission rate, and disease management).Population movements are increasingly due to globalization.Non-immune populations can be exposedto infection in new areas; infected people can moveto new areas taking schistosomes with them. Poorpeople moving to new areas often fail to escape thepoverty that drove them to move in the first place.Forced population movements are associated withextreme vulnerability to disease, especially due tomalnutrition and the absence of safe water and sanitation.Sub-Saharan Africa has the largest number ofrefugees of any world region, around 2 700 000. Thedata on those who have been internally displacedare less reliable, but suggest far larger numbers,overall, than those officially recognized as refugees(UNDP, 2005:table 23).Researchers need to update the earlier assessmentsof how water resources development affects the statusof schistosomiasis (Hunter et al., 1993). The ecologicaland social disruptions caused by large damsare now better understood than they were ten yearsago. Current concern about the Three Gorges Damon the Yangtze River in China appears to focus onecological change (the movement of vector snails),but construction also involves a vast forced and voluntarymovement of millions of people, carryingwith them their diseases, culture and behaviour. Isit still sufficient to call for intersectoral collaborationin planning and in disease impact assessment? Whatrole, if any, do international agencies, donors andother interested parties have in protecting the healthof people affected by such projects?Urbanization is also an aspect of globalization, withthe push/pull pressures of rural poverty and urbanopportunity resulting in movement to towns. Manyimpoverished people move to shanty towns onReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0787

the peri-urban fringes of large population centres,where infrastructure for health, water and sanitationhas not yet been established. Assumptions thatschistosomiasis is a rural disease need to be revisedbecause:1. Rural people bring their diseases with them tothe rapidly expanding population centres.2. Unsafe sanitation and water supplies, plusunchanged behaviour, will facilitate the establishmentof disease transmission in urbanslums.3. Migration and globalization have broken downestablished ideas of what constitutes ‘rural’ and‘urban’. These definitions are not consistentfrom country to country. Definitions reflect pastcultural and social realities, and administrativeconvenience. In the Nile delta, water and sanitationconditions in villages with a population of10 000 or more may be similar to those in poorurban areas. In Brazil, metropolitan regions aredefined as urban but appear to include smallscattered settlements in which conditions arevery similar to those in rural areas.Governance is a globalization issue, as today, morethan ever before, many decisions made by a governmentare limited, or controlled, by internationalinstitutions, multinational businesses and regulatoryframeworks; some have a positive impact, many arenegative. Governance can be defined as ‘a set oftraditions and institutions by which authority in acountry is exercised’. The main areas of concern forgovernance are: voice and accountability, politicalstability, government effectiveness, the rule of lawand corruption (Kaufmann et al., 2003). Corruptionis facilitated as corrupt local nationals take advantageof international financial facilities to siphon offvast sums of money that could have been used forsocial programmes. Indicators of good governanceare subjective, and depend on the preconceptionsand objectives of those making the assessments.They can provide a general indication of the extentto which governments can provide services to theirpeople that are affordable and equitably distributed.They are often used by donor agencies to determinewhether debt can be forgiven, and if aid should beprovided, and if so, how much. Especially in poorcountries that are heavily aid dependent, coordinationby donors at the national level now stronglysupports intersectoral planning. This offers intriguingnew possibilities for health ministries to thinkoutside their usual parameters, and for disease controlprogrammes to become more closely integratedwith other health initiatives.Within ministries of health, health sector reform(HSR) is heavily influenced (and financed) by internationalorganizations and donors. It is directedprimarily at streamlining management, upgradingfacilities and training health personnel. Its involvementin actual health interventions is limited to theeffective delivery of a package of essential services.Relevant essential services for an endemic area mayinclude schistosomiasis surveillance and treatment.HSR planners pay lip service to equity in accessto health care. However, in practice, HSR policies,focusing on management-related issues and costeffectiveness, do not leave much room for equityconsiderations. Even among uniformly poor populations,the very poor may not be reached (Armstronget al., 2003).Children of school ageA major SDH knowledge area is early child development.However, many health problems facedby older, school-age children are similar to thoseof younger children. They are also rooted in socialdeterminants such as poverty, malnutrition, andpoor hygiene that are linked to the lack of safewater and sanitation. New research approaches areneeded on the nutritional vulnerability of schoolagechildren who suffer from schistosomiasis andother intestinal parasites.In poor endemic countries in sub-Saharan Africa,up to one-third of the children under five may bestunted, indicating long-term nutritional deficiency.Most attention focuses on growth deficitamong young children but it is likely to continueas polyparasitism, which impedes the absorptionof nutrients, and children face added nutrientdemands during puberty. Studies among olderchildren have found a correlation between schistosomiasisand childhood stunting. Assis et al. (2004)pioneered a new approach by including food intakewhen looking at nutritional status and S. mansoniinfection in the poor north-eastern Brazilian stateof Bahia. They found that children aged 7–14 whowere heavily infected or had an inadequate intake oflipids (fats) were at higher risk of stunting than noninfectedchildren.This research suggests possibilities for further explorationof the link between inadequate nutritionalintake and schistosomiasis, drawing on findings inlocal settings, and incorporating considerations oflocal dietary preferences and food availability andaffordability. Such research could also strengthenthe argument for delivering schistosomiasis treatmentalongside treatments for other locally endemicdiseases, and nutritional supplements. This wouldbe cost effective, as treatment would target the samegroups.88 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

More research is needed on locally appropriate strategiesto treat out-of-school children as less than halfof the children in endemic countries in Africa maybe enrolled in school. While many children withdrawor attend school irregularly because they areneeded to work or live far from school, only a smallproportion will attend regularly enough to be coveredin school-based programmes. However, outof-schoolchildren are more likely to be at risk ofinfection. A study in a poor rural area of Egyptfound that out-of-school children, especially girls,had far higher rates of infection than did those inschool. The research team designed a protocol forreaching these children within the existing schoolbasedframework (Husein et al., 1999).In poor countries in Africa, the deworming programmesupported by Partnership for ChildDevelopment (which includes treatment for schistosomiasis)is being delivered through schools, onthe grounds that schools are more ubiquitous thanhealth centres, and that teachers can be trained togive out the drugs. Little research appears to havebeen done on delivering treatment to out-of-schoolchildren in these countries through the school system.Given the focus on school-age children, and theproven role of education in fostering social developmentand health, such health programmes couldform part of an overall strategy to encourage schoolattendance by children from poor families by providingfree meals, health care and small paymentsto children who attended regularly. If a school systemis not deemed suitable for the delivery of suchprogrammes, alternative strategies for reachingschool-age children could be modelled on community-basedstrategies such as those used in Ugandato deliver treatment for schistosomiasis, onchocerciasisand intestinal helminths, and in Nigeria forschistosomiasis, lymphatic filariasis and onchocerciasis(Ndyomugyenyi et al., 2003)The challenge of new strategies andcompeting health prioritiesToday schistosomiasis control has moved away fromits earlier focus on integrated projects incorporatingspecific schistosomiasis-related interventions suchas diagnosis, treatment, health education, vectorcontrol, and coordination with programmes to providesafe water and sanitation. At the present time,schistosomiasis is more often seen as an element inbroader programmes that combine schistosomiasiscontrol with other health interventions. At the sametime the distinction between top-down vertical disease-specificprogrammes and local-level horizontalprogrammes may no longer be relevant. The newemphasis is on intersectoral programmes and otheractivities encouraged (or dictated) by new globalizingforces, including multinational companies andinternational health programmes. Schistosomiasisprogrammes should now be identified as networks:a web of relationships that links organizations andindividuals across organizations (Reich, 2002).The health priorities of poor countries in sub-Saharan Africa, especially those being devastatedby the HIV/AIDS epidemic, also need to be recognizedby researchers. Providing basic health care inlow income countries costs around US$ 30–40 percapita, yet most poor countries spend less than US$6 per capita on health (UNDP, 2005:63). People livingon less than US$ 1 a day cannot be expected topay for health care. In such a context, the concept ofcost recovery is a non-starter that can only succeedin shutting out the poor from health care. Just overone-third of the people in sub-Saharan Africa livein countries that have experienced a decline in HDIsince 1990 because of the combined impact of HIV/AIDS and structural adjustment policies (UNDP,2005:21). Even if current attempts to relieve debt usethe money to restructure health and education, thechallenge for the poorest countries to provide effectiveand sustainable schistosomiasis control is formidable.Where should schistosomiasis researchposition itself in this new context?CONCLUSIONS: NEW DIRECTIONSFOR RESEARCH ON THE SOCIALDETERMINANTS OF HEALTHResearch on the social determinants of schistosomiasisis now focusing on the poorest populations insub-Saharan Africa, where governments and householdshave very limited resources. The poorest people,those least likely to be able to pay for healthcare even if it is provided nearby, are those mostlikely to be at risk from schistosomiasis. A researchagenda needs to incorporate the following specificareas of research that reflect the current realities inpoor countries in sub-Saharan Africa:• The impact of population movements on schistosomiasiscontrol.• A new look at gender and schistosomiasis: women’svulnerability; pregnant women; female (andmale) schistosomiasis; the structural underpinningsof women’s low status that result in theirmarginalization in the control programmes ofvarious countries and localities.• Strategies for reaching school-age childrenthat take account of local conditions, feasibility,sustainability.• The role of urbanization, including the extent towhich schistosomiasis is an urban or rural problem,and whether these terms are still relevant.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0789

Some of these conclusions are not specific to schistosomiasis.They are the unavoidable consequence oflinking the disease to poverty, and of looking at thesituation from a vantage point largely outside schistosomiasisresearch. Within this framework, equitybecomes a central issue. Technical topics, such as thesocial aspects of diagnostics and morbidity measurement,may appear less important but they, too,can be filtered through the lens of equity. In termsof schistosomiasis research and methodology, anapproach to schistosomiasis via its social determinantsrequires some new definition for once standardconcepts, and a methodology for appropriatelocally oriented research.AcknowledgementsI am grateful for comments and encouragementfrom Jans Aagaard-Hansen, Birgitte Bruun andSheldon Watts. Susan Watts alone is responsible forthe views expressed in this publication.ReferencesArmstrong J et al. Inequities among the very poor:health care for children in rural southern Tanzania.The Lancet, 2003, 361(9357):561–566.CSDH (Commission on Social Determinants ofHealth). Towards a conceptual framework for analysis andaction on the social determinants of health. Draft discussionpaper for the CSDH, May 2005. Geneva, WorldHealth Organization, 2005[a].CSDH. Action on the social determinants of health:learning from previous experience. Background paperfor the CSDH, March 2005. Geneva, World HealthOrganization, 2005[b].Curtis V, Cairncross, S. Effect of washing hands withsoap on diarrhoea risk in the community: a systematicreview. Lancet Infectious Diseases, 2003, 3(5):275–281.Feachem RGA. Poverty and inequity: a proper focusfor the new century. Bulletin of the World HealthOrganization, 2000, 78(1):1–2.Feldmeier H et al. Male genital schistosomiasis andhaemospermia. Tropical Medicine and InternationalHealth, 1999, 4:791–793.Hunter JM et al. Parasitic diseases in water resourcesdevelopment: the need for intersectoral negotiation.Geneva, World Health Organization, 1993.Husein MH et al. Who misses out with school-basedhealth programmes? A study of schistosomiasis controlin Egypt. Transactions of the Royal Society of TropicalMedicine and Hygiene, 1996, 90:362–365.Lee JW. Public health is a social issue. The Lancet, 2005,365:1005–1006.Leutscher PD et al. Increased prevalence of leukocytesand elevated cytokine levels in semen fromSchistosoma haematobium-infected individuals. Journalof Infectious Diseases, 2005, 191(10):1639–1647.El Katsha S, Watts S. Gender, behavior, and health: schistosomiasistransmission and control in rural Egypt. NewYork and Cairo, American University in Cairo Press,2002.Kaufman D, Kraay A, Mastruzzi M. Governance mattersIII: governance indicators for 1996–2002. World Bankworking paper, 2003 (http://worldbank.org/wbi/governance/pubs/govmatters3.html).Marmot M. Social determinants of health inequalities.Lancet, 2005, 365:1099–1104.Ndyomugyenyi R, Kabatereine N. Integrated community-directedtreatment for the control of onchocerciasis,schistosomiasis and intestinal helminths infectionsin Uganda: advantages and disadvantages. TropicalMedicine and International Health, 2003, 8(11):997–1004.Reich MR. Reshaping the state from above, from within,from below: implications for public health. SocialScience and Medicine, 2002, 54:1669–1675.Saker L et al. Globalization and infectious diseases: areview of the linkages. Geneva, UNICEF, UNDP, WorldBank, WHO Special Programme for Research andTraining in Tropical Diseases, 2004 (Social, Economicand Behavioural Research, Special Topics no. 3 [TDR/STR/SEB/ST/04.2]).Szreter S, Woolcock M. Health by association? Socialcapital, social theory, and the political economy ofpublic health. International Journal of Epidemiology,2004, 33(4):650–667.Talaat M et al. The social context of reproductivehealth in an Egyptian hamlet: a pilot study to identifyfemale genital schistosomiasis. Social Science andMedicine, 2004, 58:515–524.UNDP. Human Development Report 2005. New York,UNDP, 2005.Watts S. Women, water management, and health.Emerging Infectious Diseases, 2004, 10:2025–2026.90 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

WORKING PAPER 12.Ecological and otherfactors related toschistosomiasisStephen T. McGarveyInternational Health Institute Brown University,Providence, RI 02912, USAINTRODUCTION ANDBACKGROUNDSchistosomiasis infection and disease control programmesusing praziquantel have generally beensuccessful in reducing intensity of infection andassociated severe morbidities. But transmissionremains active in many areas of the world with alikely increase in the proportion of individualsinfected at low intensity levels. There is increasingevidence that low intensity of infection appears tobe associated with level of malnutrition, assessed byanthropometry and anaemia, as well as cognition.Recent work by our group at Brown University alsosuggests that morbidity increases in schistosomiasispatients co-infected with geohelminths. Thus,further reduction of schistosomiasis transmission isdesirable. This follows from one of the WHO goalsto develop strategies for sustainable control.One approach to sustainable control is to developmathematical models of schistosomiasis transmission.Such models may provide useful insights forpredicting what effect chemotherapy control strategiesmight have on the transmission dynamics of theinfection, and can measure effectiveness in termsof number of cases of infection prevented. Modelsmay also test the effects of other interventions suchas snail control, and, in the case of Schistoma japonicum,infection control in other mammalian definitivehosts.Age-structured population dynamic models for S.mansoni and S. haematobium, useful for predicting thedevelopment of early and late disease in humans,have been developed and validated with field databy M.S. Chan and colleagues. This group also mademodels for the development of early and late diseasedue to S. japonicum but these did not includeanimal hosts. These models assume that the larvalstage of the parasite is always at equilibrium (due toits very short life expectancy). Therefore they do notinclude parameters associated with changes in thesnail and/or larval populations.These models do allow sensitivity analysis wherethe influence of certain parameters on the overallconclusions can be assessed by varying one parameterat a time or using stochastic methods. Finally,they are useful for comparing the potential costeffectiveness of alternative control strategies, informationthat is important in the decision-makingprocess when only scarce resources are available.These models are however limited because they donot include individual contact rate and assume thatall individuals of a given age acquire infection andcontaminate the environment at the same rate.For the case of S. japonicum, building transmissionmodels may require inclusion of domestic and wildanimals’ infection parameters. A review of nonexperimentalstudies in China that we publishedseveral years ago indicated reductions in humaninfection in communities over time after changesin handling of animals and animal faecal disposalpractices. More recent work in press by D. McManusand colleagues indicates that bovines, especiallybuffaloes, may be responsible for the persistence ofhuman schistosomiasis transmission in the PoyangLake region of Jiangxi Province. Their experimentalstudy tested the hypothesis that buffalo are majorreservoirs for human infection in marshland/lakeareas. After establishing similar characteristics in thestudy villages, they compared human and buffaloinfection intensity and prevalence over several yearsin an intervention village where humans and buffaloeswere treated with praziquantel, and in a controlvillage where only humans were treated. Over thefour-year study, human schistosomiasis incidence inthe intervention village decreased, but in the controlvillage it increased. Buffalo chemotherapy resultedin a decrease in buffalo infection rate in the interventionvillage, which coincided with the reductionin human infection rate in the last two years of thestudy. Mathematical modelling predicted that buffaloesare responsible for 75% of human transmissionin Jishan. This experimental study not only showsthe importance of bovines for transmission in Chinabut suggests that mathematical models may be usefulfor providing estimates of the health and economicimpacts of human and animal chemotherapyand environmental modifications to reduce schistosomiasistransmission in China.Related work on S. japonicum transmission modellinghas been done by R. Spear and colleagues inSichuan, China. These very detailed studies of transmissionand associated factors focus on the developmentof mathematical models and pay close attentionto uncertainty in estimations, using Bayesian methodsto more accurately calibrate diverse data suchas snail population biology, ambient air and watertemperature, rainfall, spatial data and indices, S.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0791

japonicum infection parameters, including eggs andestimated worms, and chemotherapy. Evidenceindicates that focal snail control, egg control, andcrop type have a strong influence on infection transmission.Based on data from 20 villages, the evidenceshows that transmission is higher with useof human and animal manure-based fertilizer forgrowing tobacco and vegetables compared to chemicalfertilizers used for rice farming. They suggestthat composting and/or waste treatment of manuremay reduce transmission.Another recent set of studies on schistosomiasistransmission conducted by C. King and colleaguesfocused on snail distribution and focality of transmissionof S. haematobium in Kenya. Their analysesfocused on heterogeneities of S. haematobiumtransmission across time and space on a sub-villagescale. They found significant clustering of infectionintensity (density) around specific water sites,with the significance radius varying by age group.The region of influence for a given site appears tobe 500m–1000m. Further work on survival analysisof adjusted risk for reinfection by village is inprogress by this group and shows that village locationremains most significant. Median time to reinfectionvaried from three years to well over eightyears in villages situated right next to each other.The studies suggest that very local effects should betaken into consideration when establishing a controlprogramme.Related work by this group on treatment allocationstrategies was aided by the development of a transmissionmodel. This model assumed fairly constanttransmission factors across the years, with some sitesbeing worse than others and distance effects similarto those observed in the field. For targeted efforts, itwas clear that treatment of the subset of all childrenacross the area was much more effective than treatingthe subset of 2–3 worst villages, either alone orseveral at a time. This was because of the interlockingtransmission pathways between villages thatshare water sites. In the latest ongoing modellingstudies, the impact of treating one or more snail siteseither alone or in combination with the delivery ofhuman medication is being pursued. It is intended totake into account evidence of the seasonality ofinfected snails, and thus design the optimal timingof possible snail control.ECOLOGY AND TRANSMISSION OFS. JAPONICUM IN THE PHILIPPINESThe brief summary above indicates that severalschistosomiasis research groups have developedpopulation dynamic models to assess the impact ofchemotherapy, snail control and environmental modificationson human or animal infection. Our goal inworking on S. japonicum ecology and transmissionin The Philippines is to develop an age-structureddynamic model, using field data, that includes thesnail host, mammalian hosts, and parameters thatcould represent the effect of anthropogenic environmentalchanges due to farming, irrigation and livestockmanagement on the transmission dynamics.To our knowledge, no model has yet incorporatedthe whole ecology of the S. japonicum transmissioncycle, including the animal, human and snailhosts. The mathematical model will help our understandingof the transmission dynamics of S. japonicuminfection and help in predicting the effects ofcontrol strategies. Field data from a site where thedisease has been in a state of equilibrium for severalyears are needed to validate such a model andto assess the impact of rice farming techniques andanimal husbandry on the transmission dynamics ofinfection and disease in humans. Once the patternof infection has been well described in a model, theparameters of mathematical models can be modified,based on field data, to explain the dynamics oftransmission in other areas.We proposed the following specific aims: 1) to determinethe effects of variation and changes in irrigationand rice farming methods on transmission of S.japonicum to snails and to human and animal definitivehosts; 2) to determine the effect of variationin S. japonicum infection in animals, and of animalbehaviour and management practices, on S. japonicumtransmission; 3) to develop a generalizable predictivemodel of the ecology and transmission of S.japonicum based on temporal and spatial variationin rice farming practices, human infection parameters,and animal numbers and infection parameters;4) to compare the predicted effect of anthropogenicenvironmental change on human and animalS. japonicum infection using three different analyticapproaches: a) a Bayesian hierarchical model; b) anage-structured population dynamic model; and c) ageographic information systems model.The research uses a longitudinal observationaldesign. At baseline we collected transmissionparameters for humans, other mammals and snails.We also collected water contact data on humans andsocio-demographic information. The longitudinalfollow-up interval was 12 months after baseline andmass treatment of all village residents. The majoroutcome concerns human incidence of infection.The major design contrast was irrigated villages vs.non-irrigated villages to enable interpretation of differencesin infection transmission to humans thatare based on irrigation, after adjustment for other92 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

aspects of S. japonicum transmission such as animalinfection and management.Hierarchical cluster sampling was used so that wecould estimate and adjust the effects of clusteringat different levels: individual, household, farm, andvillage. This is based on the fact that units of observationin such an ecological study are not independentbut clustered.We chose 50 villages, 25 with water managementand 25 without water management. In each villagewe randomly recruited 35 households and in eachhousehold we asked 4–6 members to participate. Ineach village we attempted to study 35 animals ofeach of five species: water buffalo, pigs, dogs, catsand rice field rats. We made geocoded maps of allvillages with water courses, water management andrice fields included. Snail sampling was based onocular survey of all water courses, and then samplingat sites based on vegetation and flow characteristicsthat are usual for presence of Oncomelaniasnails. A smaller pilot study to assess genetic differencesin S. japonicum across the several mammalianhosts and in the snails is also under way.Our results to date include the development andpublication of Bayesian modelling techniques toestimate uncertainty of infection parameters by age,sex and village. These estimates were then used todevelop an age structured dynamic transmissionmodel based on equilibrium transmission conditionsin three Leyte villages in 1981 before praziquanteluse. The model showed quite reasonableresults with mass treatment of humans and othercontrol measures on scenarios of snail reduction. Themodel structure will be refined as we integrate moredetailed data from the ongoing data collection.We developed and standardized animal parasitologymethods for assessment of animal infection intensity,including adjustments for uncertainty. This isbased on an adaptation of the Danish BilharziasisLaboratory (DBL) method. Faecal samples from allanimals were collected for one to five days in fourvillages. For all species, the sensitivity estimates ofonly one stool sample were less than 80%. However,the sensitivity improved to more than 96% in allspecies when three or more faecal samples were collectedon three separate days. The specificity wasestimated to be above 92% across all species, even ifjust a single sample is used. Our results suggest thatthe DBL-technique is valid for the detection of infectionwith S. japonicum in animals, and that sensitivityestimates are excellent when faecal samples arecollected on at least three different days. MonitoringS. japonicum infection in animal reservoirs with avalid test could contribute to more effective publichealth control programmes.Using this validated diagnostic test for animal infection,we estimated the S. japonicum infection proportionsin 2178 dogs, 2379 cats, 4310 pigs, 1900water buffaloes and 1399 rats from which we collectedfaecal specimens for one to three days. Theproportion of S. japonicum infection over all 50 villageswas 61.33% for rats, 30.30% for dogs, 4.24% forcats, 1.93% for pigs, and 1.63% for carabao (waterbuffalo). There was substantial inter-village variationin animal prevalence.The baseline human S. japonicum prevalence wasbased on 1427 households and 6917 individualsfrom 50 villages. A total of 5624 (81.3%) participantsprovided at least one stool sample. Using Bayesiantechniques to adjust for measurement error, theprevalences of those lightly and at least moderatelyinfected varied, respectively, from 0% (0%–3.1%)to 45.22% (36.5%–53.9%), and from 0% (0%–1.6%)to 22.95% (16.39%–31.15%), from village to village.Using the 0–7 year old group as a reference category,the odds ratio (OR) of being infected among malesand females aged 17–40 years was 8.76 (6.03–12.47)and among 11–16 year olds 8.59 (4.74–14.28). Peoplewho did not work on a rice farm had a lower prevalenceof infection than those working full time on arice farm. There was no difference in human infectionintensity or prevalence between the irrigatedvillages and non-irrigated villages.To estimate the association of animal and humaninfection at baseline, we used faecal samples for5623 humans, 2178 dogs, 2379 cats, 4310 pigs, 1900water buffaloes and 1399 rats collected for one tothree days. A Bayesian hierarchical cumulative logitmodel with adjustments for age, gender, occupationand measurement error in the Kato-Katz methodwas used. The average eggs per gram of faeces (epg)in dogs was strongly correlated with that of cats,pigs and rats. The average epg in cats was associatedwith that in dogs and pigs. The average epgin water buffaloes was not strongly associated withthat in any other animals. In univariate models, thehuman infection ORs of a unit increase in the village-levelaverage epg of cats and dogs were 1.98(1.25–3.22) and 1.15 (1.06–1.26), respectively. In multivariatemodels, intensity in dogs and cats was alsopositively associated with the OR of human intensityof infection.Unlike the suggestion from China, we did not findany association between the intensity of infectionin water buffaloes and humans. This may be due tothe low prevalence of infection, of less than 2%, inReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0793

water buffaloes and to the aggregation of two-thirdsof these infected animals in one village. This suggeststhe epidemiology of S. japonicum in mammalsand its link to human infection is different in SamarProvince from that reported in China.We are actively working in several areas, including:• Estimating and testing an age structureddynamic transmission model with the baselinedata. This includes spatial modelling.• The one-year follow-up after mass treatment,which was completed in December 2005.Analysis of follow-up infection rates will focuson estimating the impact of human, animal, snail,farming, geospatial and other characteristics atbaseline and follow-up.• Development of an age-structured dynamictransmission model using the longitudinal infectiondata and all relevant factors associated withtransmission in the regression models.• Looking for the association between differentspatial layers and infection incidence, to determineif any spatial associations with transmissionare true effects or the result of failure to understandthe different scales or levels, i.e. the ecologicalfallacy.Financial SupportThe USA National Institutes of Health and NationalScience Foundation, Ecology of Infectious DiseaseProgram: NIH Fogarty International Center Grantno. TW01582.CollaboratorsST McGarvey, Brown University, USA.H Carabin, University of Oklahoma, USA.R Olveda, E Balolong Jr, V Tallo, R Gonzalez, P Alday,G AliguiResearch Institute for Tropical Medicine (RITM),Manila, The Philippines.AL Willingham III, Danish Centre for ExperimentalParasitology, Frederiksberg, Denmark.T Fernandez Jr , Leyte State University, Baybay, ThePhilippines.S Riley, Hong Kong University, Hong Kong.J Webster, Imperial College, London, UK.L Joseph, McGill University, Montreal, Canada.H Madsen, Danish Bilharziasis Laboratory,Charlottenlund, Denmark.94 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

WORKING PAPER 13.Research on themolluscan intermediatehosts for schistosomiasis:what are the priorities?Eric S. LokerDepartment of Biology, University of New Mexico,Albuquerque, New Mexico 87131, USA.AbstractHuman-infecting schistosomes and the snails that supporttheir life cycles remain all too common in today’s world, andwe must remain diligent in funding studies related to theseorganisms. Dramatic changes in the distribution and abundanceof snails hosting schistosomes are under way or can beanticipated, so we must closely monitor such changes becausewhere the appropriate snails go, the schistosomes typicallyfollow. We also need to continue to develop modern tools togain a deeper basic understanding of snail biology, and to bettercomprehend the interactions between schistosomes andsnails, particularly in real-life field settings. We need to applymodern techniques to learn more about the unseen naturalenemies of both snails and schistosome sporocysts, and tolearn more about other relevant snail-transmitted pathogens,including the species of non-human schistosomes that causecercarial dermatitis. We must improve the dissemination ofrelevant information to workers in endemic areas who oftensuffer from poor access to new knowledge. Finally, there is animportant need to maintain a critical mass of malacologists,both to capitalize on the promise offered by exciting toolsnow or soon to be available, and to avoid losing our accumulatedpractical knowledge of medically important snails andtheir role in transmission of schistosomiasis.INTRODUCTIONWithout snails, there can be no schistosomiasis.Because schistosome-transmitting snails occur invery particular ecological circumstances that aresubject to rapid change in an increasingly humandominatedworld, one of the greatest challenges tounderstanding the future of this neglected yet persistenthuman disease is to try to understand howsnails will be affected by global changes in climate,increased pollution of aquatic habitats, continuedtransport of exotic and invasive species, constructionof dams and irrigation systems, mass movements ofhumans, and changes in human population densityand standards of living. Some of these factors suchas continued high levels of poverty and civil unrestwill have more predictable effects on transmission,but others, like climate change, pollution of aquatichabitats or movement of exotic species, will haveimpacts that are far harder to predict. For example,increased pollution of water bodies with humanwastes might favour transmission, but pollutionwith agricultural or industrial wastes may have thebeneficial impact of eliminating transmission, butfor all the wrong reasons. Because schistosomes bynecessity follow the snails, we must not ignore thesnails as they will ultimately dictate where in theworld schistosomiasis can occur, and likely at whatlevel of prevalence it can occur.Having said this, snails should not be viewed asthe enemy – or the target. Indeed, they are, like us,unwitting participants in the life cycles of schistosomesand other helminths of medical and/or veterinarysignificance. Snails are an integral part of thebiosphere and attempts to eradicate them are notonly misguided from a conservation point of view(Kristensen and Brown, 1999), but unlikely to besuccessful (Lardans and Dissous, 1998). Given thepervasive problems of pollution and introductionof exotics (Pointier, David and Jarne, 2005), the daywill likely come when the presence of indigenousschistosome-transmitting snails in an aquatic habitatwill be considered a sign of environmental healthand something about which to be happy. Rather itis the parasites that depend on snails and humansfor their survival that must be controlled. This issomewhat different from contemplating the controlof a typical arthropod-borne pathogen like malariawhere the vector, such as a mosquito, is also obnoxiousand harmful to people in its own right. Snailsare by contrast innocent bystanders.So, if snails are not the enemy, is there any realimperative to learn more about their biology? Theanswer is unequivocally ‘yes’ because the more weknow about the intricacies of the parasite–snail relationship(Lockyer et al., 2004), the broader is ourconceptual base from which to draw unique solutionsregarding parasite control. Furthermore, asnoted above, conditions in the developing tropicswill favour massive changes in the distribution andabundance of snails of medical or veterinary significance.We need to be able to anticipate and respondto such changes.MONITORING AND PREVENTINGCHANGES IN SNAIL DISTRIBUTIONAND ABUNDANCEThe aquarium and aquatic plant trade, the incessantmovement of people and their goods, and evennatural dispersal events, all conspire to move snailsfrom one location to another (Pointier, David andJarne, 2005). The hermaphroditic or parthenogeneticreproductive habits of many snails (Jarne andStadler, 1995) favour their successful introductionReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0795

into new locations. Thus a Biomphalaria glabrata-likesnail was dispersed naturally to Africa within thepast five million years creating dramatic new opportunitiesfor schistosome parasites there (Woodruffand Mulvey, 1997; Campbell et al., 2000; DeJong etal., 2001). Through the activities of humans, ironicallylikely those involved in schistosomiasis research, the‘second coming’ of B. glabrata to Africa, to the NileDelta, was accomplished in the last 50 years (Lotfyet al., 2005). The neotropical Biomphalaria tenagophilahas appeared in central Africa (Pointier et al., 2005),and B. straminea, a particularly invasive exotic, nowthrives in Asia and many other parts of the world(Pointier, David and Jarne, 2005). The latter two speciescan both host S. mansoni. Indoplanorbis exustus,the host for three schistosome species of ruminantsin southern Asia, has also appeared in Africa and theCaribbean region (Pointier, David and Jarne, 2005).Fortunately, other introductions, such as of Bulinusspecies to the neotropics, have not to our knowledgeyet been effected, and all measures should be usedto prevent this from occurring.At the same time as potential schistosome hosts arebeing redistributed, other snails such as Melanoidestuberculata or Helisoma duryi are also being widelyintroduced around the globe, including to theneotropics. Although these introductions mayhave beneficial impacts on schistosome transmission,as observed particularly on the Caribbeanislands, they ultimately have many unfavourableaspects (Kinzelbach, 1995), such as displacementof native (often endangered) snails and potentialto introduce associated trematodes (Scholz andSalgado-Maldonado, 2000), that may also threatenendangered native vertebrate species.Less dramatic range extensions, such as of B. glabratainto southern Brazil (Graeff-Teixeira et al, 2004) or ofB. alexandrina down the course of the Nile (Lotfyet al., 2005), also bear scrutiny. As noted recentlyin Nature (Marshall, 2005), and as seen all too commonlyin snail habitats in both the neotropics andAfrica, many of the aquatic habitats in which schistosome-transmittingsnails occur are now incrediblyfouled by pollution. It is often necessary to kickaway the refuse to get to the water to find snailswhich are nonetheless there and even thriving. Theimpact that such rampant pollution will have onschistosomiasis will be significant. For example,what is causing the change in distribution of schistosomiasisalong the course of the Nile (Abdel Wahabet al., 1993), with sharply falling prevalence of S.haematobium and a rise in the relative abundance ofS. mansoni? Among the many possibilities that mustbe considered is the role of pollution, now extensivein the canals of the delta. A reasonable expectationis that such habitats will increasingly be colonizedby globe-trotting snails with high levels of tolerancefor pollution, such as physids (Dillon et al., 2002).Fortunately, although physids do transmit dermatitis-causingavian schistosomes, they do not playa role in the transmission of other parasites of medicalor veterinary significance, although the likelihoodof them acquiring such a capability cannotbe discounted. The uncertainties regarding whereand when new situations will arise with respect tosnails is further compounded by the impact of globalclimate change (Martens et al., 1997; Sutherst,2004) and the construction of massive water developmentprojects such as dams that influence snailhabitats across huge areas (Zheng et al., 2002; Sowet al., 2002).WHO has a role to play with respect to encouragingregulations that make it less likely for snails to beaccidentally distributed, for providing updates aboutwhere and when new introductions have occurred,and possibly assisting focal control programmeswhere feasible to eradicate newly-introduced exoticsof medical significance. It is also imperative tohighlight the global degradation of freshwater habitatsand the host of public health problems associatedwith this degradation. It is sobering and ironicto imagine that WHO could some day announce theeradication of schistosomiasis from the Nile delta,but any excitement would potentially be mutedby the realization that the eradication was becausethe aquatic habitats there were so fouled as to preventany self-respecting macroinvertebrate such as asnail from surviving.Because of the massive scale of anticipated environmentalchange, studies to understand the basicecology and ecological preferences of schistosometransmittingsnails remain critical. In particular,studies that help to define the nature of competitiveinteractions with invasive snails such as Melanoides(Giovanelli, Vieira, and da Silva, 2002; 2005), or thathelp to define the tolerances of snails with respectto different categories of pollutants, are particularlyimportant. Also helpful for understandingthe impact of changing habitats across broad geographicscales are remote sensing techniques (Setoet al., 2002).The highest priority for the WHO with respect tomolluscan aspects of schistosomiasis is to recognizethat snail and parasite faunas are in a state of rapidflux and that this may create surprising new opportunitiesfor transmission in some places, may preventtransmission in others, and may serve as a bellweather for detecting even more profound environ-96 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

mental and health changes associated with degradationof aquatic environments around the world.DEVELOPING A MODERN TOOLKITTO STUDY THE BASIC BIOLOGYOF SNAILS AND ASSOCIATEDPARASITESAt the same time as maintaining a global overviewof the biogeography of snails and associated parasites,it is also necessary to ‘turn inward’ and gaina greater appreciation of the basic biology of snails,trematode larval stages, and their interactions. Forthis, a modern toolkit is required. Given the enormousimpact that modern approaches have had onfurthering our understanding of mosquitoes andtheir parasites (Heckel, 2003; Christophides et al.,2004), no less should be sought for the snails thattransmit schistosomes and other parasites.One of the most prominent model organisms amongsnails is Biomphalaria glabrata: it is relatively easy torear in the laboratory, as is its associated parasite,Schistosoma mansoni. One disadvantage of the widespreadstudy of B. glabrata is the possibility that itwill be accidentally introduced into new locations.Studies with B. glabrata have already shown thepotential to illuminate general principles of invertebrateimmunobiology (Zhang et al., 2004) and hostparasiteinteractions (Lockyer et al., 2004), so theimpact of these studies is important on a broaderstage as well.Development of modern tools for use with B. glabratais well under way, with the support and encouragementof a consortium of biologists working withsnails, and several funding organizations includingWHO. The National Human Genome ResearchInstitute (NHGRI) has supported the constructionof a high quality bacterial artificial chromosome(BAC) library that is now available to the public.Furthermore, B. glabrata has been selected bythe NHGRI to be the subject of a genome sequencingproject,** which will likely be completed beforethe decade is over. Both BAC library and genomesequencing projects feature the BB02 strain of B. glabrata,an S. mansoni-susceptible isolate recently collectedfrom Minas Gerais in Brazil.*** This will beamong the first molluscan genome sequences to becompleted.Other important tools are already being developed.To go along with the genome sequence, it will beinvaluable to have microarrays so that the transcriptionalactivity of snail genes, such as in responseto schistosome infection or changing environmentalcircumstances, can be monitored. cDNA microarrayswith over 2000 non-redundant features havealready been developed in the UK (C.S. Jones, personalcommunication), and oligo-based arrays areunder construction in the US. The microarrays canbe updated and enlarged as we obtain informationabout more snail genes. Going hand in hand withthe development of microarrays is the developmentof expressed sequence tag (EST) libraries, both byindividual investigators (C. M. Adema, personalcommunication; Mitta et al., 2005; Davison andBlaxter, 2005) and through the assistance of sequencingcentres. The Sanger Centre, for example, is likelyto provide 100 000 ESTs to complement the B. glabratagenome sequencing effort.The first paper using RNA interference (RNAi)to facilitate functional studies of snail gene productshas recently been published (Jiang, Loker andZhang, 2006). The FREP2 gene, normally expressedat increased levels following exposure to digenetictrematode parasites such as S. mansoni orEchinostoma paraensei, was targeted for knockdown.Double-stranded RNA (dsRNA), corresponding tospecific regions of the FREP2 gene, was introducedinto snails by direct injection into hemolymph.Knockdown efficiency was examined at the transcriptlevel using quantitative polymerase chainreaction(PCR) (qPCR) and Northern blot analysis,and expression levels were shown to be significantlyreduced (~70%–80% knockdown). The establishmentof RNAi techniques in B. glabrata will enableus to elucidate the function of genes that we believeplay a role in defence against pathogens such as S.mansoni.Proteomics is yet another important approach to bedeveloped with respect to snail–schistosome studies.Automated mass spectrometry approachesoffer the promise of providing enormous quantitiesof information regarding the protein and peptidecomposition of individual snail organs or tissues.Having information about the snail proteome willprove to be useful in providing annotation to thehuge amount of snail genome sequence anticipatedto be forthcoming. Another valuable tool alreadyavailable for use is the ability to culture trematodelarvae in the presence of cells of the Biomphalaria glabrataembryonic cell line (Bge cells) (Coustau andYoshino, 2000; Bixler et al., 2001; Coppin et al., 2003),* http://www.genome.gov/page.cfm?pageID=10001852** http://www.genome.gov/12511858*** http://biology.unm.edu/biomphalaria-genome/BB02STRAIN.htmlReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0797

aising the potential for eventual routine culture ofschistosome sporocysts without the need to maintainsnail colonies.Although the first priority will be to develop thetoolkit to support studies of B. glabrata as a model,thus enabling us to gain deeper insights into snail–schistosome interactions, we should most emphaticallynot lose sight of the fact that most human casesof schistosomiasis still occur in Africa, and probablyalways will. Thus it will be relevant to learn moreabout species such as Biomphalaria pfeifferi, Bulinustruncatus, and Bulinus globosus which play importantroles in transmission in tropical Africa. Transferral ofmuch of the technology to these species should thenbe possible and should be encouraged because itshould not be assumed that the fundamental natureof all schistosome–snail relationships is the same.This might be particularly true for the Asian schistosomestransmitted by pomatiopsid snails whichhave generally been little studied.SOME ADDITIONAL TOOLS TOFACILITATE OUR UNDERSTANDINGOF SCHISTOSOME–SNAILINTERACTIONS IN THE FIELDAdditional tools and approaches are also neededto better understand schistosomes and snails in thefield. For example, one useful approach to serve asan alternative to classical methods for determiningprevalence of schistosome infection amongsnail hosts is PCR-based methodology to detect thepresence of even minute amounts of schistosomeDNA in snails, including cryptic prepatent infections(Hanelt et al., 1997; Jannotti-Passos et al., 1997;Hamburger et al., 1998, 2004).One important phenomenon of direct relevance totransmission is the degree of compatibility betweenlocal snails and schistosomes. Although much ofthe recent work on schistosome–snail compatibilityhas focused on the differences between isolates orinbred snail lines that are either fully susceptible orstrongly resistant to schistosome infection (Coelhoet al., 2004; Lockyer et al., 2004; Carton et al., 2005),evidence from the field suggests that absolute resistanceis rare, and that that the “success or failure ofan infection does not depend on the snail susceptibility/resistancestatus, but on the ‘matched’ or‘mismatched’ status of the host and parasite phenotypes”(Théron and Coustau, 2005). The basicidea here is that if a particular schistosome miracidiumhas a genetic constitution that appropriatelymatches a snail of a particular genetic constitution, asuccessful encounter will occur. If such a match doesnot occur, then the parasite will be recognized anddestroyed. The low prevalence of infection notedfollowing exposure to low doses of miracidia in naturalsnail–schistosome combinations suggests thatsuch mismatches regularly occur in the field, and canplay an important role in diminishing the number ofpatent infections achieved. Having better tools toassess the early fate of sporocysts in snails wouldhelp us to understand the role of this phenomenonin nature. For example, using a PCR-based assayto monitor the presence of S. haematobium larvaein bulinid snails, Hamburger et al. (2004) showedthat many more snails had been exposed to parasitesthan had actually developed cercariae-producinginfections. An explanation consistent with thedata is that miracidium–snail encounters are morecommon than realized, but that a failure of somesporocysts to develop in some snails keeps patentinfection rates low. This has fundamental implicationswith respect to schistosome transmission.Other practical tools for the study of schistosomesin snails have already been devised, such as the useof hybridization of Southern blots to a polymorphicrepetitive DNA element (Minchella et al., 1995) toprovide insight into how many different schistosomegenotypes are present within a given snail.Additional techniques, such as an ability to quantifythe amount of schistosome biomass in a particularsnail, would also be useful for understanding theepidemiology of snail infections in the field.With respect to the snails themselves, one of the longstandingneeds for schistosomiasis workers in thefield has been to have reliable means to determinewhich species of snails they are working on. Theapplication of molecular techniques to both amplifyand provide sequence data for key reference geneslike ITS 1 and 2, 18S, 28S, 16S, ND1 and CO I is provingto be extremely helpful, not only with respectto providing a more reliable yardstick for speciesdeterminations (Vidigal et al., 2002, 2004; Lotfy etal., 2005), but also for development of robust phylogeniesthat have allowed us to gain a much greaterappreciation of the evolutionary history of schistosome-transmittingsnails (DeJong et al., 2001; Joneset al., 2001; Morgan et al., 2002; Atwood et al., 2004).By application of molecular methods, two species ofbulinid snail differing in susceptibility to S. haematobiumhave been identified on Zanzibar, thus considerablyclarifying where transmission is possibleand directing control efforts (Stothard et al., 2002).This provides a good example of the importance ofaccurate snail identification and the value of medicalmalacology for eventual control efforts.98 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

STUDIES OF THE NATURAL ENEMIESAND SYMBIONTS OF SNAILSExcept in a focal or insular context, it is difficult toimagine how populations of snails would ever becontrolled at a level sufficient to interrupt transmissionin a sustainable, cost-effective, environmentallyacceptable way. Snails transmitting schistosomiasisoften have considerable abilities to aestivate, tobe passively dispersed, or to quickly re-populateareas because of their rapid rates of reproduction.Attempts to control snails through the applicationof molluscicidal chemicals derived from either thechemical industry or from local indigenous plantswould seem to face a severe uphill battle given theincreasingly strong public resistance to the widespreadapplication of chemicals to the environment.The evidence that such chemicals have specific effectson target snails is often equivocal (Monkiedje et al.,1991; Oliveira and Paumgartten, 2000; Giovanelli etal., 2002).Also likely to be of limited potential for future controlefforts on a continental scale are most methodsof biological control that have been proposed,including the use of exotic generalist predators/competitors that carry unacceptable ecological risks(Cowie, 2001). It seems unlikely that indigenouspredatory/competitor molluscs can be counted onto achieve sustainable control, otherwise we wouldalready see ample evidence of their effectiveness.Even the introduction of indigenous species intoenvironments where they do not already occur maycarry hazards, especially with respect to rice-growingor creating new opportunities for disease transmission(Yousif and Lämmler, 1975; Teo, 2001).Here it is argued that even though sustainable,environmentally-acceptable snail control may be anear-impossible goal, it is nonetheless important tocontinue to learn more about the natural enemies orsymbionts of snails, particularly the ones that areat present either poorly characterized or unknown.When snail symbionts have been examined withmodern molecular-based methods, some surprisingresults have emerged. Thus snails and other molluscshave been shown to harbour members of apoorly known clade of eukaryotic symbionts lyingclose to the divergence between fungi and animals,the Mesomycetozoea (Hertel et al., 2002).As an example of our ignorance with respect tosnail symbionts, not a single virus from any snailof medical significance, or to my knowledge fromany gastropod, has ever been isolated. Such virusesalmost certainly exist – it would be unusual for anygroup of organisms to be devoid of viruses. Theymay routinely kill snails in the field for all we know.Furthermore, many of the tools needed to characterizesnail viruses are already in hand, most notablythe Bge snail cell line. Extracts of snails from naturalpopulations could be readily prepared and platedonto Bge monolayers. Then any plaques revealedcould be subjected to further study in search of viralparticles. Snail viruses could be useful as controlagents, may adversely affect schistosome development,or may be convenient agents for generatingtransgenic snails. Virtually nothing is known abouthow snails defend themselves from viruses. It isconceivable that RNAi-related mechanisms areused to discourage viral infections, and if so, thenthe study of molluscan viruses may offer valuableclues for how to better exploit RNAi to knockdownsnail genes, potentially including those required forsnails to nurture larval trematodes.Also poorly known are the bacterial associates ofschistosome-transmitting snails. Although somestudies of culturable bacteria have been undertakenusing Biomphalaria, including snails from naturalhabitats (Ducklow et al., 1979, 1981), no studies usingPCR-based methods to survey the bacterial diversityassociated with snails have been undertaken.Thus it is not at all clear if snails have a bacterialflora that simply mimics the aquatic environment inwhich they live, is typical of other aquatic invertebrates,or if they harbour specialized and unculturablespecies. Knowing more about the bacterial floraof snails is important because such bacteria mayoffer specific opportunities for control, or for introducingexotic genes into snails. Also, bacterial associateswith snails may influence the susceptibility ofsnails to schistosomes or other trematodes.Two final examples of poorly known symbionts offreshwater snails deserving of study are nematodesand chaetogasters. Some nematodes from terrestrialsnails, like their entomopathogenic relatives frominsects, carry potentially lethal bacteria into snails(Glenn and Wilson, 1997; Grewal et al., 2003). It isnot known if freshwater snails have similar counterparts,or if molluscopathogenic nematodes of terrestrialsnails could be adapted to freshwater snails.Also unknown is the impact such nematodes andtheir bacterial associates might have on developinglarval trematodes. Chaetogasters are ectosymbioticoligochaetes of snails and are of interest becausethey can consume both schistosome miracidia andcercariae, and may play a role in protecting snailsfrom infection (Rodgers et al., 2005). There is muchto learn about snail symbionts, and it seems certainthat some of these associates will prove to bebiologically unique and may have useful proper-Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/0799

ties with respect to controlling snails or their larvaltrematodes.SPOROCYSTS AS THE TRUE TARGETSOF CONTROL EFFORTS: THE NEEDTO DEVELOP NEW APPROACHESAs noted above, with respect to controlling schistosomiasisat the level of the molluscan host, the trueenemy is not the snail that is hosting the parasite butthe schistosome sporocysts that colonize the snail.It is these sporocysts that will eventually producethe infective stages – cercariae – that infect humans.In general, especially with the advent of a host ofmolecular techniques, particularly PCR, there arenow new opportunities to look for, identify, and topotentially manipulate natural enemies or symbiontsof sporocysts. Since the molecular era began,there has been virtually no attempt to follow up onpromising studies of the microsporidian hyperparasitesof trematode larvae (Canning, 1981). Howcommon are these in nature? How many differenttaxa are capable of infecting trematode, includingschistosome, larvae? Can these be grown in vitro(for example in cultures of Bge cells) and then beintroduced into natural populations of schistosometransmittingsnails?Some trematodes are well-known hosts for rickettsialparasites, most notably Neorickettsia helminthoecatransmitted by Nanophyetus salmincola in thePacific Northwest. There is now evidence, based onthe use of PCR amplifications, to indicate that rickettsiaemay be more commonly associated with larvaltrematodes than previously thought (Park et al.,2003; Chae et al., 2003; Pusterla et al., 2003; Gibsonet al., 2005). Do rickettsiae infect the intramolluscanstages of human or animal-infecting schistosomes?We don’t know.Other groups of symbionts of larval trematodesvery well might come to light, including virusesor potentially members of the Mesomycetozoea. Ingeneral, it would be helpful for funding agencies toencourage exploration, using modern approaches,for novel associates of larval trematodes that mayhave considerable control potential, including withsomething typically lacking, the possibility of specificitywith respect to controlling sporocysts.A final consideration with respect to larval schistosomepopulation dynamics is the ultimate effectof human-mediated ecological simplification. Thiswill also have the effect of eliminating other vertebratesand invertebrates that serve as hosts for metacercariaeor adults of trematode species that alsocycle through snails like Biomphalaria, Bulinus orOncomelania. The significance of this is that theseother trematodes, by virtue of competing with, orpreying upon, the larvae of schistosomes, may exerta larger measure of natural control than we wouldotherwise suspect (Esch et al., 2001). Thus ecologicalsimplification could potentially have the effectof intensifying schistosome transmission in someareas.NOT PARASITES OF HUMANS BUTSTILL IN NEED OF STUDY: THESCHISTOSOMES THAT CAUSECERCARIAL DERMATITISThroughout the world, the cercariae of schistosomesof animals, especially those from birds, cause dermatitiswhen they penetrate the skin of people incontact with waters of natural habitats (Verbrugge etal., 2004). Although it has generally been consideredthat such cercariae die in the skin, recent work suggeststhat this is not always the case, and that someparasites from such infections may persist and causeneurological problems (Hradkova and Horak, 2002).There is ample evidence that outbreaks of dermatitisoccur continually around the world, both in marineand freshwater habitats (Larsen et al., 2004), in somecases involving exotic species of gastropods as hosts(Cohen, personal communication). We currentlyhave only a hazy picture of the diversity of schistosomespecies involved in dermatitis outbreaks, apicture rendered all the more hazy by the complicationsof interpreting the classical literature. Again,with the advent of molecular methods for identificationof dermatitis-causing cercariae and correspondingadults (Brant et al., 2006), and of the associatedsnails, we have significant new opportunities tolearn more about this entire phenomenon. Studies ofthe basic biology of dermatitis, including the potentialfor prolonged human infection with non-humanschistosome cercariae, should be undertaken.THE NEED FOR RELIABLEINFORMATION TRANSFER TODEVELOPING COUNTRIES AND FORMAINTAINING A CRITICAL MASS INMEDICAL MALACOLOGYOne of the ongoing ironies of schistosomiasisresearch is that much of the necessary backgroundinformation and literature, and many of the newtools and techniques, are far more readily availablein developed countries than in endemic areas.Some programmes like the education of buddingAfrican malacologists by the Danish BilharziasisLaboratory, have done much to improve not onlythe level of training of scientists from developing100 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

countries but also the flow of relevant informationto them. Primarily through the use of the worldwideweb, potentially through the central organizationof the WHO, there should be a renewed attemptto provide schistosomiasis field workers in developingcountries with as many opportunities as possibleto get accurate and practical updates regardingvarious aspects of medical malacology. Provisionof techniques to collect and identify snails usingboth classical and modern techniques, along withcopies of the supporting references, would be veryappropriate. Attention to regional differences in thesnail fauna would also be very helpful. Additionaltopics worthy of inclusion would be outlining thetechniques for separating and isolating snails, identificationof the types of cercariae that are producedby snails, again with the supporting original references,and protocols for how to apply some of thenewer molecular methods for determining if snailsare infected with schistosomes.As a final comment, if we are to continue to capitalizeon the new tools and discoveries available fromrecent studies of schistosomes and their associatedsnails, we need to be mindful of the need to train thenext generation of malacologists so we do not losecritical mass and the accumulated knowledge andexperience base we now have. It is also imperativethat centres of malacological training be supported,not only for their own original research but to permittraining of students from developing countrieswhere schistosomiasis or other snail-transmittedparasites are problematic.SUMMARY OF NEEDSNeeded knowledge/studies/activities on the molluscanaspects of schistosomiasis include:• Monitoring of changes in the distribution andabundance of schistosome-transmitting snails,preferably with the involvement of an active networkof medical malacologists and incorporatingnew tools such as remote sensing and geographicinformation systems.• Continued development of a modern toolkit tofacilitate in-depth study of snails and larval trematodesand their interactions.• Development of more specific modern tools tofacilitate the study of snails and associated larvalschistosomes in field settings.• More complete understanding of the naturalsymbionts and associates of schistosome-transmittingsnails.• More thorough investigation of the natural enemiesof schistosome sporocysts.• More knowledge about the etiological agents andepidemiology of cercarial dermatitis.• Better facilitation for transfer of relevant informationto scientists in developing countries.• Continued support for a critical mass of medicalmalacologists, including centres to support trainingof scientists from developing countries andsupport for scientists from developed countrieswilling to work in the often difficult field conditionswhere schistosomiasis transmission occurs.AcknowledgmentsThe author thanks the members of the ‘Parasites andHosts’ reading group at the University of New Mexicofor their helpful feedback. This work was supportedby NIH Grant Number RR-1P20RR18754 from theInternational Development Award (IDeA) programof the National Center for Research Resources, andby NIH grants AI24340 and AI44913.ReferencesAbdel-Wahab MF et al. Is Schistosoma mansoni replacingSchistosoma haematobium in the Fayoum? AmericanJournal of Tropical Medicine and Hygiene, 1993, 49:697–700.Attwood SW et al. A DNA-sequence based phylogenyfor triculine snails (Gastropoda: Pomatiopsidae:Triculinae), intermediate hosts for Schistosoma(Trematoda: Digenea): phylogeography and the originof Neotricula. Journal of Zoology, 2004, 262:47–56.Bixler LM et al. Axenic culture of Schistosoma mansonisporocysts in low O 2 environments. Journal ofParasitology, 2001, 87:1167–1168.Brant SV et al. An approach to revealing blood flukelife cycles, taxonomy, and diversity: provision of keyreference data including DNA sequence from singlelife cycle stages. Journal of Parasitology, 2006, 92:77–88.Campbell G et al. Molecular evidence supports anAfrican affinity of the neotropical freshwater gastropod,Biomphalaria glabrata, Say 1818, an intermediatehost for Schistosoma mansoni. Proceedings of the RoyalSociety of London Series B, 2000, 267:2351–2358.Canning EU. Microsporidia for trematode control.Parasitology, 1981, 82:120–121.Carton Y, Nappi AJ, Poirie M. Genetics of anti-parasiteresistance in invertebrate. Developmental andComparative Immunology, 2005, 29:9–32.Chae JS et al. Prevalence and sequence analyses ofNeorickettsia risticii. Rickettsiology: Present and FutureDirections, 2003, 990:248–256.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07101

Christophides GK, Vlachou D, Kafatos FC.Comparative and functional genomics of the innateimmune system in the malaria vector Anopheles gambiae.Immunological Reviews, 2004, 198:127–148.Coelho PMZ et al. Biomphalaria tenagophila/Schistosomamansoni interaction: Premises for a new approachto biological control of schistosomiasis. Memorias doInstituto Oswaldo Cruz, 2004, 99:S109–111.Coppin JF et al. Gene expression changesin Schistosoma mansoni sporocysts induced byBiomphalaria glabrata embryonic cells. ParasitologyResearch, 2003, 89:113–119.Coustau C, Yoshino TP. Flukes without snails:Advances in the in vitro cultivation of intramolluscanstages of trematodes. Experimental Parasitology, 2000,94:62–66.Cowie RH. Can snails ever be effective and safebiocontrol agents? International Journal of PestManagement, 2001, 47:23–40.Davison A, Blaxter ML. An expressed sequence tagsurvey of gene expression in the pond snail Lymnaeastagnalis, an intermediate vector of Fasciola hepatica.Parasitology, 2005, 130:539–552.DeJong RJ et al. Evolutionary relationships and biogeographyof Biomphalaria (Gastropoda: Planorbidae)with implications regarding its role as host of thehuman bloodfluke, Schistosoma mansoni. MolecularBiology and Evolution, 2001, 18:2225–2239.Dillon RT et al. Populations of the European freshwaterpulmonate Physa acuta are not reproductivelyisolated from American Physa heterostropha or Physaintegra. Invertebrate Biology, 2002, 121:226–234.Ducklow HW et al. Bacterial flora of the schistosomevector snail Biomphalaria glabrata. Applied andEnvironmental Microbiology, 1979, 38:667–672.Ducklow HW, Clausen K, Mitchell R. Ecology ofbacterial communities in the schistosomiasis vectorsnail Biomphalaria glabrata. Microbial Ecology, 1981,7:253–274.Esch GW, Curtis LA, Barger MA. A perspective onthe ecology of trematode communities in snails.Parasitology, 2001, 123:S57–S75Gibson KE et al. Neorickettsia risticii is vertically transmittedin the trematode Acanthatrium oregonenseand horizontally transmitted to bats. EnvironmentalMicrobiology, 2005, 7:203–212.Giovanelli A et al. The molluscicidal activity ofniclosamide (Bayluscide WP70 (R)) on Melanoidestuberculata (Thiaridae), a snail associated with habitatsof Biomphalaria glabrata (Planorbidae). Memorias doInstituto Oswaldo Cruz, 2002, 97:743–745.Giovanelli A, Vieira MV, da Silva CLPAC. Interactionbetween the intermediate host of schistosomiasis inBrazil Biomphalaria glabrata (Planorbidae) and a possiblecompetitor Melanoides tuberculata (Thiaridae): I.Laboratory experiments. Memorias do Instituto OswaldoCruz, 2002, 97:363–369.Giovanelli A, Vieira MV, da Silva CLPAC. Interactionbetween the intermediate host of schistosomiasis inBrazil, Biomphalaria glabrata (Say, 1818) and a possiblecompetitor, Melanoides tuberculata (Muller, 1774): Afield study. Journal of Molluscan Studies, 2005, 71:7–13.Glen DM, Wilson MJ. Slug-parasitic nematodes as biocontrolagents for slugs. Agro Food Industry Hi-Tech,1997, 8:23–27.Grewal PS et al. Parasitism of molluscs by nematodes:Types of associations and evolutionary trends. Journalof Nematology, 2003, 35:146–156.Graeff-Teixeira C et al. The initial epidemiologicalstudies in the low endemicity schistosomiasis area inEsteio, Rio Grande do Sul, the southernmost Brazilianstate, 1997 to 2000. Memorias do Instituto Oswaldo Cruz,2004, 99:S73–78.Hamburger J et al. A polymerase chain reaction assayfor detecting snails infected with bilharzia parasites(Schistosoma mansoni) from very early prepatency.American Journal of Tropical Medicine and Hygiene, 1998,59:872–876.Hamburger J et al. Large-scale, polymerase chainreaction-based surveillance of Schistosoma haematobiumDNA in snails from transmission sites in coastalKenya: A new tool for studying the dynamics of snailinfection. American Journal of Tropical Medicine andHygiene, 2004, 71:765–773.Hanelt B et al. Detection of Schistosoma mansoni inBiomphalaria glabrata using nested PCR. Journal ofParasitology, 1997, 83:387–394.Heckel DG. Genomics in pure and applied entomology.Annual Review of Entomology, 2003, 48:235–260.Hertel LA, Bayne CJ, Loker ES. The symbiontCapsaspora owczarzaki, nov. gen. nov. sp., isolated fromthree strains of the pulmonate snail Biomphalaria glabratais related to members of the Mesomycetozoa.International Journal for Parasitology, 2002, 32:1183–1191.Hradkova K, Horak P. Neurotropic behaviour ofTrichobilharzia regenti in ducks and mice. Journal ofHelminthology, 2002, 76:137–141.Jannotti-Passos LK et al. PCR amplification of themitochondrial DNA minisatellite region to detectSchistosoma mansoni infection in Biomphalaria glabratasnails. Journal of Parasitology, 1997, 83:395–399.102 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Jarne P, Stadler T. Population genetic structure andmating system evolution in freshwater pulmonates.Experientia, 1995, 51:482–497.Jiang Y, Loker ES, Zhang SM. In vivo and in vitroknockdown of FREP2 gene expression in the snailBiomphalaria glabrata using RNA interference.Developmental and Comparative Immunology, 2006,30:855–866.Jones CS et al. Molecular evolution of freshwater snailintermediate hosts within the Bulinus forskalii group.Parasitology, 2001, 123:S277–S292.Kinzelbach R. Neozoans in European waters – exemplifyingthe worldwide process of invasion and speciesmixing. Experientia, 1995, 51:526–538.Kristensen TK, Brown DS. Control of intermediatehost snails for parasitic diseases – A threat to biodiversityin African freshwaters? Malacologia, 1999,41:379–391.Lardans V, Dissous C. Snail control strategies forreduction of schistosomiasis transmission. ParasitologyToday, 1998, 14:413–417.Larsen AH, Bresciani J, Buchmann K. Increasing frequencyof cercarial dermatitis at higher latitudes. ActaParasitologica, 2004, 49:217–221.Lockyer AE et al. Trematodes and snails: an intimateassociation. Canadian Journal of Zoology, 2004,82:251–269.Lotfy WM et al. A molecular survey of Biomphalariain Egypt: is B. glabrata present? American Journal ofHygiene and Tropical Medicine, 2005, 73:131–139.Marshall J. Environmental health: megacity, megamess ... Nature, 2005, 437:312–314.Martens WJM, Jetten TH, Focks DA. Sensitivity ofmalaria, schistosomiasis and dengue to global warming.Climatic Change, 1997, 35:145–156.Minchella DJ, Sollenberger KM, Desouza CP.Distribution of schistosome genetic diversity withinmolluscan intermediate hosts. Parasitology, 1995,111:217–220.Mitta G et al. Gene discovery and expression analysisof immune-relevant genes from Biomphalaria glabratahemocytes. Developmental and Comparative Immunology,2005, 29:393–407.Monkiedje A, Anderson AC, Englande AJ. Acutetoxicity of Phytolacca dodecandra (Endod S) andniclosamide to snails, Schistosoma mansoni cercaria,tilapia fish, and soil microorganisms. EnvironmentalToxicology and Water Quality, 1991, 6:405–413.Morgan JAT et al. A phylogeny of planorbid snails,with implications for the evolution of Schistosoma parasites.Molecular Phylogenetics and Evolution, 2002,25:477–488.Oliveira EC, Paumgartten FJR. Toxicity of Euphorbiamilli latex and niclosamide to snails and nontargetaquatic species. Ecotoxicology and Environmental Safety,2000, 46:342–350.Park BK et al. Identification of trematode cercariaecarrying Neorickettsia risticii in freshwater streamsnails. Rickettsiology: Present and Future Directions,2003, 990:239–247.Pointier JP, David P, Jarne P. Biological invasions: thecase of planorbid snails. Journal of Helminthology, 2005,79:249–256.Pointier JP et al. A neotropical snail host of Schistosomamansoni introduced into Africa and consequencesfor the schistosomiasis transmission: Biomphalariatenagophila in Kinshasa (Democratic Republic ofCongo). Acta Tropica, 2005, 93:191–199.Pusterla N et al. Digenetic trematodes, Acanthatriumsp and Lecithodendrium sp., as vectors of Neorickettsiaristicii, the agent of Potomac horse fever. Journal ofHelminthology, 2003, 77:335–339.Rodgers JK et al. Multi-species interactions amonga commensal (Chaetogaster limnaei limnaei), a parasite(Schistosoma mansoni), and an aquatic snail host(Biomphalaria glabrata). Journal of Parasitology, 2005,91:709–712.Scholz T, Salgado-Maldonado G. The introductionand dispersal of Centrocestus formosanus (Nishigori,1924) (Digenea : Heterophyidae) in Mexico: A review.American Midland Naturalist, 2000, 143:185–200.Seto E et al. The use of remote sensing for predictivemodeling of schistosomiasis in China. PhotogrammetricEngineering and Remote Sensing, 2002, 68:167–174.Sow S et al. Water-related disease patterns before andafter the construction of the Diama dam in northernSenegal. Annals of Tropical Medicine and Parasitology,2002, 96:575–586.Stothard JR et al. New insights into the transmissionbiology of urinary schistosomiasis in Zanzibar.Transactions of the Royal Society of Tropical Medicine andHygiene, 2002, 96:470–475.Sutherst RW. Global change and human vulnerabilityto vector-borne diseases. Clinical Microbiology Reviews,2004, 17(1):136–173.Teo SS. Evaluation of different duck varieties for thecontrol of the golden apple snail (Pomacea canaliculata)in transplanted and direct seeded rice. Crop Protection,2001, 20:599–604.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07103

Théron A, Coustau C. Are Biomphalaria snails resistantto Schistosoma mansoni? Journal of Helminthology, 2005,79:187–191.Verbrugge LM et al. Swimmer’s itch: Incidence andrisk factors. American Journal of Public Health, 2004,94:738–741.Vidigal THDA et al. A Multiplex-PCR approach toidentification of the Brazilian intermediate hosts ofSchistosoma mansoni. Memorias do Instituto OswaldoCruz, 2002, 97:S95–97.Vidigal THDA et al. Analysis of the first and secondinternal transcribed spacer sequences of the ribosomalDNA in Biomphalaria tenagophila complex (Mollusca: Planorbidae). Memorias do Instituto Oswaldo Cruz,2004, 99:153–158.Woodruff DS, Mulvey, M. Neotropical schistosomiasis:African affinities of the host snail Biomphalaria glabrata(Gastropoda: Planorbidae). Biological Journal ofthe Linnean Society, 1997, 60:505–516.Yousif F, Lämmler G. The suitability of several aquaticsnails as intermediate hosts for Angiostrongylus cantonensis.Zeitschrift fur Parasitenkunde, 1975, 47:203–210.Zhang SM et al. Diversification of Ig genes in aninvertebrate. Science, 2004, 305:251–254.Zheng J et al. Relationship between the transmissionof Schistosomiasis japonica and the constructionof the Three Gorge Reservoir. Acta Tropica, 2002, 82:S147–156.104 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

WORKING PAPER 14.Schistosomiasisand immunityKenji HirayamaDepartment of Molecular Immunogenetics, Instituteof Tropical Medicine, Nagasaki University, 1-12-4Sakamoto, Nagasaki 852-8523, Japan.ABSTRACTGenetic predisposition to severe forms ofschistosomiasis japonicaIn China, we have identified two major genes related tothe severity of liver fibrosis of chronic schistosomiasis, onean HLA class II gene and the other the IL-13 gene. The frequencyof the HLA-DRB5*0101 (B1*1501) allele and that ofthe IL-13 promoter A/A (IL-13P A/A) genotype was elevatedin fibrotic patients, although the two genes are located on differentchromosomes, chromosomes 6p and 5q, respectively.Subjects with both genotypes had odds ratios (OR) of 24.5,much higher than the sum of the ratios for each individualgenotype (OR = 5.1 for HLA-DRB5*0101, OR = 3.7 for IL-13PA/A). That the effects of the two susceptibility markers aresynergistic rather than additive strongly suggests that thepathogenic Th2 response directly influences the prognosis ofpost-schistosomal liver fibrosis.Miniature pig is a unique model for humanschistosomiasisCLAWN mini-pig was infected with a Chinese strain ofSchistosoma japonicum by skin penetration of 200 cercariae.The recovery rate of adult worms in the portal vein wasalmost 50% and they completely matured to excrete eggs 9weeks after the challenge infection. Although they showeda naturally healing pattern of infection after 20 weeks ofinfection, the miniature pig was revealed to be a permissivehost. We established this model system and tried to use it forvaccine development. Hopefully this model will be applicableto studies on the prevention and treatment of chronicschistosomiasis.GENETIC PREDISPOSITIONTO SEVERE FORMS OFSCHISTOSOMIASIS JAPONICAOur recent findings clearly indicate the presenceof genetic factors that can predict the prognosis ofschistosomiasis japonica. The identification of genesassociated with susceptibility or resistance to thesevere forms will help us to understand its pathogenesis,and finally to devise new treatments.To identify the genes responsible, two differentapproaches are generally undertaken: targeted geneanalysis and genome-wide survey. We adopted theformer method, focusing especially on immunityrelatedgenes such as those for human leukocyteantigen (HLA), cytokines, and adhesion molecules.HLA genes are highly polymorphic and their allelesare well characterized at the DNA sequence level.For example, the HLA-DRB1 gene has over 100 allelesin the human population. In particular, HLA-DR, -DQ, -DP, -A, -B, and -C are believed to functionas immune-response proteins directed against exogenouspathogens. Cytokines are also believed toplay important roles in controlling the intensityand duration of immune response. Recently, singlenucleotide polymorphisms (SNPs) have beenobserved very commonly in the promoter regionsof some cytokines, including tumour necrosis factor(TNF), interleukin (IL)-4, IL-13, and interferon-γ.Several studies have demonstrated that these polymorphismsdirectly affect promoter activity.Polymorphisms in HLA class II genes andthe IL-13 promoter and schistosomal liverfibrosisSchistosomiasis japonica is a chronic helminthicinfectious disease that affected at least 860 000 individualsin China in 1995. Morbidity and mortalityare dependent on its chronic sequela, post-schistosomalhepatosplenic disease, which is characterizedby liver fibrosis, portal hypertension, ascites accumulation,oesophageal varices, and eventual death.The liver fibrosis seen in these patients is inducedby a granulomatous immune response againstthe eggs that are deposited in the periportal area.Schistosomal egg-antigen-specific CD4 + T cells playa major role in the formation of granuloma throughTh2-type cytokine production in experimental schistosomiasismansoni. However, in humans, little isknown about the immunological response duringthe chronic phase of hepatosplenic disease. Becauseonly 5%–10% of patients with chronic schistosomiasisjaponica develop hepatosplenic disease, andbecause the granulomatous response is initiated byCD4 + T cells reactive to schistosomal antigen, polymorphismsof the HLA class II antigens, whichcontrol the reactivity of the CD4 + T cells, may be associatedwith susceptibility to hepatosplenic disease.Indeed, associations between schistosomal hepatosplenicdisease and HLA alleles have been reportedfor schistosomiasis mansoni and for schistosomiasisjaponica. Recently, more objective diagnostic methodsusing ultrasonography have become popularand have been standardized to measure changes inliver morphology. Therefore, we used this methodto categorize the patients into a ‘fibrotic’ group anda ‘non-fibrotic’ group, and examined their geneticcharacteristics by analysing the polymorphisms ofReport of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07105

candidate genes encoding HLA class II and class Iantigens, TNF-α and cytokines.A total of 230 current or former patients withchronic schistosomiasis japonica were examined forliver changes. All patients were from the agriculturalvillage of Beishan, in Yushan county, China,and had their first episode of infection and treatmentat least ten years before this study began. Themean age of the subjects was 52.6 ± 10.5 years andthe mean time since their initial treatment was 27.4± 8.8 years. Ultrasonographic diagnosis was carriedout according to the WHO standard for diagnosisof liver fibrosis due to schistosomiasis japonica.Ultrasonographic diagnosis determined that therewere 44 persons with grade 0 fibrosis, 81 with gradeI fibrosis, 99 with grade II fibrosis, and six with gradeIII fibrosis. The presence of hepatitis B virus (HBV)was not assessed in these patients, but the prevalenceof HBV is about 15% in Jiangxi Province. Mostof the men in the village smoke tobacco and drinkalcoholic beverages, but the women generally donot. The patients had all been treated with praziquantelafter each positive faecal examination throughouttheir lives, but it was not possible to estimate theprecise total worm burden of each patient duringthe clinical course of the disease. Therefore, we tentativelydefined an appropriately exposed person assomeone with a record of repeated treatments forschistosomiasis japonica over a ten-year period.HLA class I and II allele typingThe DNA typing of the HLA-DRB1 gene was performedwith the PCR sequence-specific oligonucleotideprobes (SSOP) method used at the XIthHLA workshop. HLA-B DNA typing was performedas previously described. In total, 29 allelesfor HLA-DRB1, three for HLA-DRB3, two forHLA-DRB5, 13 for HLA-DQA1, 11 for HLA-DQB1,four for HLA-DPA1, 18 for HLA-DPB1, and 24 forHLA-B were detected in this population. No significantdifference in the frequency of the HLA-Btypes was observed in the two groups defined bythe severity of their fibrosis. On the contrary, thefrequencies of several HLA class II alleles were significantlyincreased or decreased in the fibroticgroup. When we compared the frequencies of allelesbetween grade 0 and grades I, II, and III, we foundthat HLA-DRB1*1101 (P < 0.001), DQA1*0501 (P

Table 1. Synergistic effect of DRB5*0101 (DRB1*1501) and IL-13P-A/A genotype in developing fibrosisHLA-D RB5* IL-13P Normal(grade 0) n=36(%)Fibrosis(grade I, II, III)n=156 (%)OR95% CI0101 A/A 0 (0.0) 21 (13.4) 24.5 1.41–424.00101 – 2 (5.6) 18 (11.5) 5.1 1.08–23.9– A/A 12 (33.3) 78 (49.7) 3.7 1.64–8.17– – 22 (61.1) 39 (25.0)Additive effect of DRB1*1101 and IL-13P-B alleles on resistanceHLA-DR B1* IL-13P Normaln=36 (%)Fibrosisn=156 (%)OR95% CI1101 B 8 (22.2) 9 (5.7) 9.0 2.78–29.11101 – 4 (11.1) 7 (4.9) 5.8 1.42–23.6– B 15 (41.7) 49 (36.2) 3.1 1.26–7.59– – 9 (25.0) 91 (58.3)AcknowledgementsChen Honggen, Yin Dong, Gu Xiaonan, and ZhangShaoji of Jiangxi Province Institute of ParasiticDiseases; Mihoko Kikuchi of Nagasaki University;and Jianxiang Liu and Hong-Chang Yuan ofShanghai Medical University contributed to thestudy.MINIATURE PIG IS A UNIQUE MODELFOR HUMAN SCHISTOSOMIASISIn looking for the ideal animal model for Schistosomajaponicum infection, miniature pigs were percutaneouslyinfected with 200 S. japonicum cercariae, andparasitological, pathological and serological aspectsof the infection were monitored. Egg excretion intofaeces began at 5 weeks post-infection (PI), and pronouncedexcretion of the eggs continued from 8weeks to 17–20 weeks PI. The average numbers ofeggs per gram of faeces (epg) of the two pigs duringthe period 8–20 weeks were 288 and 277 respectively.After 20 weeks PI, the epg gradually decreased anddisappeared until 28 wks PI. One pig was sacrificedand examined at 27 weeks PI and the other at 47weeks PI. The number of adult worms recoveredfrom the former pig was 35 and from the latter was15. Based on this preliminary observation, vaccineexperiments were performed using two differentsystems: 1) radiation attenuated cercariae vaccine,and 2) nasal vaccination using recombinant paramyosinand cholera toxin. We observed partial protectionafter vaccination.As shown in fig. 1, vaccination with radiation attenuatedcercariae protected the pigs against challengeinfection with 200 cercariae. When we vaccinatedpigs with recombinant paramyosin plus choleratoxin by nasal administration, we observed a veryserious adverse event of pneumonitis after the challengeinfection. Because IL-4 levels in the serumwere significantly elevated in this group, hypersensitivityreaction was suspected to be provoked bythe infection after nasal immunization with choleratoxin plus paramyosin. Moreover, paramyosin vaccinationwas only effective at reducing the femaleworm burden.Figure 1. Radiation attenuated cercariae vaccine Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07107

Miniature pig:• Fifty per cent recovery after the challenge infectionindicated that miniature pigs are a permissivehost.• Attenuated cercariae vaccine reduced the numberof eggs.• Mucosal immunization decreased the number offemale worms.• Cholera toxin plus paramyosin provoked severeacute pneumonitis after challenge infection.AcknowledgementsKanji Watanabe of the Institute of TropicalMedicine at Nagasaki University, Takeshi Naraof Juntendo University, and Takeshi Arakawa ofRyukyu University contributed to this study.108 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

WORKING PAPER 15.Genomics and proteomics:towards new targets inschistosome researchR. Alan WilsonDepartment of Biology, University of York, PO Box 373,York YO10 5YW, UKThe first years of the 21st century have seen quiteremarkable advances in our knowledge of the schistosomegenome and the application of new technologiessuch as microarrays and proteomics to exploitthe accumulating information. In this working paperI shall review the many possibilities now open toresearchers. Potential pitfalls and limitations arealso considered, together with the technical obstaclesthat must be overcome before the maximumbenefits for schistosomiasis control can accrue.The bulk of material covered relates to Schistosomamansoni for two reasons. Firstly, it is the most tractablespecies experimentally, so research on it generallysets the pace. Secondly, it is the species on whichI have undertaken most of my investigations overthe last 35 years. The narrow focus is not intended tobelittle the efforts made with S. japonicum where thedifficulty in maintaining the snail intermediate host,and the small amount of cercarial material obtainable,create special problems. The same is true forthe experimentally even more difficult S. haematobium,where effort needs to be concentrated becauseit infects the largest number of individuals in sub-Saharan Africa, causing the greatest morbidity andannual mortality among the three principal humanschistosomes. 1THE SCHISTOSOME GENOMEShotgun sequencing of the S. mansoni genome wasundertaken 2002–2004 as a joint effort between TheInstitute of Genomic Research (TIGR), Rockville,USA, and the Wellcome Trust Sanger Institute(WTSI), Cambridge, UK; it generated more thanthree million reads to provide approximately 8xcoverage of the 280 MB genome. A major intrinsicobstacle to genome assembly has been, and remains,the presence of large amounts of repeat sequence(comprising up to 40% of the genome, mostly in anumber of retrotransposon families [see below]). Agenome database, SchistoDB.org, was created andversion 1 of the draft assembly was released to theresearch community in February 2005, with automaticannotation of the genes. Another limitationhas proved to be the inefficiency of the gene findingprograms (this is not unique to schistosomes). Threewere used (Phat, SNAP and glimmerHMM) to pickout genes from the DNA sequence, and they rarelyagree precisely on what represents the predictedcoding region. Nevertheless, with careful interrogation,it is possible to discover many novel features ofschistosome gene structure.Following release of version 1 of the draft genome,work has continued at WTSI, under the supervisionof Dr Matt Berriman, to improve the assembly by thegeneration and sequencing of a fosmid library constructedfrom randomly sheared DNA. As a resultthe genome has now been assembled into 13 000supercontigs with an N50 of 824 kb, i.e. 50% of thenucleotides are in scaffolds > 800 kb. This is aboutthe size of the average protozoan chromosome; incontrast, the individual schistosome chromosomesare around 30–40 Mb each, which gives some ideaof the magnitude of the assembly task. Work hasalso continued at TIGR, under the supervision of DrNajib el-Sayed, to retrain the gene finding programswith a larger number of full length coding sequences(CDS). Version 3 of the assembly is currently beingscreened at TIGR with the improved gene finders toobtain a new set of predicted genes which will formthe substrate for gene annotation, both automaticand manual (two annotators are currently employedfull time at WTSI). It is anticipated that version 3 willbe released to the community shortly, with publicationof the genome paper scheduled for mid 2006.In the short term it is unlikely that the genome willbe assembled into eight chromosome-sized chunks,with genes assigned to each. One obstacle is the paucityof gene mapping to individual chromosomes, inwhich the pioneering work has been undertaken asa collaboration by Drs LoVerde and Hirai. 2,3A sequencing project for S. japonicum is also underway based at the Chinese National Human GenomeCentre in Shanghai. A draft assembly of the Chinesereads has been attempted at WTSI but the currentstatus of the project is unclear (Berriman, personalcommunication).ProspectsHelminth genomes are an integral part of the nextfive-year plan at WTSI, commencing mid 2006.Efforts to improve the quality of the S. mansonigenome sequence will continue. S. haematobium isalso listed and the priority it receives will dependon the enthusiasm and lobbying of the schistosomeresearch community. Possession of three schistosomegenome sequences will confer significant ben-Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07109

efits, especially in the sphere of gene finding (cf. thesequencing of five species of yeast 4 ).THE TRANSCRIPTOMEThe characterization of expressed schistosome genesreally got under way in 1995 with the publication ofthe first expressed sequence tag (EST) project 5 thatadded more than 400 new sequences to the database.In the next eight years, about 15 000 EST sequenceswere put into the public domain. The situation thenchanged dramatically with the generation, analysisand simultaneous publication of two largeEST datasets for S. mansoni 6 and S. japonicum. 7 Theformer study, by a Brazilian consortium, used theORESTES technique 8 to sample mRNA from six lifecycle stages (egg, miracidium, sporocyst germ ball,cercaria, lung schistosomulum and adult). Analysisof the 120 000 ESTs revealed a genome containing atleast 14 000 genes, with an estimated 7000 expressedin each life cycle stage, around 1000 of which werethought likely to be stage-specific. The transcriptomedataset was estimated to sample 92% of S. mansoniexpressed genes. 6 The latter study by a Chinesegroup sampled mRNA from adult worms and eggs. 7A total of >43 000 ESTs were assembled into >13 000clusters which the authors believed comprised mostof the protein-coding genes (~15 000) in the parasite(this conclusion leaves little scope for stage-specificexpression).These datasets have proved invaluable for genefinding but also revealed the large number of transcribedretrotransposons, 9 none yet demonstratedto be actively moving around the genome. The datahave also opened up the possibilities for in silicoanalyses of biochemical and cellular mechanisms,for example in development, cell adhesion andsignalling. 6,7 The research community is now wellplaced to characterize pathways for which we havesome knowledge, and to begin the more difficulttask of investigating systems novel to schistosomes.At least 65% of schistosome EST clusters have nohomology with the genes of other organisms andmany of these will surely encode proteins that contributeto the unique features of the genus.Possession of a well characterized transcript databasewill permit the construction of a genome-widemicroarray with which to investigate patterns ofgene expression throughout the life cycle and withinindividual tissues. A number of studies have alreadybeen published with arrays that inevitably achieveonly partial coverage. (To the author’s knowledgeat least five separate S. mansoni and two S. japonicumarrays have been constructed, cf. the filarial researchcommunity, which has settled on one Brugia malayiarray with access for all.) Both cDNAs 10,11 and oligonucleotides12 have been printed onto glass slides andused to investigate a number of biological questions.To date, these have centred on gender-associatedand stage-specific expression, but the possibilitiesare endless. The first small-scale S. mansoni cDNAarray 10 was used to identify 12 female and 4 maleassociatedgene transcripts, and these observationswere subsequently expanded using a much largeroligonucleotide array that revealed 197 transcriptswith a gender biased pattern of gene expression inthe adult schistosome. 12 A small S. japonicum cDNAmicroarray also highlighted around 20 female and 8male-associated transcripts in two different isolatesof the parasite. Finally an array based on mRNAexclusively from the lung schistosomulum, containing>6000 features representing >3000 genes, wasused to screen mRNA from six other life cycle stagesto pinpoint genes highly expressed in, or specific to,the lung stage. 11 A total of 563 genes proved to bedifferentially regulated across the life cycle stagesused, around 50 of which were highly expressed atthe lung stage.A limitation in current microarrayconstructionThe current microarrays have been largely constructedusing cDNAs either taken from the publicdatabases or purpose generated. Until we get adefinitive list of CDS from the genome sequencingproject, a serious obstacle lies in the way of extendingthe arrays to provide greater genome coverage.The fact that the Brazilian S. mansoni transcriptomeproject generated ESTs using the ORESTES techniquethat relies on random priming, means thattheir strandedness is unknown. They can be compiledinto clusters, but the strandedness of theseclusters will only be known if they contain one ormore ESTs from conventionally generated cDNAs.We estimate that, of the >30,000 clusters and singletsin the S. mansoni database, >20 000 are composedexclusively of ORESTES sequences. The problemfor array construction could be solved by printing‘sense’ and ‘antisense’ copies from each clusterwith unknown strandedness on the slide, but thiswould increase its size by around 70% (from 30 000to 50 000 features) and its cost proportionally.The triploblastic acoelomate trapInvestigations that ask questions simply about gender-or stage-specific expression do not encounterthe triploblastic acoelomate problem. Schistosomeshave a solid body plan with differentiated cellsand tissues representing the major organ systemsof higher animals, such as nerve, muscle, gut,nephridia and gonads. (It is only necessary to look110 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

at electron micrographs of miracidia to see howmany cell types can be packed into a small space.)Furthermore the cells are firmly adherent to eachother, and methods do not exist for their separation.This becomes a problem when the investigatorwants to determine where in the parasite genes ofinterest are being expressed. For example, if surfaceexpressedgenes that might serve as vaccine candidatesare sought, then it is important to determinethat they are expressed in tegument cell bodies orgut epithelia and not in some cell type buried deepwithin the organism. Equally, when attempting todesignate the components of a signalling pathway,the investigator needs to know that all candidatesare expressed in the same cell type.Prospects• A genome wide microarray for each schistosomespecies should become feasible when the full listof CDS is available. Ideally, following the filariasismodel, this would be constructed by a consortium,with access for all researchers, at cost.There is an abundance of biological questionsthat can be tackled by transcriptome analysis andthus plenty of scope for many research groups.• Establishing the cell/tissue in which genes areexpressed needs to be addressed if array resultsare to be made meaningful at a level beyond simplestage-specificity.• The capacity for reverse genetics in schistosomesis in its infancy. Transient transfection of reportergenes has been achieved 13,14,15 but no system isavailable for stable transfection into the germline. There is not even a schistosome cell line 16that would permit homologous gene disruptionor over expression.• Disruption of gene function has been achievedwith small interfering RNAs (RNAi) but theeffects are presently limited to only a few lifecycle stages and are short term. 17,18,19 More efficientways of introducing the RNA constructsinto the parasite need to be developed.All the above demand high priority for researchefforts in the immediate future if the full benefits ofmicroarray analysis are to accrue.PROTEOMICSThe proteome can be defined as the total proteincomplement of an organism, tissue, cell or organelle.The suite of techniques that has been developed providesa way to link any protein to its encoding DNA(provided the sequence is in the database). The firststep is to separate a complex mixture into its constituentproteins. For soluble proteins this is read-ily achieved by 2D electrophoresis (2DE), usingimmobilized pH gradients for the first dimension. 20Although 2DE has its detractors, it has one singularadvantage over other separation techniques in thatthe relative amounts of constituents within a givenpreparation can be quantified, using image analysisand densitometry software. A second approachinvolves trypsinisation of the protein mixture followedby separation of the peptides by liquid chromatography(LC). Alternatively, proteins may beseparated by 1D electrophoresis, trypsinised, andthe peptides separated by LC. LC approaches areideal for insoluble proteins such as membrane constituents,but there is presently no easy way to obtaininformation on the relative amounts of different proteinsin such a mixture.The final step in proteomics is to subject the sampleto mass spectrometry (MS). MALDI ToF MS willproduce a peptide mass fingerprint from the trypticdigest of a single gel spot. Selected peptides canthen be fragmented by collision with a gas to yieldfragmentation spectra. Database searching withe.g. Mascot software against theoretical digests ofS. mansoni cDNA sequences or predicted CDS fromthe genome assembly, translated in all six readingframes, enables the link between the parent proteinand its CDS to be made. However, a putative functioncan only be assigned if an annotation is available(remember that 65% of S. mansoni EST clustershave no homology to other organisms).Proteomics has some advantages over microarrayanalysis, particularly because the expressed proteinsendow a cell or parasite stage with its specific functions,whereas detection of mRNA does not alwaysequate to the presence of protein. In addition, theacoelomate body plan is not an insuperable obstacleto analysis of protein expression at the cell or tissuelevel since a life cycle stage can be fractionatedusing conventional cell biological techniques suchas gradient centrifugation. On the other hand, sensitivityis an issue and, unless desired protein subsetscan be enriched, scarce constituents will not beidentified.A number of schistosome proteomic studies havealready been published and the influence of theapproach is set to grow since it can provide answersto questions of composition that were posed in somecases decades ago. The first report compared the solubleproteome of S. mansoni across four life cyclestages 21 revealing that the abundant cytosolic componentssuch as 14-3-3, actin, enolase, and aldolasewere common to the four stages investigated.Furthermore, the list included several of the firstgeneration vaccine candidates such as triose phos-Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07111

phate isomerase, glyceraldehyde-3-phosphate dehydrogenase,glutathione-S-transferase and fatty acidbinding protein. Subsequent studies have focusedon the composition of the adult tegument separatedfrom worm bodies by freeze-thaw treatment 22 andfurther enriched by density gradient centrifugationand differential extraction. 23 The results of theseinvestigations have enabled the protein constituentsof the tegument and its surface membrane complexto be explored. Furthermore, the proteins of bothparasite and host origin, most exposed on the externalsurface, have been investigated by surface biotinylation.24 Lastly, the cercarial secretions used inhost skin penetration have been characterized 25 andseveral proteases and putative immunomodulatorsidentified. 26ProspectsProteomics has developed to the point where thereare two very obvious applications that can rapidlygenerate new knowledge:• Composition of the parasite–host interface. Thiswill require a combination of tissue fractionationand the collection of secretions. Inevitably, to getsufficient material for analysis, much of the workwill need to be performed with in vitro culturedstages where integrity is essential to avoid generationof spurious composition data. This avenuewill undoubtedly identify novel vaccine candidatesand immunomodulators.• Pull down assays with bait proteins to recoverinteracting partners in e.g. signalling pathways,cell adhesion. Given the amount of materialinvolved, the approach will probably be limitedto adult worm preparations. However, itmay prove invaluable for pinpointing novel drugtargets.THE SCHISTOSOME GLYCOMESimilar techniques to MS analysis can also beapplied to the glycan chains attached to schistosomeproteins and lipids. The parasite fractions of interestare first treated enzymatically or chemically torelease the glycans. A glycan mass fingerprint canthen be generated by MS and, due to the relativelysmall number of sugar structures involved, empiricalcompositions obtained. 27 Linkage analysis canthen be performed to identify the precise monosaccharidesinvolved and their glycosidic bondlinks, allowing the complete glycan structures to bededuced. To the author’s knowledge at least twogroups, at the University of Leiden, The Netherlands(Dr C Hokke), and Imperial College, London (Prof.A Dell), are actively involved in analysing schisto-some glycan structures but no papers have beenpublished to date.ProspectsAs with proteomics, glycobiology is undergoinga rapid expansion in techniques and possibilities.The current limitations in synthesizing the deducedstructures for experimental purposes are beingsolved and the first glycan arrays have been constructed.28 It should thus soon be theoretically possibleto ‘print’ the full range of glycan structures fromschistosomes and use them, for example, to probethe acquired immune responses of human and laboratoryhosts to schistosome infection or vaccination.In parenthesis, it should be noted that glycanepitopes are often the predominant stimulatorsof antibody production. 29 Another application ofsuch arrays would be in the identification of interactingpartners within the parasite or among hostmacromolecules.THE IMMUNOMEIn theory, the combination of proteomics and serologyshould provide a powerful tool to identifyantibody targets among schistosome proteins andglycans. At a superficial level this is the case, withthe combination of 2DE separation of soluble proteins,their blotting onto membranes and probingwith antibody permitting the most reactive proteinsto be identified by MS. However, in the author’sinvestigations, the reactive proteins turn out to bethe same abundant cytosolic proteins that werecloned from expression library screens using antiseraa decade or more ago. In the one publishedstudy using the blotting approach, 30 the same glycolyticenzymes, chaperones and muscle proteinswere again the dominant antigens. Conversely, antibodydetection of proteins on Western blots appearsto be one or two orders of magnitude more sensitivethan gel stains such as Sypro Ruby so that strongreactions are often present that have no visible counterparton the gel suitable for MS analysis.ProspectsTechnical issues need to be addressed before characterizationof the immunome becomes a usefultool for e.g. pinpointing vaccine candidates. Onepossibility to increase the sensitivity of proteomicsin general is pre-depletion of protein fractionswith a cocktail of antibodies against the abundantcytosolic proteins so that larger quantities of scarceproteins can be loaded onto gels for 2D separation.In this context, obtaining sufficient parasite materialfrom stages other than adult worms or cercariaewill be a challenge. Finally, the problem of mem-112 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

ane proteins needs to be addressed. These couldwell represent important vaccine targets but theyare not amenable to 2DE and blotting and they arealso much scarcer than cytosolic components. It ispossible that a combination of detergent extractionof membranes and immuno-precipitation would beadequate for the purpose, provided that conformationalepitopes were not destroyed.CONCLUSIONSCollectively, the several avenues outlined aboveprovide the possibility for unprecedented gains inour knowledge of schistosomes and their interactionswith the mammalian host. The future is bright,but both ingenuity and resources are needed if rapidprogress is to be made.References1) van der Werf MJ et al. Quantification of clinicalmorbidity associated with schistosome infection insub-Saharan Africa. Acta Tropica, 2003, 86:125–139.2) LoVerde PT et al. Schistosoma mansoni genomeproject: an update. Parasitology International, 2004,53:183–192.3) Hirai H, Hirai Y. FISH mapping for helminthgenome. Methods in Molecular Biology, 2004,270:379–394.4) Kellis M et al. Sequencing and comparison of yeastspecies to identify genes and regulatory elements.Nature, 2003, 423:241–254.5) Franco GR et al. Identification of new Schistosomamansoni genes by the EST strategy using a directionalcDNA library. Gene, 1995, 152:141–147.6) Verjovski-Almeida S et al. Transcriptome analysisof the acoelomate human parasite Schistosomamansoni. Nature Genetics, 2003, 35:148–157.7) Hu W et al. Evolutionary and biomedical implicationsof a Schistosoma japonicum complementaryDNA resource. Nature Genetics, 2003, 35:139–147.8) Neto ED et al. Minilibraries constructed fromcDNA generated by arbitrarily primed RT-PCR: analternative to normalized libraries for the generationof ESTs from nanogram quantities of mRNA.Gene, 1997, 186:135–142.9) DeMarco R et al. Saci-1, -2, and -3 and Perere, fournovel retrotransposons with high transcriptionalactivities from the human parasite Schistosomamansoni. Journal of Virology, 2004, 78:2967–2978.10) Hoffmann KF, Johnston DA, Dunne DW.Identification of Schistosoma mansoni genderassociatedgene transcripts by cDNA microarrayprofiling. Genome Biology, 2002, 3:Research 0041.11) Dillon GP et al. Microarray analysis identifiesgenes preferentially expressed in the lung schistosomulumof Schistosoma mansoni. InternationalJournal for Parasitology, 2006, 36(1):1–8.12) Fitzpatrick JM et al. An oligonucleotide microarrayfor transcriptome analysis of Schistosoma mansoniand its application/use to investigate gender-associatedgene expression. Molecular and BiochemicalParasitology, 2005, 141:1–13.13) Davis RE et al. Transient expression of DNA andRNA in parasitic helminths by using particle bombardment.Proceedings of the National Academyof Sciences of the United States of America, 1999,96:8687–8692.14) Wippersteg V et al. HSP70-controlled GFP expressionin transiently transformed schistosomes.Molecular and Biochemical Parasitology, 2002,120:141–150.15) Wippersteg V et al. Biolistic transformation ofSchistosoma mansoni with 5’ flanking regionsof two peptidase genes promotes tissue-specificexpression. International Journal for Parasitology,2005, 35:583–589.16) Bayne CJ et al. In vitro cultivation of cells from larvalSchistosoma mansoni. Journal of Parasitology,1004, 80:29–35.17) Skelly PJ, Da’dara A, Harn DA. Suppression ofcathepsin B expression in Schistosoma mansoniby RNA interference. International Journal forParasitology, 2003, 33:363–369.18) Boyle JP et al. Using RNA interference to manipulateendogenous gene expression in Schistosomamansoni sporocysts. Molecular and BiochemicalParasitology, 2003, 128:205–215.19) Correnti JM, Pearce EJ. Transgene expression inSchistosoma mansoni: introduction of RNA intoschistosomula by electroporation. Molecular andBiochemical Parasitology, 2004, 137:75–79.20) Ashton PD, Curwen RS, Wilson RA. Linking proteomeand genome: how to identify parasite proteins.Trends in Parasitology, 2001, 17:198–202.21) Curwen, RS et al. The Schistosoma mansoni solubleproteome: a comparison across four life-cyclestages. Molecular and Biochemical Parasitology, 2004,138:57–66.22) van Balkom BW et al. Mass spectrometric analysisof the Schistosoma mansoni tegumental sub-proteome.Journal of Proteome Research, 2005, 4:958–966.23) Braschi S et al. The tegument surface membranesof the human blood parasite Schistosoma mansoni:a proteomic analysis after differential extraction.Proteomics, 2006, 6(5):1471–1482.24) Braschi S, Wilson RA. Proteins exposed at theadult schistosome surface revealed by biotinylation.Molecular and Cellular Proteomics, 2006,5(2):347–356.Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07113

25) Knudsen GM et al. Proteomic analysis ofSchistosoma mansoni cercarial secretions.Molecular and Cellular Proteomics, 2005, 4(12):1862–1875.26) Curwen RS et al. Identification of novel proteasesand immunomodulators in the secretions of schistosomecercariae that facilitate host entry. Molecularand Cellular Proteomics, 2006, 5:835–844.27) Kawar ZS et al. Novel poly-GalNAcbeta1-4GlcNAc(LacdiNAc) and fucosylated poly-LacdiNAcN-glycans from mammalian cells expressingbeta1,4-N-acetylgalactosaminyltransferase andalpha1,3-fucosyltransferase. Journal of BiologicalChemistry, 2005, 280:12810–12819.28) Drickhamer K, Taylor ME. Glycan arrays for functionalglycomics. Genome Biology, 2002, 3(12):reviews1034.29) Eberl M et al. Antibodies to glycans dominate thehost response to schistosome larvae and eggs:is their role protective or subversive? Journal ofInfectious Diseases, 2001, 183:1238–1247.30) Mutapi F et al. Praziquantel treatment of individualsexposed to Schistosoma haematobiumenhances serological recognition of defined parasiteantigens. Journal of Infectious Diseases, 2005,192:1108–1118.114 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07

Special Programme for Research & Trainingin Tropical Diseases (TDR) sponsored byUNICEF/UNDP/WorldBank/WHOTDR/World Health Organization20, Avenue Appia1211 Geneva 27SwitzerlandTel: (+41) 22 791-3725Fax: (+41) 22 791-4854tdr@who.intwww.who.int/tdrThe Special Programme for Research and Training in Tropical Diseases(TDR) is a global programme of scientific collaboration established in1975. Its focus is research into neglected diseases of the poor, withthe goal of improving existing approaches and developing new waystoprevent, diagnose, treat and control these diseases. TDR is sponsoredby the following organizations:World Bank