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14–16 November 2005 Geneva, Switzerland The Special Programme for Research and Training in Tropical Diseases (TDR) is a global programme of scientific collaboration established in 1975. Its focus is research into neglected diseases of the poor, with the goal of improving existing approaches and developing new ways to prevent, diagnose, treat and control these diseases. TDR is sponsored by the following organizations: Special Programme for Research & Training www.who.int/tdr in Tropical Diseases (TDR) sponsored by UNICEF/UNDP/World Bank/WHO World Bank TDR/SWG/07 WHO Library Cataloguing-in-Publication Data:

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All photos are from the TDR Photo library: WHO/TDR/Craggs, Crump, Edwards, Pagnoni, Reile, Stammers and Taylor-Robinson. Report of the Scientific Working Group meeting on Schistosomiasis Geneva, 14–16 November, 2005 TDR/SWG/07 Original: English

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Executive summary ...... 1 Background and rationale ...... 2 Objectives and overview ...... 4 Priorities ...... 12

Annex 1 AGENDA: Scientific Working Group on Schistosomiasis ...... 17 Annex 2 LIST OF PARTICIPANTS: Scientific Working Group on Schistosomiasis ...... 21 Annex 3 WORKING PAPERS: Scientific Working Group on Schistosomiasis ...... 27  WORKING PAPER 1. Research needs of the national schistosomiasis control programme in China ...... 28  WORKING PAPER 2. Current situation and research needs for schistosomiasis control in 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 Schistosomiasis  WORKING PAPER 10. The sociocultural context of schistosomiasis control: current knowledge 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 schistosome research ...... 109

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

iv Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Executive summary

More than 600 million people worldwide are at risk of schistosomiasis, and close to 200 million are actually infected continuously or intermittently. One of the main problems facing control of this major public health threat is, paradoxically, caused by previous successes in the battle against the disease. For example, reduction in the intensity of schistosomiasis during the past 25 years has made assessment of the disease less reliable in areas under sustained control since currently used diagnostic methods are not sufficiently sensitive to accurately determine the prevalence and worm burdens in these environments. Sustained control not only makes surveillance increasingly difficult but also holds back the clinical testing of vaccine candidates and contributes to the perception of the disease as a problem of the past. In fact, transmission is at the root of the problem and is unaffected by current control activities, resulting in high re- infection rates, even after mass treatment. The need for frequent re-treatment thus limits the success of control efforts, particularly in sub-Saharan Africa, which harbours about 85% of all schistosomiasis 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 a background of the need to better define the impact of schistosomiasis, discussions focused on the fact that the disability-adjusted life year (DALY) index, which is generally used as a yardstick when comparing the relative importance of diseases, does not accurately account for the full range of morbidities caused by schistosomiasis. For instance, the DALY index leaves out less well recognized (subtle) pathology of schistosomiasis such as anaemia, delayed growth and development, cognitive impairment, and sexual dysfunction. It was agreed that a 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 regularly Schistosomiasis collect straightforward data on, for example, anaemia in endemic populations, and develop standardized measures for more intricate outcomes of infection such as on work capacity and cognition. The SWG also recognized the need to support training, capacity building and collaboration across borders. It encouraged TDR to expand its role in initiating and maintaining research networks, including forming partnerships with industry, particularly with small to medium-sized businesses in endemic countries. In addition, the SWG encouraged coordination and, when possible, integration between control activities targeting different diseases in the same geographical area. Acknowledging the link between schistosomiasis and poverty, the SWG pointed to the acute need for research on the social determinants of schistosomiasis as well as the need for health systems research to improve programming. The potential benefits of cross-disciplinary research were particularly emphasized.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Background and rationale

Schistosomiasis is the collective name for infection by one (or more) of five Schistosoma species (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 can occasionally infect humans, e.g. S. bovis and S. magrobowei. This complex helminth infection requires alternate development between an intermediate snail host and the final mammalian host, both of which are indispensable for maintaining the parasite. In humans, the nature of the disease is largely immunological and only indirectly due to the parasitic worm itself; the pathological lesions emanate from inflammatory reactions to the large number of parasite eggs which are retained in host tissues rather than excreted with the faeces or urine (to infect the snail). The majority of schistosome species cause intestinal schistosomiasis, where the adult worm lives in the mesenteric venules of the host. However, the highest number of human infections is caused by S. haematobium, which has a predilection for the blood vessels around the bladder and causes urinary disease.

Spectrum of clinical pathology

Morbidity S. mansoni/S. japonicum S. haematobium General Acute schistosomiasis Acute schistosomiasis Anaemia Anaemia Organ-specific Hepatomegaly Vesicular wall hardening pathology Splenomegaly Bladder cancer Ectopic egg granulomas Ectopic egg granulomas Alternative venous circulation Kidney malfunction Genital schistosomiasis Genital schistosomiasis Schistosomiasis Developmental Cognitive dysfunction Cognitive dysfunction impairment Delayed growth/stunting Delayed growth/stunting

Understanding the problem and initiating the correct avenues of research to deal with it are pivotal 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 schistosomiasis can be controlled in areas where the necessary financial resources exist. However, elimination as a public health threat has proved difficult. Schistosomiasis is reported to exist in 76 countries 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 all over the last few decades, the overall situation changed dramatically following introduction

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 of the drug praziquantel, particularly after its price was reduced making mass chemotherapy possible. The resulting reduction in morbidity represents a major step forward, but high re- infection rates, even after repeated cycles of mass chemotherapy, limit the success of control efforts 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 control programmes such as Brazil, Egypt and The Philippines. China’s successful control programme reduced 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 clearly demonstrates the risk of re-emergence of schistosomiasis when a control programme moves into the consolidation phase and focuses on the final endemic areas while being less vigilant in other areas. The role that management and health system aspects of control programmes often play in such scenarios is understudied.

The rapid and sustained fall in morbidity in all areas under control has smoothed over the fact that control approaches have not evolved further, resulting in a widening of the gap between what is demanded from the field and what can be delivered. One paradoxical outcome of the reduction in morbidity is the dearth of improvements in available control tools. Surprisingly, even if research has generated various novel serological assays of potential application, the fall in intensity of the disease has not been met with more sensitive diagnostic capabilities in the field. The situation is similar in other areas. For example, although some progress has been made on the pre-clinical assessment of synthetic peroxides, the number of available effective drugs has been reduced from three to one, while the development of vaccines, which might have 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, while Schistosomiasis slow process development and a lack of industrial participation is hampering the development of new tools at the other end. The need for improvement, evident from a number of recent WHO informal consultations, resulted in this long-delayed SWG meeting on Schistosomiasis.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Objectives and overview

The objectives of the SWG were to define the research needs in the field of schistosomiasis and to assess the effectiveness of currently available tools and strategies for control. In addition, the SWG was asked to review global research activities, identify gaps between needs and ongoing research efforts, and indicate the means to address these gaps. The SWG was also expected to indicate ways of strengthening existing and new partnerships and to provide TDR with an overall strategy and scientific direction for research on schistosomiasis for the next five years.

General The SWG met in Geneva, 14–16 November 2005, to review the current needs for research and make 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 agree on, would be of little value unless the impact of schistosomiasis was better defined. A thorough meta-analysis, presented by Dr C. King, pointed out that the strong negative bias of the current disease-adjusted life years (DALY) index for schistosomiasis is largely due to failure to include less well recognized (subtle) pathological signs such as anaemia, delayed growth/development, cognitive impairment, and sexual dysfunction. Rather than exclusively addressing organ-specific morbidity arising from egg-associated inflammatory reactions and fibrosis, a wider morbidity spectrum should be acknowledged. It was generally felt that a revision of the DALY index to better reflect the true burden of disease is thus overdue. As this question influences all other activities under review, the SWG recommended that investigators regularly collect straightforward data, e.g. on anaemia, and also develop standardized measures

Schistosomiasisfor more intricate outcomes of infection such as on work capacity and cognition. Longitudinal clinical studies and operational research should be initiated in endemic areas and target not only the general population but particularly the many high-risk sub-groups. Such studies should include treatment interventions combined with outcome assessments at multiple time points following therapy and results should be linked to studies of socioeconomic status as well as patients’ estimates of the impact of infection on quality of life.

Diagnostics To gain a more complete view of schistosomiasis and its impact on society demands the development of better tools in terms of rapid diagnostic techniques, image-assisted clinical diagnosis, and reliable predictive risk maps based on geographical information systems (GIS) and satellite-based remote sensing (RS). Field diagnosis continues to rely on direct microscopy, as it has since the beginning of control programmes. However, the relative insensitivity of this technique is a problem which has gained prominence during the last

Report 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 of infection (both in humans and snails), while it can be argued that vaccine development is premature until the effects of vaccines can be reliably verified in clinical trials. Currently only very pronounced effects are verifiable, which is not sufficient since even a partially effective vaccine would be useful as a complement to chemotherapy. As a first step, a standardized approach 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 ‘subtle pathology’ and ectopic presentations of egg-associated pathology requires the application not only 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 non- invasive techniques to be extended to conditions such as genital schistosomiasis, infection during pregnancy, cardio-pulmonary disease, and intestinal schistosomiasis.

Data derived from national programmes provide detailed knowledge regarding local, regional and global prevalence. Regular updates of prevalence, based on both reported and adjusted estimates including information about the assays used, would facilitate follow-up of the impact of control measures. In addition, parasitic diseases control programmes would benefit from integration with other public health interventions; coordination of control would be useful in areas where several parasitic infections overlap. For example, studies on co-infection and co- therapy with malaria, geohelminth infections, and filariasis would clearly be fruitful in relation to the outcomes of infection e.g. on cognition, work capacity, and anaemia. The opportunity

now exists to study the impact of artemisinins on the epidemiology of schistosomiasis in areas Schistosomiasis where it co-exists with malaria, for which these drugs are used widely. This opportunity should not be missed. In the same vein, randomized placebo-controlled trials of praziquantel treatment in pregnant and lactating women in both high and low areas of transmission would augment the safety record for this drug. It is also important to consider the potential impact on drug efficacy of HIV (and HTLV-1) infection or immunosuppressive drugs.

Chemotherapy Currently, schistosomiasis control relies almost entirely on chemotherapy and yet only one drug, praziquantel, is available. This is a potentially dangerous situation which points to the need to identify effective new drugs. However, while the identification of new drugs is important, additional work on praziquantel is also required. For example, a formulation containing only the effective stereoisomer rather than the current mixture of isomers would have better effect and fewer side effects, while randomized placebo-controlled trials of

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 praziquantel in pregnancy, lactating women and children would furnish needed information on the impact of treatment on birth outcomes and maternal and child health. Even if praziquantel is a very safe and effective drug, pharmacovigilance should be kept up and any treatment failure and incidence of severe side effects systematically investigated. Perceived side-effects of treatment should also be analysed in the context of control programme activities as a whole in order to throw light on the social dynamics behind adherence (‘socio-vigilance’). There is an 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 against malaria but also have schistosomicidal properties. Studies of their mechanisms of action should be encouraged and efforts should be made to produce and test analogue compounds which also act against the adult worm. Drug development and production should be ensured by establishing a developmental pipeline following the example of Medicines for Malaria Venture (MMV) for antimalarial drugs. The capacity to move through the discovery process from target identification to lead compound (including optimization, safety, and pharmacokinetics) is in place in several centres in various countries. However, while there is capacity for high- throughput screening 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 be addressed before development of new drugs for schistosomiasis can begin in earnest.

The treatment offered by control programmes is purely anti-schistosomicidal and, while periodic treatment prevents the development of severe disease, it does not always ameliorate existing

Schistosomiasissevere disease. Therefore drugs able to reverse severe pathology or to halt severe disease progression are also required. There is thus a need to investigate drugs that are used for other fibrotic diseases, or to develop drugs such as immunomodulators for use in schistosomiasis.

Immunology and genomics Basic research with a focus on immunology and genomics plays an important role in a number of areas, such as in vaccine and drug development, and for elucidating the immune mechanisms which result in morbidity. We need to identify immunological markers of morbidity and resistance, and their relation to genetics, in order to facilitate studies on immunoregulation and mechanisms of human resistance (naturally acquired and vaccine- induced). This research is also important for determining the impact of schistosomiasis on other 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 to clarify 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 there is now a need for full annotation of the genomes. The S. haematobium genome also requires sequencing, and later the genome of Oncomelania (the S. japonicum intermediate snail host). These tasks plus the sequencing of other schistosome strains (such as the Philippine strain of S. japonicum) will allow studies on comparative genomics. As annotation of the genomes is being carried out, the nomenclature in relation to transcriptome and proteome libraries should be harmonized, and post-genomics tools such as microarrays and proteomics applied to identify stage-specific antigens or pathways that can be targeted for development of vaccines, drugs and diagnostics. Resources, e.g. microarrays representing the complete genome for each schistosome species, and combined host/parasite microarrays to study host/ parasite interactions, should be developed and standardized and made available for the whole schistosomiasis community. Other worthy goals are to identify host alleles that aggravate or reduce 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 basic biology of schistosomes and to produce immortalized schistosome cell lines for screening for new vaccine antigens and drug targets.

Vaccine development With 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. Most scientists are convinced that effective vaccines against schistosomiasis can be developed since irradiated cercariae regularly induce 70% or better protection, and human populations in endemic areas exhibit various degrees of resistance. While less than 10% of all antigens discovered have been targeted for further development as vaccine candidates, several Schistosomiasis promising candidates have been identified and thoroughly researched, and the results validated in different laboratories. However many of these have suffered subsequent challenges at the stage of scaling-up production according to GMP, now an important selection criterion in assessing vaccine candidacy.

Since the original list of priority antigens was chosen by a TDR committee in 1997, only a few more vaccine candidates have appeared. Of the original antigens, Sh28-GST and Sm14-FABP continue to be of interest, the former because it has successfully passed all developmental steps including phase I/II trials, and the latter because further fundamental and applied production research has moved it close to industrial production. Although all candidates produced so far target infection (except Sh28-GST and Sm28-GST, which target both infection and parasite fecundity), all research directions should be pursued including anti-morbidity effects and blocking of transmission.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Ecology and transmission There is a clear need for markers to assess transmission, especially in areas of low endemicity and in pre-elimination foci. These areas also need to be examined regarding the evidence that some feral animals can act as reservoir hosts, at least for S. mansoni. Methods to assess cercarial density and to detect early-stage infection in snails would be very useful and would complement diagnosis in humans (and reservoir hosts) and help evaluate the details of transmission. RS is well suited for determining snail habitats and should be used with GIS to produce predictive risk maps and mathematical models of transmission. With regard to snail control, both environmental management and use of focal chemical molluscicides should be evaluated. Apart from biological factors, social factors play an important role in transmission in specific ecological zones, where their role should be assessed and cross-disciplinary studies pursued to better understand the dynamics.

Social Issues Overall, schistosomiasis can be characterized as a disease of poverty. However, the evidence linking social resources, economic status, and infection at community and household levels needs to be better defined. These relationships can be described through quantitative as well as qualitative analysis of changes taking place over time, taking into account the focal nature of transmission and following the migration of households/family members. Suitable sites for research on social and economic determinants would be locations where new water resources development projects are taking place and where control programmes are being implemented. Here, exploratory studies of social change could be combined with investigations of shifts in asset ownership over time in order to make the targeting of interventions more equitable Schistosomiasisand provide tools for measuring impact of interventions. Furthermore, such studies could explore how control programmes can respond to vulnerability, which constrains people’s ability to seek health care, cope with illness and suffering, and adhere to therapy schemes. Understanding the contexts and processes that create vulnerability to infection, weaken resilience, and compromise equity in access to diagnostics, health information, treatment and the benefits of preventive measures, e.g. safe water supply and sanitation, necessitates an eco- bio-social approach. Research using this approach needs to address micro- as well as macro- levels of analysis and be sensitive to asymmetries of gender, age, occupation, ethnicity, and income level.

The recognition of ‘subtle morbidities’ in schistosomiasis creates a new platform for researching the social and economic impacts of this disease. Community-based studies combining quantitative and qualitative methods can explore the impact of infection on

Report 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 households to compensate for the impacts of infection. The same combination of methods can explore the social and economic impacts of chronic disease and genital schistosomiasis in men and women and the possible stigma associated with these conditions. An understanding of these processes will provide valuable information for designing control programmes.

It can be assumed that the emergence, resurgence, and persistence of schistosomiasis are closely linked to the specific social and eco-epidemiological setting as well as to large-scale forces such as shifts in resource flows and environmental change. Insights gained by previous control initiatives and regional or national experiences offer opportunities to strengthen the design 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 determination of the cost-effectiveness of various control approaches. Furthermore, health systems research will help in understanding how the impact and sustainability of control programmes also rely on 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 control Even if prevalence has so far only been affected marginally, sustained reduction in intensity of disease and morbidity is evident in all areas under control. The case for elimination of

schistosomiasis as a public health threat, at least for its elimination in some parts of the world, Schistosomiasis is thought to be feasible. There are reasons to believe that this will one day become reality and thus there is a need to plan for it in advance.

When externally funded control programmes have come to an end, and to maintain the benefits of these, studies need to be extended to include post-control interventions. Care for patients with 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-level planners would do well to think about it at an early stage and also to calculate the possible benefits of coordination with and linkage to established programmes such as the Lymphatic Filariasis Elimination Programme, the Expanded Programme on Immunization (EPI), and the World Food Programme’s school feeding programme and maternal/child health initiatives.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Capacity building and partnerships Health issues in developing countries are now moving from an area of ignorance and neglect to a more prominent standing on the political agenda. Evidence of this can be seen in the strengthened management of existing initiatives which has resulted in tangible improvements of public health, while specific diseases are starting to be tackled by new public–private partnerships. Such collaborations bring advantages for resource-poor environments resulting in unique engagements in the health-related problems of disease-endemic countries. The first serious collaboration between those dealing with a neglected disease and industry came about through the observation that ivermectin, a drug used to treat heartworm infection in dogs, was effective for the treatment of human onchocerciasis (river blindness). TDR worked with the US pharmaceutical corporation Merck to develop the product, which was finally registered for human use in 1989. Merck has since made the commitment to produce the drug free of charge for endemic areas in Africa for as long as it is needed. This commitment has become the cornerstone of the very successful control programme for onchocerciasis that has been joined by numerous governments and non-governmental agencies. However, this successful collaboration was not immediately followed by similar ventures. It took almost a decade before the idea took root and similar partnerships started to form, which shows that it is not easy to convince industry of the mutual benefits of collaboration and that it falls on the donor agency to follow up and develop the partnership. Several industrial partnerships now exist, but none in the field of schistosomiasis. However, an artemesinin partnership with the pharmaceutical industry is run through MMV, and this may yet benefit schistosomiasis. Also, a Chinese institution ran a number of large-scale clinical trials in the 1990s, in collaboration with Kunming Pharmaceutical Corporation, which demonstrated that artemether and derivatives of Schistosomiasisthis 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 effective tool for control and treatment; this perception is compounded by the focal nature of the disease and its low prevalence in relatively well controlled areas. As a result, there are few incentives for students and researchers to engage in postgraduate training, and few opportunities to apply their new skills, while funds for research subsequent to postgraduate training appear to be evaporating. Further, many scientists who were previously engaged in schistosomiasis research have now either moved on to other diseases or are aging and nearing retirement without adequate replacements having been trained. It is difficult for a disease like schistosomiasis to compete 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 and

10 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 influenza. Nevertheless, there is a strong need to train scientists in disciplines that contribute to research on new or improved methods for the prevention, control and treatment of schistosomiasis. Priority areas for training include new diagnostics, clinical trials, management of new treatment regimens and future vaccine trials, and cost-effective methods for identifying transmission areas using GIS/RS. In addition, well-trained social scientists are needed who can address the issue of social determinants and human behaviour fundamental to controlling and perhaps one day eliminating schistosomiasis.

Several organizations with similar goals to TDR are now working together to improve the lot of the people in the third world. While the signs of change are slowly but unmistakably appearing, and capability strengthening and training are becoming more important, there is no quick solution to remedying the imbalance between supply and demand for trained scientists specializing in schistosomiasis research. Possible avenues to pursue include involving young graduate students in schistosomiasis networks early in their training before they have chosen a disease speciality, and increasing mentoring throughout their training by senior scientists. Overall, the profile of the importance and public health impact of schistosomiasis must be raised in universities and research organizations so that scientists are encouraged to participate in the global schistosomiasis research agenda. Schistosomiasis

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 11 Priorities

Research needs in the field of schistosomiasis were discussed by the SWG members. The research 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 the less well recognized (subtle) pathological signs are taken into account, better reflecting the true burden of disease. • Investigators to regularly collect data on subtle morbidities (e.g. anaemia, physical and cognitive development) and to develop standardized measures for intricate outcomes of infection such as on work capacity and cognition both for schistosomiasis and for coinfections with malaria, geohelminths, lymphatic filariasis, etc. • Conduct systematic studies on the prevalence of ectopic presentations of schistosomiasis, in particular of neuroschistosomiasis. • Conduct longitudinal clinical studies and operational research targeting various high-risk sub-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 and populations. • Determine schistosomiasis distribution preferably together with other parasitic diseases to benefit 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-endemic

Schistosomiasisand pre-elimination foci. • Sequence the Oncomelania genome. • Develop a strong focus on risk map prediction (determination of possible and real snail habitats) 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 encourage developers and industrial partners to standardize assays. • Define ultrasound findings using computerized tomography, magnetic resonance imaging and tissue harmonic imaging.

12 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 • Publish without delay the current recommendations for a standardized image pattern methodology 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-effectively generate the single, effective praziquantel stereoisomer. • Study the mechanisms of action of schistosomicidal drugs (artemisinins) and continue research 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 and systematically investigate any treatment failure of praziquantel and incidence of severe side effects. • Conduct without delay randomized, placebo-controlled trials of praziquantel treatment in pregnancy 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 of immunosuppressive 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 intervention programmes.

Immunology and genomics

• Define the mechanisms of human resistance and the impact of immunoregulation, and Schistosomiasis develop immunological markers for morbidity and resistance to infection, relating them to genetic 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 heavy infection and/or severe disease. • Investigate immunological involvement in the subtle morbidities and the impact of schistosomiasis on pregnancy outcomes. • Clarify the occurrence and immunological mechanisms of rebound morbidity after treatment in S. japonicum, and investigate rebound morbidity in infections due to S. mansoni and S. haematobium.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 13 • Develop a toolbox permitting genetic manipulations (RNAi, transfections, transgenics) to advance 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, and sequencing of the S. haematobium genome, and support comparative genomic studies of other 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 and proteome 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 are significant 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 most

Schistosomiasisvulnerable 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 in relation to control programmes and their linkages to other interventions as well as health systems with the view to increase the impact of control programmes and the sustainability of achievements.

Post-transmission • After schistosomiasis has been eliminated, continue the surveys and maintain the benefits that have been achieved, documented and promulgated. • Investigate the possible benefits of coordination with, and linkage to, control programmes for other parasitic diseases, and to established initiatives in the health sector in general.

14 Report 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-based tools and statistical analysis to produce predictive models (rather than simply to produce distribution maps of parasites and infected hosts). • Reinforce the training of malacologists and taxonomists, particularly in disease endemic countries, and encourage networking. • Establish a schistosome vaccine network to encourage productive collaborations and standardization of study protocols (schistosomiasis vaccine development has, to date, been highly fragmented). • Establish an immunological network to harmonize protocols for human field studies. Schistosomiasis

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 15 WHO Library Cataloguing-in-Publication Data:

“TDR/GEN/06.1”.

ISBN 92 4 156334 6 (NLM classification: WC 765) ISBN 978 92 4 156334 5

Printed in Italy

Design: Thierry Cailler

All photos are from the TDR Photo library: WHO/TDR/Craggs, Crump, Edwards, Pagnoni, Reile, Stammers and Taylor-Robinson. Annex 1 AGENDA: Scientific Working Group on Schistosomiasis Schistosomiasis

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 17 Day 1, Monday 14 November Time Item Name 09.00–09.30 Introduction of participants Dr D. Colley, Chairperson Welcome address Dr J.H. Remme, TDR Dr L. Savioli, Director, WHO Communicable Diseases Control, Prevention and Eradication (CPE) 09.30–09.45 Meeting objectives and process Dr L. Chitsulo, TDR 09.45–10.00 Introductory remarks and overview Dr D. Colley 10.00–10.20 Global status of schistosomiasis and its control Dr D. Engels, CPE 10.20–10.30 Current strategic emphases for schistosomiasis research in TDR Dr L. Chitsulo, TDR 10.30 – 11.00 Coffee Break 11:00–12.00 Research needs of national schistosomiasis control programmes National control managers: China, Egypt, Uganda 12:00–12.30 Quantifying the disease burden due to schistosomiasis control Dr. C.H. King 12.30–14.00 Lunch 14:00–14.30 Schistosomiasis in women of child-bearing age, including pregnancy Dr G.R. Olds 14.30–15.00 Measuring schistosomiasis morbidity Dr B. Vennerwald/Dr D. Dunne 15.00–15.30 Clinical schistosomiasis Dr J. Lambertucci 15.30–16.00 Coffee Break 16.00–16:30 Progress towards detecting schistosomiasis Dr A. Rabello 16.30–17.00 Research towards new treatment for schistosomiasis Dr D. Cioli 17.00–17.30 The socio-cultural context of schistosomiasis control Ms B. Bruun/Dr J. Aagaard-Hansen Closure – 1st day

Day 2, Tuesday 15 November Time Item Name 08.30–09.00 Ecological and other factors influencing schistosomiasis transmission Dr S. McGarvey 09.00–09.30 The intermediate host for schistosomiasis Dr E. Loker 09.30–10.00 Immunity in schistosomiasis Dr K. Hirayama 10.00–10.30 The current status of schistosomiasis vaccines Dr P. LoVerde 10.30–11.00 Coffee Break 11.00–11.30 Genomics and proteomics: towards novel targets in schistosomiasis Dr R.A. Wilson research 11.30–12.00 Scientific progress with respect to S. japonicum Dr Feng Zheng 11.30–13.00 Lunch break 13.00–15.00 Working groups 15.00–15.30 Coffee break 15.30–17.30 Working groups Closure – 2nd day

18 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Day 3, Wednesday 16 November Time Item Name 08.30–09.10 Plenary report: Working Group I Rapporteur 09.10–09.50 Plenary report: Working Group II Rapporteur 09.50–10.30 Plenary report: Working Group III Rapporteur 10.30–11.00 Coffee break 11.00–11.40 Plenary report: Working Group IV 11.40–12.30 Small group to review draft conclusions and recommendations SWG Chairperson/rapporteurs 12.30–14.00 Lunch break 14.00–15.30 Plenary discussion and amendment of conclusions and recommendations All 15.30–16.00 Coffee break 16.00–16.30 Any other business 16.30–17.00 Concluding remarks Chairperson, Director TDR Closure of the meeting Closure – final

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 19 WHO Library Cataloguing-in-Publication Data:

“TDR/GEN/06.1”.

ISBN 92 4 156334 6 (NLM classification: WC 765) ISBN 978 92 4 156334 5

Printed in Italy

Design: Thierry Cailler

All photos are from the TDR Photo library: WHO/TDR/Craggs, Crump, Edwards, Pagnoni, Reile, Stammers and Taylor-Robinson. Annex 2 LIST OF PARTICIPANTS: Scientific Working Group on Schistosomiasis Schistosomiasis

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 21 Temporary advisors

Dr Jens Aagaard-Hansen Dr Daniel Colley Danish Bilharziasis Laboratory Centre for Tropical and Emerging Global Diseases Institute for Health Research and Development University of Georgia Jaegersborg Allé 1D Biological and Sciences Building DK 2920 Charlottenlund Room 629, 100 Cedar Street DENMARK Athens, Georgia 30602 Tel: (45) 77 32 7784 USA Fax: (45) 77 32 7733 Tel: (1) 706 542 4112 Email: [email protected] Fax: (1) 706 542 3582 Email: [email protected] Professor Rashida Barakat Professor of Medical Parasitology Dr Rodrigo Correa-Oliveira Tropical Health Department M.S. FIOCRUZ, Centro de Pesquisas High Institute of Public Health “René Rachou” 165 El Horreya Avenue Av. Augusto de Lima 1715 Alexandria Caixa Postal 1734 EGYPT 30190-002 Belo Horizonte MG Tel: (20) 3 542 7010 BRAZIL Fax: (20) 3 428 8436 Tel: (55) 31 295 3566 Email: [email protected] Fax: (55) 31 295 3115 Email: [email protected] Dr Robert Bergquist Ingerod 407 Dr Alain Dessein S-45494 Brastad Laboratoire d’Immunologie et SWEDEN Génétique des Maladies parasitaires Tel: (46) 5 234 33 36 Faculté de Médecine Email: robert@ ingerod.net 27 boulevard Jean Moulin 13385 Marseille Cedex 5 Dr Birgitte Bruun FRANCE Danish Bilharziasis Laboratory Tel: (33) 4 91 32 44 52 Institute of Health Research and Development Fax: (33) 4 91 79 60 63 Jaegersborg Allé 1D Email: [email protected] DK 2920 Charlottenlund DENMARK Dr Michael John Doenhoff Tel: (45) 77 32 7784 University of Wales Fax: (45) 77 32 7733 School of Biological Sciences Email: [email protected] Bangor Gwynedd LL57 2UW Dr Donato Cioli UK Institute of Cell Biology Tel: (44) 01248 35 1151 32 via Ramarini Fax: (44) 01248 37 0731 or 1644 00016 Monterotondo Scalo Roma Email: [email protected] ITALY Tel:(39) 06 9009 1355 Dr David William Dunne Fax: (39) 06 9009 1259 University of Cambridge Email: [email protected] Department of Pathology Microbiology and Parasitology Division Tennis Court Road Cambridge CB2 1QP UK Tel: (44) 1223 333690 or 333695 Fax: (44) 1223 333346 or 353492 Email: [email protected]

22 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Professor Alan Fenwick Dr Sung-Tae Hong Schistosomiasis Control Initiative Department of Parasitology Dept. of Infectious Disease Epidemiology and Tropical Medicine and Institute of Endemic Diseases Imperial College Seoul National University College of Medicine St Mary’s Campus, Norfolk Place Seoul 110-799 London W2 1PG KOREA UK Tel: (82) 2 740 8343 Tel: (44) 20 794 3418 Fax: (82) 2 765 6142 Email: [email protected] Email: [email protected]

Dr Zheng Feng Dr Narcis B. Kabatereine National Institute of Parasitic Diseases Vector Control Division Chinese Center for Disease Control and Ministry of Health Prevention P.O. Box 1661 207 Rui Jin Er Road Kampala 200025 Shanghai UGANDA CHINA Tel: (256) 41 251 927 Tel: (86) 21 6437 6308 Fax: (256) 41 346 885 Fax: (86) 21 6433 2670 Email: [email protected] Email: [email protected] Dr Charles King Dr Paul Hagan Centre for Global Health and Diseases Faculty/Institute of Biomedical and Life Science Case Western Reserve University Division of Infection and Immunity 10900 Euclid Avenue University of Glasgow Cleveland, Ohio USA 44106-7286 Wolfson Link Building (Room 365) USA Glasgow G12 8QQ Tel: (1) 216 368 3667 UK Fax: (1) 216 368 4825 Tel: (44) 141 330 2545 Email: [email protected] Fax: (44) 141 330 4758 Email: [email protected] Professor Jose Roberto Lambertucci Universidade Federal de Minas Gerais Dr Christoph Hatz Estudos de Medicina Experimental Swiss Tropical Institute Nucleo de Estudos Sobre Esquistoss. PO Box Avenida Alfredo Balena 190 4002 Basel Belo Horizonte 3000 SWITZERLAND BRAZIL Tel: (41) 61 284 8255 Email: [email protected] Fax: (41) 61 284 8183 Email: [email protected] Dr Eric S. Loker University of New Mexico Prof Kenji Hirayama Department of Biology Department of Molecular Immunogenetics Albuquerque, NM 87131 Institute of Tropical Medicine USA Nagasaki University Tel: (1) 505 277 5508 1-12-4 Sakamoto, Nagasaki 852-8523 Fax: (1) 505 277 0304 JAPAN Email: [email protected] Tel: (81) 95 849 7818 Fax: (81) 95 849 7821 Professor Philip LoVerde Email: [email protected] State University of New York School of Medicine and Biomedical Sciences Professor Mamoun M.A. Homeida (Microbiology) Academy of Medical Sciences and Technology 138 Farber Hall, 3435 Main Street P.O. Box 12810, Khartoum Buffalo NY 14214-3078 SUDAN USA Tel: (249) 11 223 385 Tel: (1) 716 829 2459 Fax: (249) 11 224 799 Fax: (1) 716 829 2169 Email: [email protected] Email: [email protected]

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 23 Dr Henry Madsen Professor Francois Noel Danish Bilharziasis Laboratory Universidad Federal do Rio de Janeiro Institute for Health Research Centro de Ciencias da Sauda, Sala J1-17-ICB and Development Dep. Farmacología Basica e Clinical Jaegersborg Alle 1D Ilha do Fundao, DK-2920 Charlottenlund 21491-590 Rio de Janeiro, RJ DENMARK BRAZIL Tel: (45) 3162 6168 Tel: (55) 21 25 62 67 32 Fax: (45) 3962 6121 Fax: (55) 21 25 62 66 59 Email: [email protected] Email: [email protected]

Dr Margaret Mafe Dr G. Richard Olds Nigerian Institute of Medical Research Medical College of Wisconsin Public Health Division Department of Medicine 6 Edmond Crescent 9200 W. Wisconsin Avenue Yaba, Lagos Milwaukee, Wisconsin 53226 NIGERIA USA Tel: (234) 803 349 1386 Tel: (1) 414 456 6705 Email: [email protected] Fax: (1) 414 456 6219 Email: [email protected] Dr Stephen T. McGarvey International Health Institute Dr Ana Rabello Brown University Laboratório de Pesquisas Clínicas Box G-B 497 Referência/Treinamento em Leishmanioses Providence RI 02912 Centro de Pesquisas René Rachou USA Fundaçao Oswaldo Cruz Tel: (1) 401 863 1186 Av. Augusto de Lima 1715 Fax: (1) 401 863 1243 30190-002 Belo Horizonte, MG Email: [email protected] BRAZIL Tel: (55) 31 32 95 35 66 Professor James H. McKerrow Fax: (55) 31 32 95 21 15 University of California, San Francisco Email: [email protected] Tropical Disease Research Unit QB3 508B, UCSF box 2550, 1700 4th Street Dr Joachim Richter San Francisco, CA 94143-2550 Tropical Diseases Unit USA Clinics for Gastroenterology Email: [email protected] Hepatology and Infectious Diseases University of Duesseldorf Dr Donald Meter McManus Moorenstr 5 Queensland Institute of Medical Research D-40225 Duesseldorf Molecular Parasitology Laboratory GERMANY 300 Herston Road Tel: (49) 211 81 16800 Brisbane QLD 4020 Fax: (49) 211 3190639 AUSTRALIA Email: [email protected] Tel: (61) 7 3362 0401 Fax: (61) 7 3362 0104 Dr Andreas Ruppel Email: [email protected] University of Heidelberg Department of Tropical Hygiene Dr Victor Mwanakasale Im Neuenheimer Feld 324 Tropical Disease Research Centre D-69120 Heidelberg Parasitology unit GERMANY PO Box 71769 Tel: (49) 6221 56 50 44 Ndola Fax: (49) 6221 56 59 48 ZAMBIA Email: [email protected] Tel: (260) 2 680 059 Fax: (260) 2 621 112 Email: bí[email protected]

24 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Dr Ronaldo Santos do Amaral *Dr Susan J. Watts Programa de Controle da Esquistossomose American University inCairo Ministério da Saúde Social Research Center Fundaçao Nacional de Saúde P.O. Box 2511 Quadra 4 – Bloco N – Sala 715 Cairo 11511 CEP 79958-902 – Brasilia EGYPT BRAZIL Tel: (20) 2 797 6954 Tel: (55) 061 314 6543 Fax: (20) 2 797 7298 Fax: (55) 061 321 72 82 Email: [email protected] Email: [email protected] Professor Robert Alan Wilson Dr William Evan Secor University of York Centers for Disease Control and Prevention Department of Biology Division of Parasitic Diseases P.O. Box 373 Mailstop F-13 York, Y010 5YW Atlanta GA 30341-3742 UK USA Tel: (44) 1904 32 86 00 Tel: (1) 770 488 4115 Fax: (44) 1904 32 85 99 Fax: (1) 770 488 3115 Email: [email protected] Email: [email protected] Dr Thomas A. Wynn Dr Juerg Utzinger National Institute of Health Swiss Tropical Institute Laboratory of Parasitic Diseases Socinstrasse 57 900 Rockville Pike Buld.71 Rm 318 Basel Bethesda MD 20892 SWITZERLAND USA Tel: (41) 61 284 8129 Tel: (1) 301 496 47 58 Fax: (41) 61 284 8105 Fax: (1) 301 402 00 77 Email: [email protected] Email: [email protected]

Professor Louis-Albert Tchuem Tchuente Ms Guojing Yang National Program for Control of Schistosomiasis and Swiss Tropical Institute STH Basel Centre for Schistosomiasis and Parasitology SWITZERLAND P.O. Box 7244 Email: [email protected] Yaounde CAMEROUN Dr Mohamed Mostafa Youssef Tel: (237) 221 01 83 Schistosomiasis and Intestinal Parasites Control Fax: (237) 221 50 77 Department/Ministry of Health and Population Email: [email protected] 3 Magles El-Shaab Street Cairo 11467 Dr Birgitte Vennervald EGYPT Danish Bilharziasis Laboratory Tel: (20) 2 794 7199 Department of Parasitology/Immunology Fax: (20) 2 794 8187 Jaegersborg Alle 1 D Email: [email protected] Charlottenlund 2920 DENMARK Professor Xiao-Nong Zhou Tel: (45) 3962 6168 National Institute of Parasitic Diseases Fax: (45) 3962 6121 Chinese Center for Disease Control and Prevention Email: [email protected] 207 Rui Jin Er Road 200025 Shanghai CHINA Tel: (86) 21 64 73 80 58 Fax: (86) 21 6433 26 70 Email: [email protected]/ [email protected]

* unable to attend

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 25 WHO Regional Office staff

*Dr Thomas T.Y. Sukwa Tel: 263 233 17193 Malaria (MAL)/Communicable Disease Prevention and Email: [email protected] Control (DDC), WHO Regional Office for Africa (AFRO)

Dr Sebastio Nkunku DDC/DDC, AFRO WHO Headquarters staff

Dr Robert Ridley, Director TDR Dr Axel Kroeger, Dengue Disease Research Coordinator, Dr Jane Kengeya-Kayondo, Coordinator, TDR Implementation Research and Methods (TDR/IRM) Dr Philip Onyebujoh, TB/HIV Disease Research Dr Janis Lazdins-Helds, Acting Coordinator, Product Coordinator, TDR Development and Evaluation (TDR/PDE) Dr Yeya Toure, Malaria Disease Research Coordinator, Dr Ayoade Oduola, Coordinator, Strategic and Discovery TDR Research (TDR/SDR) Dr Johannes Sommerfeld, TDR/SDR Dr J.H.F. Remme, Coordinator, Science Strategy and Ms Henrietta Allen, WHO Communicable Diseases, Knowledge (TDR/SSK) Strategy Development and Monitoring for Parasitic Dr Fabio Zicker, Coordinator, Research Capability Diseases and Vector Control (CDS/CPE/PVC) Strengthening (TDR/RCS) Dr Colin Douglas Mathers, WHO Management and Dr Lester Chitsulo, Schistosomiasis Disease Research Health Information Systems (EIP/MHI) Coordinator, TDR Dr Dirk Engels, CDS/CPE/PVC Dr Hashim Ghalib, Leishmaniasis Disease Research Dr Lorenzo Savioli, CDS/CPE/PVC Coordinator, TDR Dr Deborah Kioy, Human African Trypanosomiasis Disease Research Coordinator, TDR

* unable to attend

26 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Annex 3 WORKING PAPERS: Scientific Working Group on Schistosomiasis

1. Research needs of the national schistosomiasis control programme in China. . 28

2. Current situation and research needs for schistosomiasis control in Egypt. . . .35

3. Implementation strategies for schistosomiasis control in Uganda, and research needs under the programme ...... 38

4. Quantification of disease burden due to schistosomiasis...... 46

5. Schistosomiasis in women of childbearing age, including in pregnancy...... 53

6. Measuring schistosomiasis morbidity...... 57

7. Clinical schistosomiasis ...... 62

8. Progress towards the detection of schistosomiasis...... 67

9. Research towards new treatments for schistosomiasis...... 72

10. The sociocultural context of schistosomiasis control: current knowledge and future research needs ...... 76

11. The social determinants of schistosomiasis ...... 84

12. Ecological and other factors related to schistosomiasis...... 91 Schistosomiasis 13. Research on the molluscan intermediate hosts for schistosomiasis: what are the priorities? ...... 95

14. Schistosomiasis and immunity ...... 105

15. Genomics and proteomics: towards new targets in schistosome research. . . . 109

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 27 WORKING PAPER 1. Research strategy adopted by the World Bank Loan Project needs of the national on schistosomiasis control in China, implemented 1992–2001. schistosomiasis control programme in China The sustained commitment of the central and local governments were key to letting China become one Xiao-Nong Zhou of the most successful countries in the world to con- National Institute of Parasitic Diseases, trol schistosomiasis. By the end of 1995, transmis- Chinese Center for Disease Control and Prevention, sion of the disease had been interrupted successfully Shanghai 200025, China in five provinces, namely Guangdong and Shanghai (in 1985), Fujian (1987), Guangxi (1989) and Zhejiang (1995). Importantly, these achievements are mainly due to the advent of praziquantel in the 1970s, and INTRODUCTION the programme has been versatile enough to permit Schistosoma japonicum is unique among all human adjustments over time to adapt to changing eco-epi- schistosomes by being a true zoonosis with over 40 demiological conditions. The experience gained thus animal reservoir hosts in nature, including cattle, buf- far can be summarized as follows: first, insisting on faloes, pigs, dogs, cats and goats. This poses special the system of ‘government planning, intersectoral difficulties in controlling transmission to humans, collaboration and broad-based community partic- especially in areas with infected bovines and water ipation’ was a key factor for setting up and imple- bodies close to villages. Generally, there are three eco- menting the control programme in a sustainable types of endemic areas, i.e. plain regions, marshland manner. Second, progress in schistosomiasis control and lake regions, hilly and mountainous regions. goes hand-in-hand with socioeconomic develop- This stratification is based on epidemiological pat- ment. Third, results obtained from pilot studies terns and the ecology of the intermediate host snail, comparing different control approaches proved use- Oncomelania hupensis. Occupational activities of ful for designing and implementing control activi- farmers and fishermen, such as cattle herding, fish- ties on a larger scale; control has to readily adapt to ing, reed cutting as well as recreational and domes- the specific eco-epidemiological setting. Fourth, col- tic activities involving prolonged water contact lead laboration of the health sector with various other to intensive exposure and increased risk of infection governmental sectors (e.g. agriculture, water con- or re-infection. Upon infection, many patients expe- servancy, forestry) is of key importance for success- rience severe morbidity resulting in disability and ful and sustainable schistosomiasis control. Finally, sometimes death if they are not treated adequately. tightly linking control efforts with operational research can enhance the programme outcome. The main goal of the national schistosomiasis control programme, initiated in 1955, is to eliminate With the economic reforms initiated in 1978 and the the disease from all endemic areas where feasible advent of globalization, Chinese society experienced by integrated approaches including chemother- remarkable changes in both urban and rural areas. apy, snail elimination, environmental modification, The social and economic transition has affected the health education and improved sanitation and safe health sector in three ways. First, responsibilities in water supply. With the progress of the national con- the economic and social sectors are shared between trol programme, different approaches were applied all five levels of government (national, provincial, depending on the period and local setting. For prefecture, county, township). Second, social serv- example, during the 1950s, nationwide case sur- ices are more responsive to individual than collective veys and active treatment of patients prevailed. In needs, and are strongly subject to market mecha- the 1960s and 1970s, apart from screening and treat- nisms. Third, certain institutions originally belonging ment of infected persons, the focus was on snail to the public sector are now gradually being priva- elimination by environmental modification, often tized. Therefore, the traditional strategy of schisto- associated with water resources development and somiasis control is hardly implemented effectively water conservancy projects, creation of new farm- any more in the endemic areas, and the transmission land by setting up embankments in areas with high pattern of schistosomiasis has altered along with transmission potential, and chemical molluscicid- the changes in socioeconomic and environmental ing. Since the 1980s, large-scale chemotherapy with conditions. New challenges have arisen, including praziquantel has become the mainstay of control. schistosomiasis now being found in the increasingly Extended chemotherapy both for man and domes- mobile population (e.g. migratory workers), and tic animals in combination with snail elimination by new transmission foci appearing as snail-infested chemical mollusciciding has been the major control areas expand along water courses or into urban

28 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 areas. The fluctuations in transmission intensity and of improved tools and control strategies in relevant infection rate are closely related to changing envi- areas. For instance, decreased compliance rates for ronmental conditions such as flood events, and new case detection due to residents’ unwillingness to threats arise from global warming which leads to cooperate with personnel from antischistosomal sta- an expansion of potential snail habitat. Due to vari- tions for faecal sample collection, low sensitivity of ous combinations of the above factors, schistosomia- the Kato-Katz technique in areas where the overall sis japonica is still transmitted in the lake regions endemicity has become low, and the high costs and of Anhui, Hubei, Hunan, Jiangsu and Jiangxi prov- environmental toxicity of the only available mol- inces, with their vast areas of O. hupensis habitats, luscicide (i.e. niclosamide) are some of the factors and it also remains endemic in mountainous regions compromising further progress in schistosomiasis of Sichuan and Yunnan provinces. It is more difficult control. In addition, there is a need to standardize to control transmission in the former lake regions the available serological diagnostic techniques and because of large grazing areas contaminated by rapid diagnostic reagents. Furthermore, repeated livestock (especially bovines), and the high risk for large-scale administration of praziquantel for mor- water contact by mobile populations working in the bidity control poses the risk of development of lakes and along the Yangtze River. The latter areas resistance. The rapid changes in socioeconomic and are characterized by diverse and complex ecologies, environmental conditions due to market reforms lower human and snail population densities, and and major ecological transformations can pose weaker economic growth when compared to other additional challenges for control efforts, especially provinces of China. The latest available data sug- when the control strategy is largely dependent on gest that schistosomiasis has re-emerged in the past a single measure as it is today, i.e. chemotherapy. five years, especially in the highly endemic areas in Effective and sustainable control of schistosomiasis the lake and mountainous regions. It is also reported will remain an elusive goal when these challenges that schistosomiasis transmission has re-emerged in are not tackled. 38 counties which had previously reached the criterion of transmission interruption or control. Exploring efficient management structures With the ongoing and rapidly expanding market When taking into account the aforementioned bio- reform in China, it becomes increasingly difficult logical, ecological and socioeconomic factors, it to maintain the old infrastructure of organizations becomes obvious that it is essential to conduct further dealing with schistosomiasis control and to adapt the research to understand the impact of the changes on current strategies to the changing needs. Especially the epidemiology of schistosomiasis japonica and to the re-emerging nature of the disease calls for a provide sound evidence to the policy-makers at var- more efficient management structure closely coop- ious levels. This will help to adjust control strategies erating with other sectors. There are, for example, efficiently, and improve the control programme’s pressing needs to further adjust control strategies, to cost-effectiveness and maximize its impact. For this effectively handle surveillance data so that epidemic purpose, we identified the research gaps and needs trends can be forecast, and to design and implement of the Chinese control programme and made recom- sound control measures that are adapted to specific mendations on future research priorities. eco-epidemiological settings.

RESEARCH NEEDS OF THE Predicting the impact of changes in NATIONAL CONTROL PROGRAMME ecological factors Despite the large body of experience and expertise It has been noted that re-emergence of schistosomia- gained through 50 years of implementation by the sis in the Yangtze River basin in recent years is national schistosomiasis control programme, the closely associated with flooding events that occurred ultimate goal of eliminating the disease as a public in schistosome-endemic areas along the Yangtze health problem in China has not been reached. This River. The floods in 1998, for example, were accom- calls for further research in various fields. panied by snail dispersal into areas previously free of snails, which in turn led to an enlarged S. japon- Development of improved tools and strategies icum-endemic area. Additionally, global warming has two potential impacts on the frequency and In view of the experience gained so far, further transmission dynamics of schistosomiasis. First, it progress in the control of schistosomiasis in hyper- is likely that the potential habitat of O. hupensis will endemic regions and elimination of the disease in expand northwards into currently snail-free areas. low-endemic regions will depend on sustained The underlying reason is that the distribution of the research of local conditions and the development intermediate host snail is limited by the temperature

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 29 of the coldest month of the year (i.e. January) and edge and technology for schistosomiasis control. is likely to shift north. Hence, disease transmission The most important issue that needs to be tackled is is also likely to shift northwards. Second, humans that few products or patents generated from studies are at an elevated risk of becoming infected with S. on schistosomiasis are available to the control pro- japonicum because more schistosomes might develop gramme. For example, some surveillance techniques from a single snail due to elevated temperatures. (e.g. C6 membrane for cercaria detection) and drugs (e.g. artemisinins) have not been widely used in the Understanding the impact of socioeconomic endemic areas although both the quick detection of factors S. japonicum cercariae in infested water and the efficacy of artemisinins to prevent acute infection with It is conceivable that over the course of the ongo- S. japonicum were demonstrated several years ago ing market reforms in China, various social factors by Chinese scientists. In another example, the con- will come into conflict with the traditional meas- cept of post-transmission schistosomiasis has been ures against schistosomiasis. For example, mobili- developed since the disease will require medical zation of people involved in schistosomiasis control care and attention long after transmission has been activities needs to be supported by the new systems. interrupted in an area. This concept has not been Furthermore, regulations should foster intersectoral studied further in China although transmission was collaboration, as integrated control methods need interrupted more than a decade ago in many previ- support by different governmental sectors, e.g. min- ously endemic areas. istries of health, agriculture, and infrastructure and development. Major water-resource development Financial support for operational research and management projects are going hand-in-hand and implementation of research findings with economic development, and are often implemented in schistosome-endemic areas. There is par- In the previous system of planned economy, both ticular concern with regard to the construction and central government and local government commit- operation of the Three Gorges dam and the South- ted much effort on applied research to improve con- to-North water transfer project. Both projects are trol activities. Even during the World Bank Loan likely to have negative health effects, i.e. spread of Project in the 1990s, about 2% of the loan was used schistosomiasis into previously non-endemic areas; for operational research, which helped to moni- and hence there is a need to develop and implement tor and improve the quality of the national control sound mitigation strategies. In addition, some of programme. But after the end of the World Bank the anti-flood policies, such as ‘returning reclaimed Loan Project, the investment in research activities on land into lake, levelling dykes between main levees, schistosomiasis control was reduced by about 90% and building new towns for resettlement’, will cause annually when compared to the amount during the many snail-eliminated areas to become snail habi- project. Hence it is urgent to support operational tats again, which will not only increase the transmis- research to cope with the growing needs due to the sion risk for the local population but also change the higher priority given to schistosomiasis control by transmission pattern. It is estimated that large parts the State Council since 2004. Missing support for the of 6670 km2 of farmland will be transformed back implementation of research findings is to be blamed into lake areas and are at considerable risk of inter- for the fact that not a single diagnostic kit had been mediate host snail infestation. officially certificated by the end of 2004 although various diagnostic kits were being widely used in different endemic provinces. As a result, quality SHORTCOMINGS IN RESEARCH control is difficult and the epidemiological data gen- The following research gaps and needs were identi- erated from the provincial surveillance systems can- fied in the Chinese national schistosomiasis control not be compared to each other. programme. Research capacity Innovation in theory and technique Research capacity is still at a low level. Many Innovations in theory and techniques could help us research projects operate at a low level of innova- to better understand the dynamic epidemiology of tion, merely repeating what has been done before by schistosomiasis, as well as to improve the current others and not responding to changes in social and control strategies. Additional research is necessary economic context or to scientific advances. Thus the to develop new knowledge and technology to over- capacity is not able to contribute to improvement come problems such as the weak linkages between and adaptation of control strategies. Other research basic research and operational research which is projects follow the global progress in science, but do blocking the sustainable development of knowl- not 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 geo- Operational research relevant to control graphic information systems (GIS) has been used strategy for snail habitat surveillance and risk prediction for Operational research has an emphasis on new tech- more than five years in several provincial institutes nology, eco-epidemiological determinants, techni- and universities in China, but its use is still limited to cal standardization, social justice on disease burden, a few institutions and it has not been used in hyper- and novel products to be implemented in control endemic mountainous areas. Also the development programmes. The ultimate goal of the proposed of a candidate vaccine and genome studies of S. research is to further focus the control programmes japonicum are limited to only a few laboratories. on crucial points to make them more sustainable and cost effective. Internal and external collaborations Recently, much attention has been paid to collab- New technology oration, both with regard to information sharing Based on the current background and capacity, the and technology transfer. For example, the Regional following technologies will be developed in order to Network on Asian Schistosomiasis (RNAS) involves improve the national control programme: scientists from a dozen countries and was initi- • Techniques for assessment of treatment effec- ated by scientists from China and the Philippines tiveness – looking for special techniques able to with the assistance of TDR. The Tropical Medicine identify the effectiveness of a drug when used in Research Centre (TMRC) was established by the US large and diverse communities. National Institutes of Health (NIH) in the Shanghai- • Methods for rapid evaluation of commu- based National Institute of Parasitic Diseases (IPD). nity prevalence – developing rapid evaluation These initiatives are needed since a phenomenon approaches with combinations of information like global climate change could lead to new foci of generated from serum tests, stool examination schistosomiasis transmission becoming established and questionnaires. in previously non-endemic areas of endemic coun- • Morbidity assessment by ultrasonography – tries of Asia, but these can only be assessed by inter- standardizing morbidity indicators to provide nationally coordinated efforts. Such effects must be information for evaluation of disease burden. included in any serious discussion of future epide- • Methods for detection of infected snails – devel- miological developments, since little knowledge is oping new and simple detection methods for the available on the impact of changes in environmental larval stage of S. japonicum inside snails to allow and social context on a wider scale. rapid investigation of outbreaks of acute schistosomiasis japonica. RECOMMENDATIONS • Techniques for surveillance of Oncomelania snail habitats – improving both large and small-scale Schistosomiasis japonica is re-emerging in China, surveillance of snail habitats by application of and the top priorities in communicable diseases con- GIS and remote sensing (RS) data, as well as spa- trol have been re-defined to place schistosomiasis tial analysis methods, for use in the national sur- alongside HIV/AIDS and tuberculosis. New goals veillance system. for schistosomiasis control have been set for the next two five-year periods, together with the adoption of Eco-epidemiological determinants national guidelines for control. Transmission is aimed to be under control by 2008, and interrupted by 2015, With regard to the rapidly changing contextual in the plains and mountainous regions; and control determinants of the environment and socioeconomic of infection and transmission are, respectively, sched- level, the following epidemiological investigations uled for 2008 and 2015 in the lake regions. Taking into should be pursued with an emphasis on eco-epide- account the current status of schistosomiasis control, miological factors, health care resources and mor- the research priorities mentioned below were recom- bidity evaluation. This will also help to improve the mended to the Chinese government and WHO mis- control strategies in terms of cost-effectiveness. sion members who visited the field in February 2005. All the priorities have an emphasis on operational Investigations of the: research based on available knowledge and sup- • Interaction between schistosomiasis transmission ported by research capacity building. Due to scarce and ecosystem diversity – to provide information resources, it is recommended that the research prior- for designing control strategies based on environ- ities be those areas able to improve linkages between mental management. research and control activities, or able to improve the • Burden of disease attributable to schistosomiasis control strategies directly. and its impact on society – to provide informa-

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 31 tion to policy-makers on the actual disease bur- ardized guidance on disease management, den caused by schistosomiasis in relation to other control measures and procedures in a schisto- conditions by defining and ranking their respec- somiasis outbreak. tive burdens with an index termed ‘disability adjusted life year’ (DALY) and demonstrating the Novel products reductions achievable by schistosomiasis control. The development of the following novel products • Equity of control services in rural areas – to pro- for the control of schistosomiasis could provide val- vide evidence to policy-makers on the ideal allo- uable tools for surveillance and control interven- cation of schistosomiasis control and prevention tions in the national control programme. resources. • Novel drugs and treatment schemes – there is a • Importance of animal schistosomiasis in differ- need to assess the safety, efficacy and cost-effec- ent environmental settings – to understand the tiveness of alternative treatment schedules and roles of different animals in the transmission of delivery mechanisms, to further investigate the human schistosomiasis in different settings and use of artemisinins alone and in combination to provide information to policy-makers for use with praziquantel, and to screen for novel, orally in designing local control strategies. active antischistosomal drugs with a broad spec- • Animal management models to control trans- trum of activity against the juvenile and adult mission – to develop new tools for animal stages of the parasite. management to prevent contamination of the • Rapid diagnostic kits – there is a need to stand- environment by animal faeces. ardize tests which are sensitive enough to mon- • Impact of environmental changes on snail habi- itor the achievements of the national control tat and schistosomiasis transmission – studies of programme, and to set criteria on sensitivity and factors furthering the expansion of snail-endemic specificity with consideration of species-spe- areas, such as floods, water resources develop- cificity, shelf life, suitability for quality-control- ment projects, and climate changes, to provide led industrial production, intellectual property evaluation indicators for surveillance systems rights, availability and costs. and guidance for planning. • Molluscicides – there is a need to develop new • Impact of social and economic context on the compounds with low toxicity to non-target success of transmission control programmes – to organisms which are easy and safe to admin- improve control programmes and adapt them to ister, and to develop new biological control different eco-epidemiological settings. approaches to eliminate Oncomelania snails. • Candidate vaccine – a vaccine targeting domes- Technical standardization tic animals should be developed which reinforces The formulation of technically standardized proce- the effect of animal chemotherapy to permanently dures and policies readily adaptable to cope with reduce schistosome egg excretion by animals. changes in the local socioeconomic and eco-epidemiological context should be investigated. Studies Research platforms to maintain and in the following areas are proposed: strengthen capacity building • Standardization of strategy adjustment – deter- It is essential to build up research platforms to mination of the technical criteria for classification strengthen research capacity and optimize limited of epidemic status and technical indicators to resources by establishing collaboration mechanisms adjust the control strategy based on local eco-epi- for sharing information, experience, expertise and demiological status. resources. • Procedures for surveillance and management – determination of technical indicators for surveillance frequency and intensity, as well as Networking between laboratories standardization of management and surveillance In order to take advantage of the potential of all procedures adapted to the local setting. The sur- involved institutions in the country, the setting up of veillance systems should operationally respond networks between laboratories is urgent in order to to ecological and epidemiological challenges in a standardize the quality of intervention approaches timely and cost-effective manner. and diagnostic products and to unify the evaluation • Evaluation criteria and control measures for out- criteria. The following networks are proposed: 1) net- break surveillance and epidemic status determi- work of laboratories working on the development of nation – determination of the technical criteria diagnosis kits; 2) network of laboratories involved in defining outbreak scale and intensity, and epide- drug screening; 3) network of laboratories working miological situation, in order to provide stand- on the development of candidate vaccines.

32 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Resource banks • Bioinformatics, genome and proteome research on S. japonicum – to find the specific molecu- In order to provide standardized reference sam- lar markers and immunological characteristics ples of various strains of S. japonicum and its inter- of specific genes or antigens of S. japonicum at mediate host snail with the purpose of improving different stages, to be used for product devel- research, surveillance and control strategies, a vari- opment (e.g. novel diagnostic tools, drugs and ety of resource banks are proposed to be set up, vaccine candidates). including a schistosomiasis serum bank, a gene bank of S. japonicum and Oncomelania snails, and a Biology of the Oncomelania snail bank of standardized species or strains of S. japonicum and Oncomelania snails. • Systems biology of the interaction between S. japonicum and the Oncomelania snail – to under- Information databases stand the genetic variation and genetic co-evolution of S. japonicum and the Oncomelania snail. It is crucial to establish computerized databases for • Genetic basis of snail susceptibility to S. japoni- information sharing and exchange between research- cum infection – to understand the biological char- ers and personnel involved in the implementation acteristics and immunological mechanisms of of control programmes to improve the surveillance variations in susceptibility. systems and allow quick and adequate response to • Identification of functional genes – to investigate schistosomiasis outbreaks. These databases should the functional genes of Oncomelania for resistance encompass a schistosomiasis epidemiology data- against S. japonicum infection through genome base, a snail distribution database, a GIS database and proteome studies. on schistosomiasis and intermediate snail host distribution, and a research database for knowledge Epidemiology of schistosomiasis sharing among the scientific community. • The transmission dynamics of schistosomiasis Regional network japonica in different environmental settings – to elucidate schistosomiasis transmission patterns International collaboration is a mutually beneficial by developing transmission models employing activity facilitating progress in general and encour- environmental, demographic and socioeconomic aging the training of the next generation of research- variables, to provide the theoretical basis for ers and control staff in particular. The Regional assessment and estimation of transmission. Network for Asian Schistosomiasis (RNAS), estab- • Risk and vulnerability analysis of acute schis- lished in 1998, has been very useful in this respect tosomiasis japonica – to investigate risk fac- and is providing an excellent platform for teach- tors leading to increased vulnerability to acute ing and exchange of expertise and experiences on S. japonicum infection in order to identify mitiga- research, control and surveillance. The growth of tion measures and develop resilience strategies RNAS will further strengthen collaboration in fields against acute infections in hyper-endemic areas. such as training, risk mapping, and advocacy on • Assessment of socioeconomic impact of schis- integrating schistosomiasis control into programmes tosomiasis on disease burden – to provide an focusing on other parasitic diseases e.g. food-borne approach for defining the disease burden of trematodiasis and soil-transmitted helminthiasis. schistosomiasis and its impact by different socioeconomic dimensions in specific environmen- Basic research tal settings in order to provide new tools and Although the national schistosomiasis control pro- knowledge to update the control strategy. gramme is proceeding at a good pace, new ideas and innovative methods to consolidate achieve- Immunology of schistosomiasis japonica ments made to date are needed. This includes the • Immunological mechanisms in definitive hosts fields of basic research in the biology of S. japoni- infected with S. japonicum – to understand the cum and Oncomelania snails, epidemiology of schis- immune response and immunological mecha- tosomiasis, and immunology. nism of infection to provide background information for field trials of diagnostic kits and Biology of S. japonicum vaccine candidates. • The genetic basis of human re-infection with S. • Study on drug design by functional genomics – japonicum – to elucidate the genetic background to explore the possibility of discovering novel of human infection and re-infection with S. japon- drugs through functional genome investigations icum in hyper-endemic areas. to provide new targets based on knowledge of the genome and proteome.

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34 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 WORKING PAPER 2. Current • Prevention of spread of S. mansoni into upper situation and research Egypt. needs for schistosomiasis control in Egypt CURRENT CONTROL ACTIVITIES (STRATEGIES) Mohamed Moustafa Youssef • Selective population chemotherapy and mass Schistosomiasis and Intestinal Parasites Control chemotherapy for rural school children and pop- Department, Ministry of Health and Population, Egypt ulations in areas of high prevalence and risk. • Health education and community participation. • Focal snail control. • Environmental improvement. INTRODUCTION

Schistosomiasis caused by both S. haematobium CURRENT SITUATION AND MAIN and S. mansoni has been considered a major public ACHIEVEMENTS health problem in Egypt for several decades due to high prevalence and morbidity of the disease, espe- The current situation is that S. haematobium has virtu- cially among rural populations. After discovery of ally disappeared from the Nile Delta but is prevalent the parasite’s life cycle in 1915, Egypt started to fight in the Upper Egypt governorates, while S. mansoni is against the disease by implementing pilot projects prevalent in the Nile Delta governorates. In 1983, using either snail control or chemotherapy. the prevalence of S. haematobium was 35%, and that of S. mansoni 38.6%. By the end of 2004, both infec- The Ministry of Health and Population (MOHP) tions had been significantly reduced below 2%: S. began planning for the National Schistosomiasis haematobium with a prevalence in Upper Egypt of Control Programme (NSCP) in 1975. The implemen- 1.6%; S. mansoni with a prevalence in the Nile Delta tation of NSCP started in 1977 through the primary governorates of 1.9% (table 1; fig. 1). Progress has health care (PHC) system. been achieved in controlling schistosomiasis morbidity through improved health education, diag- The national control programme is based on selec- nosis, selective and mass chemotherapy, and snail tive population chemotherapy and mass chemo- control within the activities of the PHC system. therapy supported by health education and local application of chemical molluscicides. These control tools were implemented through NSCP (funded by the Government of Egypt, the African Development Bank, and the World Bank).

The United States Agency for International Development (USAID) and MOHP funded the Schistosomiasis Research Project (SRP) from 1988 Table 1: Control of schistosomiasis in Egypt to 1998 to develop new tools (vaccines, improved diagnostics, chemotherapy, and epidemiologic, soci- Year Prevalence of Prevalence of S. haematobium S. mansoni oeconomic and operational research). After completion of the SRP, USAID awarded a new project to * 1935 48.0% 32.0% one of the SRP components in need of further effort: ** 1983 35.0% 38.6% the Schistosomiasis Vaccine Development Program *** 1988 11.9% 16.4% (SVDP, 1998–2003), directed towards developing a *** 1993 6.6% 14.8% vaccine as an additional tool for control. *** 1996 5.0% 11.9% *** 2000 3.0% 4.2% OBJECTIVES OF THE NSCP *** 2004 1.6% 1.9% S. haematobium represents prevalence of urinary schistosomiasis in Upper Egypt • Control of morbidity by reduction of preva- S. mansoni represents prevalence of intestinal schistosomiasis in Lower Egypt lence and intensity of infection, thereby limiting * Data from: Scott, JA. The incidence and distribution of the human complications. schistosomes in Egypt. American Journal of Hygiene, 1937, 25:566–614. ** Data from: Cline BL et al. 1983 Nile Delta schistosomiasis survey: 48 years • Protection of young age groups and populations after Scott. American Journal of Tropical Medicine and Hygiene, 1989, at risk. 41(1):56–62. *** Data from: Ministry of Health and Population, Endemic Diseases Control • Protection of new settlers in areas of land Department. Annual reports on schistosomiasis control, 1988–2004. reclamation.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 35 Figure 1. Control of schistosomiasis in Egypt will need strong commitment and significant resources to maintain the achievements and prevent resurgence. +% H#]VZbVidW^jc *% H#bVchdc^ Other challenges include: • The hot spots where schistosomiasis transmis- )% sion still occurs, which require a good surveillance system. (% • Limitations in the use of chemical molluscicides '% (niclosamide, copper sulphate) due to environmental conditions. &% • The spread of schistosomiasis into newly reclaimed areas, and of S. mansoni into Upper % Egypt. * ( - ( + % ) • The ambitious social and economic agenda as &.( &.- &.- &.. &.. '%% '%% Egypt rapidly develops into a middle income country – poverty related diseases such as schistosomiasis have no place in 21st century Egypt.

LESSONS LEARNED FROM THE NSCP RESEARCH NEEDED FOR THE NSCP • Egypt has demonstrated that schistosomiasis control is a long-term but feasible process if tools • Assessment of: the sensitivity and predictive are used on a regular basis. value of the hematuria dip-stick for schistosomia- • Experience suggests that the control of schisto- sis haematobium; the sensitivity and value of the somiasis is optimal when specific control tasks Kato-Katz technique for schistosomiasis mansoni are carried out within the PHC system. in low prevalence and intensity areas; the need • External financing by foreign donors helped the for development of more sensitive and specific national authorities to accomplish their objectives diagnostic tools for use in low-endemic schisto- with local staff more rapidly than would other- somiasis areas. wise have been possible. • Operational research and a plan of action for • Egyptian experience in schistosomiasis control containing the spread of disease into newly demonstrates that no single approach is suffi- reclaimed land areas (east of the Suez Canal in cient to control schistosomiasis morbidity and Sinai, the areas surrounding Nasser lake and transmission effectively. An integrated approach Toshke). Close monitoring and surveillance in based on chemotherapy with supporting health these areas will be required as the consequences education and snail control wherever appropriate of new immigration, irrigation and drainage proved to be the ideal intervention. on the spread of schistosomiasis are difficult to • The local production of praziquantel (tablets and predict. suspension) was cost effective. The suspension • Studies to strengthen the governorate-level formulation overcame the problem of treating health teams for monitoring epidemiological data young children who were unable to swallow the and ensuring that data are systematically col- tablet formulation. lected, analysed, and reported accurately and in • A regular surveillance system is key to a success- a timely manner to the national authorities as ful campaign against schistosomiasis. well as fed back to local and district level authorities. Surveillance, planning and quality control systems at district and local levels also need to be MAJOR CONSTRAINTS AND developed. CHALLENGES • Studies to assess use of the prevalence of schisto- The current objective of the NSCP is to reduce schis- somiasis as an indirect indicator of poverty and tosomiasis to a level where it is no longer a pub- poverty-related diseases. S. lic health problem. The available evidence confirms • Studies to prevent the southward spread of mansoni that this objective has largely been achieved in most . of the governorates in Egypt. The main challenge • Studies towards eliminating urinary schisto- now is to: somiasis in most, if not all, of Egypt. • Keep the disease under control – as long as • Monitoring of drug resistance to praziquan- transmission has not been eradicated, the NSCP tel and development of alternative strategies to contain the spread of drug resistance. Egypt has

36 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 used praziquantel as the mainstay of its mass chemotherapy strategy for the last decade; this strategy has been effective and has contributed to the dramatic decrease in prevalence of the disease. However, the global decrease in price of praziquantel is encouraging use of the drug through mass chemotherapy for longer than necessary, thereby increasing the risk of drug resistance. • Prospective randomized trials of the impact of repeated mass chemotherapy on susceptibility to viral and bacterial infections. • Continued development of a schistosomiasis vaccine and building of associated research capacity, as well as studies for the development of non- invasive immunological tools for detecting schistosome antigens in urine and stool. • Trials to develop molluscicides of plant origin instead of the currently used chemical molluscicides, to conserve the environment.

ONGOING PROGRAMMES Additional activities for the NSCP involve integrating the control of schistosomiasis with the control of intestinal parasitic infection and anaemia in school- age children. This is an extension of the pilot school health programme implemented for the past six years in Behera Governorate, and originally planned to cover four bordering governorates (Kafr El- Shiekh, Gharbiya, Menoufia and rural Alexandria) selected on the basis of epidemiological and operational criteria. After one year of implementation it was decided to expand the scope of the activities to cover all the Nile Delta and selected Upper Egypt governorates. The expansion programme is a joint initiative (involving MOHP, WHO, and Italian Cooperation) to control morbidity related to schistosomiasis and intestinal helminths among school-age children (6–12 years), both enrolled and not enrolled in school.

The general objective of the expansion programme is to improve the health and nutritional status of school-age children (6–12 years old) through reduction in prevalence and morbidity due to schistosomiasis, fascioliasis and soil-transmitted helminth infections, strengthening, at the same time, the monitoring system of the Schistosomiasis and Intestinal Parasites Control Department.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 37 WORKING PAPER 3. two schistosome species parasitic in man, occurs in Implementation strategies 38 of the 56 districts, while S. haematobium is found in only 2 f the 38 districts. It is estimated that 16.7 for schistosomiasis million people are at risk of getting infected while control in Uganda, about 4 million are already infected (Kabatereine et and research needs al., 2004). Hookworm is prevalent throughout the under the programme country, but A. lumbricoides and T. trichiura are geo- graphically restricted to the southwest (Kabatereine et al., 2005). Nearly every child in Uganda is infected Narcis B Kabatereine,* Simon Brooker,** with at least one of the above helminth species, or is Artemis Koukounari,*** Fiona Fleming,*** at risk of being infected. Helminth infections are a Edridah M. Tukahebwa,* Francis Kazibwe,* major health problem in the country, particularly Yaobi Zhang,*** and Alan Fenwick*** for those living in close proximity to lakes, large rivers, dams and irrigation schemes; they cause severe * Vector Control Division, Ministry of Health, morbidity that requires urgent intervention. Kampala, PO Box 1661, Uganda. ** Department of Infectious and Tropical Diseases, In light of this, a national schistosomiasis and worm London School of Hygiene and Tropical Medicine, control programme was initiated in Uganda in 2003 Keppel Street, London WC1E 7HT, UK. with support from the Schistosomiasis Control *** Schistosomiasis Control Initiative, Department Initiative (SCI). The strategy is to control morbidity of Infectious Disease Epidemiology, Faculty of through mass annual deworming targeted at school- Medicine, Imperial College, Norfolk Place, London age children and high-risk groups in the endemic W2 1PG, UK. areas. Preventive measures focus on raising awareness about schistosomiasis and STH infections through health education, primarily in schools but INTRODUCTION also in the wider community. By combining health education and treatment, the aim is that beneficiar- International effort is currently focused on condi- ies should experience improvements in health, so tions that cause high mortality, for instance HIV/ creating a demand for treatment and, subsequently, AIDS, tuberculosis, malaria and vaccine prevent- increasing sustainability of the campaign. During able diseases. Meanwhile parasitic diseases such the pilot phase in 2003, a total of 437 500 people from as schistosomiasis and soil transmitted helminths one sub-county in each of the 18 most affected dis- (STH), that lead to significant morbidity especially tricts participated in the mass treatment campaign in poor, remote communities, are almost ignored (Kabatereine et al., 2006). Approximately 1.3 million (Savioli et al., 2004). Although their mortality rate is and 3 million people were treated in 2004 and 2005 low, the neglected diseases inflict severe disabilities respectively. After this attack phase, which was sup- on almost one billion people around the world espe- ported by SCI funding, it was hoped that infection cially among the poorest populations in developing levels would have decreased to an extent where the countries (Hunt, 2006). In addition to physical harm, Ministry of Health and the districts would be able to these diseases impose enormous economic burdens sustain the programme. on the affected communities due to lost productiv- ity. For example, the combined disability-adjusted Experience gained during the pilot phase has already life years (DALY) for schistosomiasis and soil trans- been reported (Kabatereine et al., 2006). During eval- mitted helminths (hookworms, Ascaris lumbricoides, uation it was felt that the financial records of the pro- Trichuris trichiura) is 43.5 million, second only to gramme should be analysed to assess the financial tuberculosis (46.5 million) and well ahead of malaria costs of the programme; this will also be reported. (35.7 million) and measles (34.1 million) (Mascie- The present article aims to describe the organiza- Taylor and Karim, 2003; WHO, 2002; Chan, 1997). tion, management and implementation strategy Unless the neglected diseases receive sufficient of the programme in order to identify which dis- attention, the Millennium Development Goals for tricts are performing well and where programme health will not be achieved by 2015. performance requires improvement. The paper will also facilitate replication of the control intervention Schistosomiasis itself infects about 200 million peo- in other highly endemic areas. The political will and ple, of whom 85% live in sub-Saharan Africa; while commitment of the districts to the programme, and 652 million people in 76 countries are at risk of get- the perceptions of those implementing the activities ting the infection (Chitsulo, 2000). In Uganda, schis- and receiving the treatment, will be reported. The tosomiasis mansoni, the most widespread of the Ministry of Health recommends synergy between

38 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 different disease control programmes such as lym- nurse. All these people participated in implementa- phatic filariasis, onchocerciasis, schistosomiasis tion of the programme. and STH in order to improve cost–effectiveness and reduce duplications of effort in health care deliv- Programme management ery within communities where the diseases over- Coordination of the programme was based at the lap; progress in this area is also reported. The health Vector Control Division (VCD) of the Ministry of impact and costs of the programme will be pre- Health (MOH), Kampala. The coordination team sented elsewhere. worked closely with other relevant departments in the MOH, especially the health promotion and METHODOLOGY education divisions, and collaborated with other ministries, particularly of education and local gov- Identification of target population ernment. Administration of funds and personnel at The first stage in starting the national control pro- the district level were headed by the chief admin- gramme was to use geographical information sys- istrative officer (CAO). Implementation of the pro- tems (GIS) to map out the parasitological data that gramme was however overseen by the district had been accumulated between 1997 and 2002 director of health services (DDHS), who heads the (Kabatereine et al., 2004). These data were from health department at district level. The DDHS was 23 627 people distributed in 271 schools or commu- assisted by his/her staff, mainly the district vector nities across the country. The derived map showed control officer (DVCO) and the district health edu- a wide spread of helminthiasis in the country. The cator (DHE). As at national level, the district health second stage was to overlay this map with envi- team collaborated with the education department in ronmental data to identify the ecological limits of implementation. At the sub-county level, implemen- transmission. Since no transmission occurs in areas tation was managed by the district team assisted by where the total annual rainfall is less than 900 mm sub-county executive members, community lead- and the altitude is more than 1400 m (Kabatereine ers, elders, teachers, community drug distribu- et al., 2004), these areas were set aside without need tors (CDDs) and local health workers. Treatment in for further surveys. In the third stage, high spatial schools was carried out by class teachers and in com- resolution landsat satellite data were used to define munities by CDDs who were selected by the con- lakes and rivers. It was shown that prevalence concerned communities and trained by district trainers sistently exceeded 50% in areas within 5 km of (Kabatereine et al., 2006). Supervision was the duty lakes Victoria, Kyoga, and Albert, and the Albert of the district health team assisted by the national Nile. Thus it was decided that annual mass treat- coordinating team. ment would be provided to the whole populations in these areas. In communities where the prevalence Evaluation was 20% to 50%, only school-age children were to Rigorous evaluation of the impact of control is receive annual mass treatment, and where preva- essential (Brooker et al., 2004). Determination of lence was below 20%, health facility based treatment health impact was focused on infection levels (prev- was encouraged and health education intensified. alence and intensity) and morbidity (Kabatereine et The procedure was such that every person who al., 2006). Detection by microscopy and counting of received praziquantel also received albendazole. S. mansoni eggs in faeces were used to determine the yearly prevalence and intensity of infection in a To gain experience, control activities in 2003 were randomly selected cohort. Reversibility of morbid- limited to a total of approximately 450 000 people ity was monitored in this cohort using a question- distributed in one sub-county of each of the 18 most naire administered by teachers. Morbidity was also affected districts (Kabatereine et al., 2006). Thereafter, assessed by ultrasound examination following the activities in each of the 18 districts were scaled up to Niamey protocol (Richter et al., 2000) and by palpa- include two or three more sub-counties and to target tion of liver and spleen according to Vennerwald et about 1.5 million people. The final scaling up was al. (2005). Height, weight and other anthropometric completed in April 2005, when all the endemic areas measurements were used to assess growth in school- in the country in 23 districts implemented the pro- age children. The effect of treatment on anaemia was gramme, targeting 3.5 million people. Since health assessed through measurement of haemoglobin in a care delivery in Uganda is devolved to district level, drop of blood using a haemoglobinometer. implementation was based at this level. Each district is divided into health sub-districts headed by a An annual evaluation is carried out to assess pro- medical officer. There is also a smaller health facil- gramme performance (provision, utilization, cov- ity in most parishes headed by a clinical officer or erage). All districts were visited; the multistage

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 39 sampling technique was used to select the particular communities, the random sampling technique was sub-county, schools and communities to be visited used to select teachers, CDDs and others to receive in each district, where specifically designed ques- treatment. tionnaires were administered to the CAO, DDHS and DVCO, and information was collected from RESULTS AND ACHIEVEMENTS registers. At sub-county and village levels, only the top leadership participated, while in schools and The 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 Control Programme and the Child Health Days Plus programme, 2003–2005

2003 2004 2005 May Nov May Nov May Nov Treated % Treated % Treated % Treated % Treated % Treated % NBWCP 0.43 79 - - 1.23 88 - - 2.99 87.6 - - PZQ+ALB CHD+ (ALB + - - 7.10 86.5 4.90 40.06 7.6 62.5 8.05 66.0 9.61 77.5 other treatments)

NBWCP = National Bilharzia and Worm Control Programme CHD+ = Child Health Days Plus – the NBCWP contributed albendazole for these days and is now working towards full integration PZQ = praziquantel ALB = albendazole

Figure 1. The distribution of S. mansoni at baseline in 2003 and after two years of the annual mass treatment campaign. Note that the 2006 map was derived from a rapid mapping approach (Brooker et al., 2005)

Standard parasitological survey Lot 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 different intensities of infection in children (Kabatereine et al., 2006)

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Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 41 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 of 219.6 (191.8–247.4) 73.3 (58.6–88.0) 37.4 (27.4–47.5) faeces]) 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’ 0 0 0 (n=180) % 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 results Liver Median (range) in cm (n = 368) MSL 0 (0–12) 0 (0–14) 0 (0–14) MCL 2 (0–5) 2 (0–5) 0 (0–6) Consistency (n = 366) % Normal 16.1 (12.4–19.9) 70.5 (65.8–75.2) 73.7 (69.3–78.3) % Soft 20.5 (16.4–24.6) 26.2 (21.7–30.7) 25.4 (20.9–29.9) % Firm 62.5 (57.6–67.5) 3.2 (1.5–5.1) 0.8 (0.0–1.7) % Hard 0.8 (0.0–1.7) 0 0 Irregularity % (n = 367) 0 0 NA Tender % (n = 358) 2.0 (0.5–3.4) 1.1 (0.0–2.2) 0 Spleen Median (range) in cm MCL (n = 368) 3 (0–10) 0 (0–11) 0 (0–10) MAL (n = 367) 0 (0–5) 0 (0–6) 0 (0–5) Consistency % Normal 26.1 (21.6–30.6) 63.3 (58.4–68.2) NA (n = 368) % Soft 12.2 (8.9–15.6) 22.6 (18.3–26.8) % Firm 58.4 (53.4–63.5) 14.1 (10.6–17.7) % Hard 3.2 (1.5–5.1) 0

PSL = longitudinal parasternal line scores; MSL = mid-sternal line; MCL = mid-clavicular line scores; MAL = mid axillary line scores

Programme achievements • The price of praziquantel per tablet has decreased considerably, from US$ 0.15 in 2003 to • Schistosomiasis and soil transmitted helminth US$ 0.07 in 2005. control has been included in the Health sector stra- • Praziquantel has been included on the Ministry tegic plan 2006–2011 of the Ministry of Health. of Health’s Essential Drugs list and can now be • The number of pharmaceutical companies regis- purchased on credit by the districts if necessary. tered to supply praziquantel increased from one • Deworming has become popular and all districts in 2003 to six by 2005. carry out biannual deworming under the Child Health Days programme.

42 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 RESEARCH NEEDS drugs. Furthermore, it is important to examine the protective impact of artemether, either alone • Lack of knowledge, and the poor attitude or in combination with praziquantel, on the rein- and practices of most people in schistosomia- fection rate. sis endemic areas, promote the persistence • Community-directed mass treatment of of schistosomiasis transmission despite mas- onchocerciasis and soil-transmitted helminths sive intervention measures. Advocacy for lead- with ivermectin and albendazole respectively ers, intensive health education for concerned has been shown to be cost effective in poor communities, and social mobilization are vital remote African communities with inadequate for successful disease control, but in order to trained health personnel (Ndyomugyenyi and deliver this package it is important to assess peo- Kabatereine, 2003). The method involves the con- ple’s perception of schistosomiasis, their tradi- cerned communities as lead stakeholders in solv- tional responses to the disease, and how these ing their own health problems. This approach traditional responses might affect intervention contrasts with community-based interventions measures. It is important to determine people’s where health workers are the lead agents of the knowledge, attitudes and practices concerning intervention. The community-directed treatment the causes/transmission, manifestations, treat- strategy is built on the experience of community ment and other interventions before design- members and enhances their decision-making ing appropriate health education messages. The and problem-solving capacity. The commu- impact of such messages should be regularly nity plans the drug distribution, decides on the evaluated to assess their clarity for the target method of distribution acceptable to them (e.g. population. central place or household), and when to dis- • Research to consider cultural influences on tribute. This enhances treatment coverage and health-seeking behaviour, focusing on individu- promotes the chances of sustainability. Such a als’ interpretations of their own experiences and strategy should be tested regarding the distribu- the impact of external influences, if any, is vital. tion of praziquantel. • The Ministry of Health, Uganda, has recom- • Assessment of the costs and impact of large-scale mended synergy between different disease con- control programmes is vital, not only to dem- trol programmes such as lymphatic filariasis, onstrate the health benefits but also to assess onchocerciasis, schistosomiasis, and STH, in the cost–effectiveness and show that limited order to improve the cost–effectiveness of health resources have been adequately utilized. Cost care delivery in communities where these dis- analysis might also be used to identify possible eases overlap. To facilitate this approach, it is financial barriers and opportunities important important to provide policy-makers with infor- to long-term sustainability of the programme. mation on geographical overlap of the diseases Comparisons of the cost–effectiveness of schis- by collecting existing parasitological data into tosomiasis control implemented alone vs. when a common GIS. This will help to estimate the it is integrated with other disease control pro- at-risk populations and determine the rates of grammes are vital for decision-makers. multiple infection. Studies to ascertain the infra- • Although several well controlled clinical trials structure available as well as the knowledge have demonstrated that praziquantel treatment and willingness of the community to take mul- reduces morbidity related infections (Frenzel et tiple drugs, and of drug distributors to under- al., 1999; Richter, 2003; Vennervald et al., 2005), take the distribution of multiple drugs, are vital. it is not known if the results from such clinical Furthermore, drug combinations, the efficacy of trials can be replicated under a large-scale con- the various combinations and their safety, should trol programme. Previous evaluations of most be investigated. reported large-scale interventions were usually • Uganda, like many malaria endemic countries, made on the basis of infection indicators rather is currently adopting artemisinin-based combi- than morbidity indicators (Brinkmann et al., nation drugs for first-line treatment. Most likely 1988; Engels et al., 1994). Research efforts to dem- this will impact on schistosomiasis control since onstrate the health benefit and performance (cov- artemether is known to affect juvenile schisto- erage) of large-scale community-directed mass some stages while praziquantel affects the adult treatment campaigns are therefore important parasite. It seems however that not much is (Brooker et al., 2004). known about whether the two drugs should be • WHO has recently adopted a policy of using given simultaneously and whether there are any praziquantel in pregnant women (Allen et al., pharmacological interactions, or about the side 2002). However, the efficacy of the drug in effects and cure rates of combination vs. single pregnancy has not been tested. Earlier studies

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 43 showed that successful elimination of the para- References sites requires an interplay between praziquantel Allen H et al. New policies for using antihelmintics in and the host immune system (Brindley and Sher, high risk groups. Trends in Parasitology, 2002, 18:381- 1987), and yet pregnancy is known to impair 382. protective responses, e.g. pregnancy promotes changes from TH1 to TH2 regulatory cells (Sasaki Brindley PJ, Sher A. The chemotherapeutic effect of et al., 2004). The impact of such immune changes, praziquantel against Schistosoma mansoni is depend- especially on the efficacy of the drug in expectant ent on host antibody response. Journal of Immunology, mothers, should be investigated. 1987, 139:215–220. • Rapid and accurate identification of the commu- Brinkmann UK et al. An evaluation of sampling meth- nities at highest risk of morbidity from schisto- ods within communities and the validity of parasi- somiasis is key to sustainable control (Brooker et tological examination techniques in the field. Tropical al., 2005). Although a school questionnaire can Medicine and Parasitology, 1988, 39(2):162–166. effectively and inexpensively identify communities with a high prevalence of S. haematobium Brooker S, et al. Evaluating the epidemiological (Lengeler, Utzinger and Tanner, 2002), parasito- impact of national control programmes for helminths. logical screening remains the preferred option Trends in Parasitology, 2004, 20:537–545. for S. mansoni. To reduce screening costs and Brooker S et al. Rapid assessment of Schistosoma man- time, reliable data need to be collected as rap- soni: the validity, applicability and cost-effective- idly and cheaply as possible. Lot quality assur- ness of the Lot Quality Assurance Sampling method ance sampling, which is increasingly being used in Uganda. Tropical Medicine and International Health, to monitor other health interventions e.g. vacci- 2005, 10:647–658. nation coverage (Tawfik et al., 2001), and to estimate prevalence e.g. of HTLV-1 (Houinato et al., Chan MS. The global burden of intestinal nematode 2002) and sleeping sickness (Hutin et al., 2004), infections – fifty years on. Parasitology Today, 1997, might play such a role. Recent work has demon- 13:438–443. strated the validity, applicability and cost–effec- Chitsulo L et al. The global status of schistosomiasis tiveness of this method for monitoring S. mansoni and its control. Acta Tropica, 2000, 77(1):41-51. infections in Uganda (Brooker et al., 2005), and Engels D et al. Control of Schistosoma mansoni and further work is recommended to investigate the intestinal helminths: 8-year follow-up of an urban method in different settings. school programme in Bujumbura, Burundi. Acta • The majority of studies on schistosomiasis prev- Tropica, 1994, 58(2):127–140. alence, intensity, and associated disease burden before and after treatment focus on adults and/ Frenzel K et al. Evidence for a long-term effect of a or school-age children (Vennervald et al., 2005; single dose of praziquantel on Schistosoma manso- Kabatereine et al., 2003). Surprisingly little atten- ni-induced hepatosplenic lesions in northern Uganda. tion has been given to pre-school children, par- American Journal of Tropical Medicine and Hygiene, 1999, ticularly infants of 3 years or less. Large-scale 60:927–931. mass treatment campaigns usually ignore this Houinato D et al. Interest of LQAS method in the sur- age group (Kabatereine et al., 2005), and even vey of HTLV-1 infection in Benin (West Africa). Journal the WHO treatment tablet pole does not cater of Clinical Epidemiology, 2002, 55:192–196. for them (Montresor et al., 2005). Schistosome infections in this very young age group are gen- Hunt Paul. Report of the Special Rapporteur on the right erally thought to be rare, and have frequently of everyone to the enjoyment of the highest attainable been overlooked based on the reasoning that standard of physical and mental health: mission to Uganda. their water contact frequency is highly negligi- United Nations, 19 January 2006 (E/CN.4/2006/48/ ble (Jordan and Webbe, 1993). While this may Add.2). generally be true, passive water contact of this Hutin YJ et al. Trypanosoma brucei gambiense age group originating from the behaviour of trypanosomiasis in Terego county, Northern Uganda, the mothers is sometimes high. This age group 1996. A lot quality assurance sampling survey. should in future be included in epidemiological American Journal of Tropical Medicine and Hygiene, 2004, and morbidity studies and should be considered 70:390–394. in mass treatment campaigns in communities Jordan P, Webbe, G. Epidemiology. In: Jordan P, found to be at high risk. 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 country- Vennervald BJ et al. Regression of hepatosplenomeg- wide control of schistosomiasis and soil-transmit- aly in Kenyan school-aged children after praziquantel ted helminthiasis in Uganda. Transactions of the Royal treatment and three years of greatly reduced expo- Society of Tropical Medicine and Hygiene, 2006, 100:208– sure to Schistosoma mansoni. Transactions of the Royal 215. Society of Tropical Medicine and Hygiene, 2005, 99:150– 160. Kabatereine NB et al. Soil-transmitted helminthiasis in Uganda: epidemiology and cost of control. Tropical World Health Organization. Prevention and Control Medicine and International Health, 2005, 10:1-3. of Schistosomiasis and Soil-Transmitted Helminthiasis. Report of a WHO Expert Committee. Geneva, World Kabatereine NB et al. Epidemiology and geography of Health Organization, 2002 (WHO Technical Report Schistosoma mansoni in Uganda: implications for plan- Series, No. 912). ning control. Tropical Medicine and International Health, 2004, 9:372–380. Kabatereine NB et al. Efficacy and side effects of praziquantel treatment in a highly endemic Schistosoma mansoni focus at lake Albert, Uganda. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2003, 97:599–603. Lengeler C, Utzinger J, Tanner M. Questionnaires for rapid screening of schistosomiasis in sub-Saharan Africa. Bulletin of the World Health Organization, 2002, 80:235–242. Mascie-Taylor CG, Karim E. The burden of chronic disease. Science, 2003, 302:1921-1922. Monstresor A et al. The WHO dose pole for the administration of praziquantel is also accurate in non African populations. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2005, 99:78–81. Ndyomugyenyi R, Kabatereine NB. Integrated community-directed treatment for the control of onchocerciasis, schistosomiasis and intestinal helminth infections in Uganda: advantages and disadvantages. Tropical Medicine and International Health, 2003, 8:997– 1004. Richter J. The impact of chemotherapy on morbidity due to schistosomiasis. Acta Tropica, 2003, 86:161-183. Richter J et al. Ultrasound in schistosomiasis. A practical guide to the standardized use of ultrasonography for the assessment of schistosomiasis-related morbidity. Geneva, World Health Organization, 2000 (TDR/STR/SCH 00.1). Sasaki Y et al. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Molecular Human Reproduction, 2004, 10(5):347–353. Savioli L et al. Progress in the intervention and control of schistosomiasis and soil-transmitted helminthiasis. Parasitology International, 2004, 53:103–113. Tawfik Y, Hoque S, Siddiqi M. Using lot quality assurance sampling to improve immunization coverage in Bangladesh. Bulletin of the World Health Organization, 2001, 79(6):501-505.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 45 WORKING PAPER 4. in the human host, leading to non-trivial subclini- Quantification of cal morbidity in many persons, clinical morbidity in some, and premature mortality among a small pro- disease burden due portion of those infected. to schistosomiasis The range of symptoms and physical findings Charles H. King associated with chronic schistosomiasis due to Center for Global Health and Diseases, Case Western S. haematobium, S. mansoni, or S. japonicum is well Reserve University School of Medicine, Cleveland, Ohio described in published literature.9–12 However, the USA. disabling effects of the clinical events are not well defined when viewed in terms of their net impact on a patient’s physical and social performance. Considering the WHO definition of health as a INTRODUCTION ‘state of complete physical, mental and social well- At the close of 2005, schistosomiasis remains highly being’, there is concern that earlier ‘objective’ assess- prevalent in large parts of the world, representing a ments of schistosomiasis-related health burden may continuing challenge to health planners in affected have undervalued its importance to public health. countries ranging from Africa to the Middle East, Infection outcomes without immediate health care the Philippines, mainland Asia, the Caribbean states, demands have been discounted,13 although, from a and South America. Over time, the relative impact personal and societal perspective, many of the schis- of schistosomiasis on the world health burden has tosomiasis-related physical effects have significant been intensely debated by proponents of different social and economic impact. Where it has proven health agendas. In the past fifty years, schistosomia- difficult to disaggregate the contribution of schis- sis has been variously categorized as the least to the tosomiasis to disease states such as anaemia and very worst of infectious disease burdens in affected undernutrition in the face of multiple infections or areas.1,2 disease processes, the analytic approach has often been to pass over these conditions as ‘not clearly To those unfamiliar with the field, this issue appears attributable’ to schistosomiasis alone. unresolved, and the global priority for schistosomiasis control remains in question. As assessed critically From the policy standpoint, allocation of scarce by Farooq over 50 years ago: “… this insidious and health resources is felt to require an objective com- chronic disease [schistosomiasis] lacks the drama parison of the relative impact of different health usually associated with other spectacular infections conditions, with the need to allocate these resources in the affected areas, and does not attract the atten- as efficiently as possible in order to effect overall tion that it deserves”.2 improvements in health. In this type of analysis, the time frame and analytic perspective of the analy- Since the last meeting of the Schistosomiasis Working sis can strongly influence the decisions made about Group, wide-ranging efforts have been made to bet- the value of intervention. For this reason, a careful ter quantify the global burden of disease that is reassessment of schistosomiasis-associated disease attributable to schistosomiasis. The approach has burden, taken from multiple perspectives, becomes been based on systematic examination of the availa- very appropriate. ble evidence on infection prevalence and individual 3–6 disease impact, in combination with the planning WHY A VALID QUANTIFICATION OF of focused data acquisition during the course of DISEASE BURDEN IS IMPORTANT newly introduced, large-scale national and regional control programmes.7,8 The purpose of these joint The growing commitment to monitoring health lev- efforts has been to provide better evidence-based els and to rational allocation of health resources estimates of schistosomiasis-associated morbidity has led to a proliferation of techniques to evaluate and mortality in order to inform and facilitate our health and health outcomes among individuals and public health deliberations. within populations.14 The quality-adjusted life year (QALY) and disability-adjusted life year (DALY) In this context, it is important to decide how to speak assessments are time-based approaches that seek of schistosomiasis – is it the infection per se that we to quantify the aggregate lifelong impacts of dif- are considering in our policy decisions? Or is it the ferent health states or diseases on overall health or disease, that is ultimately caused by presence of the health burden. They provide a framework for utili- infection? It is apparent that any level of schistosome tarian analysis of resource allocation whereby over- infection is associated with significant inflammation all health can be ‘maximized’ per dollar spent across

46 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 a population or a given treatment programme. The tosomiasis. As Murray has noted, ‘Knowledge of a 1990–1996 evolution of the Global Burden of Disease health state has a profound effect on preference eval- Project,15 jointly sponsored by WHO and the World uations .… knowledge leads to lower utility weights Bank, has led to widespread adoption of the DALY (death is zero)….’.15 as a metric in many sectors of international health planning. In their summary analysis, the conveners of the DALY programme agreed that: ‘The [Global Burden This approach is not without controversy;16–19 detrac- of Disease] and the calculation of DALYs linked tors point out that health-adjusted life year meas- with it must be viewed as an ongoing process with ures, while attempting to be objective, ‘…fail to give methods, data and results in steady evolution’.15 It is priority to those who are worst off, …discriminate for this reason that the DALYs assigned to schisto- against people with limited treatment potential,… somiasis now deserve reassessment. and they fail to account for qualitative differences in treatment outcomes (e.g. life-saving versus health HOW SHOULD WE CAPTURE THE improving)’.14 There is inherent age-bias in the calculation of both QALYs and DALYs, which is more ‘BURDEN OF DISEASE’? explicit in the age-weighting scheme used in cal- Quality of life involves physical, social, emotional, culating DALYs.15 The abstraction of disease-spe- and cognitive spheres, as well as presence or absence cific disability weights, without reference to social, of pain or discomfort, vitality, and one’s overall cultural, or environmental context, has been seen sense of well-being. Assessment of the impact of as leading to significant underestimation of disease disease from the patient’s perspective is not always burden in disadvantaged populations.18 well correlated with ‘objective’ findings measured on a clinical basis. Standardized interview tools for Nevertheless, it is important now to review and measuring disease impact on health-related qual- revise approaches to the estimation of disease bur- ity of life have been developed in North America dens because of the de facto prioritization of public and Western Europe. However, there are major hur- health efforts based on perceived cost-effectiveness dles in applying these findings to other cultures. of interventions. The goal of the DALY initiative ‘The notion of quality of life is, itself, a cultural con- was to ‘decouple epidemiological assessment from struct… It cannot be assumed to have universal rele- advocacy so that estimates of the mortality or disa- vance or meaning’.20 bility from a condition are developed as objectively as possible’.15 Yet as the senior investigator states, Case descriptions and case series can form the ini- ‘Paradoxically, if a measure is used, it will influence tial empiric basis for disease description, but they policy debate, permeate the thinking of decision- do not determine the actual population-based bur- makers and become part of the culture of the sub- den of disease. Older, unstructured reviews and dis- ject….DALYs are [now] used normatively, and thus ease burden estimates were often swayed by the become [the] normative measures’. extremes of disease that had been reported in the literature. Severe, but rare complications of a common In their 1996 estimates of the global burden of dis- disease will actually contribute a very small incre- ease,15 the WHO and World Bank published age- ment to the community burden of disease, whereas specific disability weights for schistosomiasis that a common complication of a common disease will ranged from 0.005–0.006, on a par for disability with have a substantial effect on determining aggregate the mildly stigmatizing disease of facial vitiligo. community disease burden. These disability weights were derived by a delib- erative panel, convened in Geneva in 1995, using a If cost–utility analysis and comparisons across multi- person-trade-off protocol (PTO) to compare a wide ple disease conditions are to be valid, it is important array of disabling conditions.15 While that process to have a good, evidence-based picture of the preva- had reproducibility in terms of ordering the severity lence of disease, as well as the disease burden for the of disability caused by different infectious and non- ‘average’ person having the condition under study.14 infectious conditions, the magnitude of the weights for schistosomiasis and other helminthic infections Current epidemiological investigation into schis- derived in this ‘Delphi’ (or expert-based) method tosomiasis disease burden focuses on refining seemed exceptionally low to many workers in the estimates of the key components of this burden esti- field of parasitic infectious diseases. A lack of famil- mation. For DALY estimation, the necessary compo- iarity of the panel with the physical consequences nents of the equation are: of schistosomiasis may have led them to seriously underestimate the disabling impact of human schis- DALY = YLL + YLD

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 47 where YLL is the years of life in a population lost effects for the impact of therapy due to the presence to premature mortality attributable to schistosomia- of co-morbidities, and cultural differences in the sis, and YLD is the healthy years of life lost due to interpretation of illness. In addition, US/European disability attributable to schistosomiasis.15,18 YLD, in techniques for estimating economic impact may not turn, is estimated by: readily transfer to the setting where subjects survive on subsistence agriculture supplemented by only YLD = D x L occasional cash income. Thus ‘subjective’ patient- preference instruments may not fully capture the where L is the duration of the disability and D is an impact of infection on disease burden. assigned disability weight for the ‘average person’ with schistosomiasis. (In the standard DALY analy- Expert estimation of disease burden sis, adjustments are also made to this product on the The Global Burden of Disease (GBD) programme basis of age at onset, and the discounting of future has attempted to derive disability weights through disability states15). the deliberations of a series of expert panels who compared hundreds of disease states to 22 bench- From this standpoint, it is essential to have accu- mark disease states that had been previously ranked rate estimates of schistosomiasis prevalence on a by consensus.15 In this ranking, schistosomiasis was regional and global basis, and of cause-specific mor- judged to be on a par with the least disabling bench- tality related to schistosome infection. In addition, mark, vitiligo, with a median disability weight of it is necessary to have accurate estimates of the dis- 0.005. This weight was meant to incorporate an abling effect of schistosomiasis, and of the average assessment of both the physical state of the infected duration of infection. The latter has been assessed individual and society’s responses (preferences) to by one of three basic approaches described below. the disease state.15 The practical implication for economic analysis is that the panel considered the aver- Observer-based estimates of disease burden age person with schistosomiasis to be one-half of In the past, much population-based field research one per cent disabled by his or her infection. The has been focused on measuring easily quantifiable assigned weight was substantially less than the outcomes, e.g. infection prevalence and intensity, weight for malnutrition (0.02), watery diarrhoea along with liver size, splenomegaly, haematuria, (0.045), or moderate/severe anaemia (0.011 to 0.09). ultrasound abnormalities, etc. For the latter out- Although schistosomiasis had been known to be comes, there was the implicit assumption that these causative in the formation of these disease states, ‘objective’ abnormalities implied disability. Some their contribution to schistosomiasis-related disabil- measures, such as hepatosplenomegaly and hae- ity estimates appears to have been overlooked in the maturia, were seen to be more common with heavy final schistosomiasis disability weight estimate. infection, and infection intensity was then taken as a proxy for morbidity risk in formulating disease- In an alternative type of expert-based approach, control strategies.21,22 Yet we, and others, have come Kirigia25 polled schistosomiasis experts using struc- to observe that infection proxies do not necessar- tured questionnaires to derive estimates of the ily map one-to-one with morbidity states (see e.g.23), annual probability of progressing from minimal and these do not necessarily map one-to-one with to severe schistosomiasis-associated disease in the disability outcomes.24 endemic setting. Subsequent life-path analysis, compared to available statistics on the prevalence of Subjective estimates of disease burden mild, moderate, and severe schistosomiasis-associated states, indicated that these expert estimates, It is apparent that some schistosomiasis-related although based on long familiarity with the conse- outcomes are not intensity related, some have a quences of schistosomiasis, were substantially too threshold effect, and some are so ubiquitous that high. ‘uninfecteds’ in a population are the abnormal. The impact of infection on an individual’s quality of life Therefore, there are limitations to all of these may be hard to assess due to the long chronicity of approaches to disability estimation. It has been infection and adaptation to the presence of disease. persuasively argued that if cost–utility analysis is Parasitic reinfection is frequently so common that an to be taken from the societal perspective, in align- individual at risk spends half his or her life infected. ment with the WHO definition of health, then the Without treatment, or personal reference to the ben- impact of infection should be based on the subjec- efits of the infection-free state, it may be difficult tive, or patient-preference, approach to assessing the for the affected person to define the impact of infec- impact of disease.26 Given a review of the available tion on his or her health status. There may be ceiling

48 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 data, most would agree that there is measurable det- REASSESSMENT OF THE riment due to schistosome infection, and significant PREVALENCE OF INFECTION AND reduction in quality of life among infected popula- OF SCHISTOSOMIASIS-RELATED tions due to its physical and social impact. In this CLINICAL OUTCOMES sense, the context of morbidity may be as important as the nature and extent of the physical proc- New work has extended WHO’s worldwide and ess involved. country-specific schistosomiasis prevalence estimates published by Chitsulo and colleagues in 27 Currently, there are limitations to using either 2000. Their estimates, which indicated 193 mil- expert-based or the alternative ‘objective’ or ‘subjec- lion cases worldwide, with 652 individuals at risk tive’ approaches to estimating disease burden due to for infection in 1995, have been recast for mid-2003, schistosomiasis. However, it is likely that our work- indicating at least 779 million now at risk and 207 28 ing estimates can be improved through structured million now infected. A careful review commis- reconsideration of established and emerging epide- sioned by the WHO Expert Committee (performed 6 miological data, and through integrated assessment by van der Werf and colleagues ) of published and of the objective, subjective, and societal factors that unpublished data for sub-Saharan Africa, the region are determinants of disability in schistosomiasis. containing > 85% of all global schistosomiasis cases, indicates an estimated 112 million cases of S. haematobium and 54 million cases of S. mansoni in this REASSESSING THE BURDEN OF region. Where possible, infection prevalence was DISEASE DUE TO SCHISTOSOMIASIS then linked to the concurrent risk of schistosomiasis- Global estimates for the burden of disease due to associated signs and symptoms, i.e. as morbidity out- schistosomiasis are critically tied to: comes. This was based on observed links between • Prevalence of the infection prevalence, its association with the observed dis- • Duration of the infection tribution of infection intensity, and the association • Years of life lost to the infection between intensity and risk for clinical disease, with • The age at which the condition is assessed adjustment for the heterogeneity of infection across • The disability attributed to the ‘average’ person larger reporting units. with the disease state being considered. From these projections, 70 million persons were esti- In order to avoid some of the limitations of the pre- mated to have haematuria in the last two weeks due vious GBD assessment, it is important to maintain to S. haematobium, with 88 million and 18 million an appreciation of the differences between acute, having minor or major bladder pathology, respec- infection-related morbidity and chronic, cumulative tively. For S. mansoni, 4.4 million were estimated to morbidity. The assessment should include an esti- have had associated blood in the stool, while 8.5 mil- mation of the schistosomiasis-attributable fraction lion had associated hepatomegaly. of important chronic morbidity states – chronic diarrhoea, abdominal pain, anaemia, undernutrition, For other outcomes, including schistosomiasis- and cognitive impairment – that were previously attributable mortality, reliable estimates could not disaggregated from their underlying causes in the be provided due to the divergence or scarcity of the 6 GBD assessment. available data.

Where there has often been overvaluation of the A recent, independent disease burden assessment, 15 mortality effect (which is more easily measured as contrasting the findings of the GBD and the WHO 6 a ‘hard’ endpoint), there is often undervaluation Expert Committee initiatives, indicated that their of chronic morbidity, in light of individual adapta- separate estimates of infection prevalence were in tion to chronic disease. There is need to appreciate fact consistent. However, their estimates of schis- the time-lag in expression of severe schistosomia- tosomiasis-attributable mortality varied by a factor sis-related disease. If age-weighting is used, it of more than 10, reflecting a large degree of uncer- 4 should incorporate an appreciation that the disa- tainty in this area. It was also noted that ‘There is no bility impact between the ages of 20 and 30 years agreement regarding the list of sequelae that should is a delayed consequence of earlier infection status be included in morbidity assessments. The limited between the ages of 10 and 20 years. availability of empirical evidence about the population distribution and duration of different non-fatal health outcomes… remains a strong limiting factor in the final selection of sequelae [that are to be considered in morbidity burden assessment]’.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 49 Table 1. Disability-associated outcomes significantly linked with schistosomiasis in meta-analysis3

Significantly associated with schistosome Significantly greater with higher Possibly associated, but insufficient infection intensity infection data for meta-analysis, or mixed methodologies used across studies Anaemia Anaemia Decreased religious activity Weight-for-height deficit Skin-fold thickness deficit Decreased personal care Limited exercise duration Diarrhoea Increased health care visits Diarrhoea Decreased cognition History of abdominal or pelvic pain Decreased work yield Exercise intolerance

Currently, the Schistosomiasis Control Initiative lence or severity of disability-linked morbidities, i.e. has initiated schistosomiasis control programmes abdominal pain, diarrhoea, dysuria, infertility, oxy-

in Uganda, Tanzania, Zambia, Burkina Faso, Niger, gen uptake (VO2 max.) deficit, anaemia, malnutri- and Mali. Additional population-based programmes tion (including deficits in weight, height, weight for have been started in Zanzibar and Cameroon. The height, skin fold thickness, per cent body fat, and use of standard operating procedures among pro- serum protein), were compared and integrated for grammes is expected to yield extensive data on summary estimates of infection impact on personal infectious burden and associated morbidity in the performance or conditions previously linked to poor various countries, as well as greater detail on the performance. impact of long-term treatment on morbidity outcomes, including ‘indirect morbidities’ such as mal- Results indicated a significant association between nutrition, anaemia and school performance.7,8 the presence of schistosomiasis infection and anaemia, chronic pain, exercise intolerance, and undernutrition, as compared to local comparison groups META-ANALYSIS OF DISABILITY- (table 1). Based on the summary effect size for hae- RELATED OUTCOMES IN moglobin reduction and the weighted odds-ratio SCHISTOSOMIASIS estimates for categorical outcomes, a proxy schis- Although the abovementioned analyses provide tosomiasis-attributable disability weight could more precise data on the world burden of infection be derived. In place of the 0.005 disability weight and infection-associated clinical findings, it must be applied to schistosomiasis by the Global Burden of considered that there is not necessarily a direct asso- Disease programme, a 2–15% disability was sug- ciation between the presence of a physical deficit or gested in the various functional dimensions of the abnormality and a related disability or handicap. average person with schistosomiasis. Much of the impact of disease depends on the indi- 15 vidual’s adaptation to the morbidity, the presence IMPLICATIONS OF REVISING or absence of co-morbidities, the social context and PREVALENCE ESTIMATES AND potential for stigmatization, and the availability of DISABILITY WEIGHTS support resources.18 The foregoing estimates yield a significant differ- With this in mind, a separate meta-analysis of avail- ence in the quantitative assessment of disease bur- able evidence has been performed for schistosomia- den due to schistosomiasis. If we are to continue sis-related outcomes viewed to be closely related to to work within the DALY system, despite its rec- disability risk among affected populations.3 After ognized limitations, then it is appropriate to utilize extensive structured review of the published and these newer, evidence-based estimates to impute a available unpublished literature from 1921–2002, more sophisticated estimate of disease burden when 135 papers with data linked to individual perform- performing cost-utility analysis. ance outcomes were abstracted and compared. The outcomes of interest included exercise intolerance, The improved, upwardly revised area and country- exercise/play deficit, work yield deficit, house- specific estimates of infection prevalence increase work deficit, personal care deficit, religious activity DALY estimates directly. The suggested 4 to 30-fold deficit, school attendance deficit, school perform- increase in schistosomiasis-related disability weight ance deficit, cognition deficit, increased health care also proportionately increases DALY estimates in a needs. In addition, studies that quantified the preva- direct manner.

50 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 As noted earlier, there is controversy as to whether Miguel and Kremer32 have emphasized the potential age-weighting of DALY outcomes is appropriate in indirect benefits or ‘externalities’ of mass treatment schistosomiasis, given the chronicity of infection and strategies for schistosomiasis and soil-transmitted the long delay between peak infection and the onset helminths. Their analysis indicates that helminth of the more severe forms of morbidity. Elimination treatment programmes can generate community of the controversial DALY age-weighting system, benefits beyond individual response to treatment. which was debated in the GBD programme,15 will These can include reductions in community trans- further increase the DALY estimates for schisto- mission and improved school attendance. In assess- somiasis due to the higher prevalence of infection ing willingness to pay, it is not clear whether effective among children. community treatment will lead to a demand for further treatment.8 Past experience in hookworm erad- In terms of global health burden, the resulting net ication programmes in poor rural areas of the US change in DALY estimates for schistosomiasis will suggests that deworming may be associated with not likely change its ranking behind malaria and TB ultimate improvement in local levels of education in overall impact.4,29 However, the change in disabil- and income.33 Well-designed studies documenting ity weighting does significantly decrease the cost of such an effect in developing countries would be a intervention per DALY prevented, reducing the esti- powerful argument towards the ultimate ‘sustaina- mate from USD 22 to USD 1–6 per DALY averted. bility’ of parasite control. This compares favourably with the Expanded Programme for Immunization (EPI, USD 12–17 per Finally, the question remains whether the DALY is DALY averted) and with other health initiatives in the appropriate metric of schistosomiasis disability. terms of cost for disability prevented. Does common ignorance of the disease and its complications perpetuate its status as a neglected disease of underserved populations? Is the age-weight- UNANSWERED QUESTIONS AND ing system used for DALY calculations appropri- RESEARCH PRIORITIES ate for a chronic condition that may persist for half As the number of large-scale schistosomiasis con- an expected lifetime, with significant lags between trol programmes in sub-Saharan Africa increases, prevalence and the development of advanced infec- a better definition of basic epidemiology and treat- tion-associated disease? ment benefits will emerge for this area. Formal anal- ysis7 should allow comparison to treatment benefits in more developed areas such as Egypt, Brazil and References China,30,31 where control programmes have been in 1. Forsyth DM. A longitudinal study of endemic uri- place for a number of decades. It is expected that nary schistosomiasis in a small East African com- extended analysis of programme outcomes will pro- munity. Bulletin of the World Health Organization, vide better insight into the impact of similar treat- 1969, 40:771-783. ment strategies in different settings, and their specific 2. Farooq M. Medical and economic importance of impact on ‘indirect morbidities’ such as nutrition schistosomiasis. Journal of Tropical Medicine and and school performance.4 New areas for extended Hygiene, 1964, 67:105–112. study should include schistosomiasis effects on cog- 3. King CH, Dickman K, Tisch DJ. Reassessment of nition, maternal and fetal survival, human sexual the cost of chronic helmintic infection: a meta- performance, and fertility. Given the strong social analysis of disability-related outcomes in endemic stigma attached to infertility, more information is schistosomiasis. Lancet, 2005, 365:1561-1569. needed on this aspect of infection-associated mor- 4. Michaud CA, Gordon WS, Reich MR. The glo- bidity. Further, given the important linkage between bal burden of disease due to schistosomiasis. Harvard schistosomiasis risk and socioeconomic status, there Center for Population and Development Studies, is need to better define the levels of individual, fam- Working Paper Series 2004, 14(1). ily, and community impact of treatment. 5. van der Werf MJ et al. Associating community It is important to know what socially important prevalence of Schistosoma mansoni infection with spheres of personal function are actually affected prevalence of signs and symptoms. Acta Tropica, by schistosomiasis infection. A better definition is 2002, 82(2):127–137. needed of subjective perceptions of schistosomia- 6. van der Werf MJ et al. Quantification of clini- sis-associated acute and chronic outcomes.24 In par- cal morbidity associated with schistosome infec- ticular, we need to gauge the differences in patients’ tion in sub-Saharan Africa. Acta Tropica, 2003, own perceptions about schistosomiasis and their 86(2–3):125–139. preferences before and after therapy.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 51 7. Brooker S et al. Evaluating the epidemiologi- 22. Warren KS. Selective primary health care: strate- cal impact of national control programmes for gies for control of disease in the developing world. helminths. Trends in Parasitology, 2004, 20(11):537– I. Schistosomiasis. Reviews of Infectious Diseases, 545. 1982, 4(3):715–726. 8. Southgate VR et al. Towards control of schis- 23. Wamachi AN et al. Increased ratio of tumor tosomiasis in sub-Saharan Africa. Journal of necrosis factor-alpha to interleukin-10 produc- Helminthology, 2005, 79(3):181-185. tion is associated with Schistosoma haemato- 9. Olveda RM. Disease in schistosomiasis japonica. bium-induced urinary-tract morbidity. Journal of In: Mahmoud AAF, ed. Schistosomiasis. London, Infectious Diseases, 2004, 190(11):2020–2030. Imperial College Press, 2001:361-390. 24. Kirigia JM. Economic evaluation in schistosomia- 10. Ouma JH et al. Disease in schistosomiasis manso- sis: valuation of health states preferences. A ni in Africa. In: Mahmoud AAF, ed. Schistosomiasis. research note. Health Economics, 1998, 7(6):551–556. London, Imperial College Press, 2001:333–360. 25. Kirigia JM. Economic evaluation in schistosomia- 11. Prata A. Disease in schistosomiasis mansoni in sis: using the delphi technique to assess effective- Brazil. In: Mahmoud AAF, ed. Schistosomiasis. ness. Acta Tropica, 1997, 64:175–190. London, Imperial College Press, 2001:297–332. 26. Gold MR et al. Cost-effectiveness in health and medi- 12. King CH. Disease in schistosomiasis haematobia. cine. New York, Oxford University Press, 1996. In: Mahmoud AAF, ed. Schistosomiasis. London, 27. Chitsulo L et al. The global status of schistosomia- Imperial College Press, 2001:265–296. sis and its control. Acta Tropica, 2000, 77(1):41–51. 13. Gryseels B. The relevance of schistosomiasis for 28. Steinmann P et al. Schistosomiasis and water public health. Tropical Medicine and Parasitology, resources development: systematic review, meta- 1989, 40(2):134–142. analysis, and estimates of people at risk. Lancet 14. Gold MR, Stevenson D, Fryback DG. HALYS and Infect Diseases, 2006 6(7):411–425. QALYS and DALYS, oh my: similarities and differ- 29. Bergquist NR, Leonardo LR, Mitchell GF. Vaccine- ences in summary measures of population health. linked chemotherapy: can schistosomiasis con- Annual Review of Public Health, 2002, 23:115–134. trol benefit from an integrated approach? Trends in 15. Murray CJL, Lopez AD, eds. The Global Burden Parasitology, 2005, 21(3):112–117. of Disease: a comprehensive assessment of mortali- 30. Zhou XN et al. An economic evaluation of the ty and disability from diseases, injuries, and risk fac- national schistosomiasis control programme in tors in 1990 and projected to 2020. Cambridge MA, China from 1992 to 2000. Acta Tropica, 2005, 96(2– Harvard School of Public Health, 1996. 3):255–265. 16. Anand S, Hanson K. Disability-adjusted life years: 31. Talaat M, Evans DB. The costs and coverage of a critical review. Journal of Health Economics, 1997, a strategy to control schistosomiasis morbidi- 16(6):685–702. ty in non-enrolled school-age children in Egypt. 17. Arnesen T, Nord E. The value of DALY life: Transactions of the Royal Society of Tropical Medicine problems with ethics and validity of disabili- Hygiene, 2000, 94(4):449–454. ty adjusted life years. British Medical Journal, 1999, 32. Miguel E, Kremer M. Worms: identifying impacts 319(7222):1423–1425. on education and health in the presence of treat- 18. Reidpath DD et al. Measuring health in a vacu- ment externalities. Econometrica, 2004, 72:159–217. um: examining the disability weight of the DALY. 33. Bleakley H. Disease and development: evidence Health Policy and Planning, 2003, 18(4):351-356. from the American south. Journal of the European 19. Schwappach DL. Resource allocation, social values Economic Association, 2003, 1:376–386. and the QALY: a review of the debate and empirical evidence. Health Expectations, 2002, 5(3):210– 222. 20. Hunt SM. Cross-cultural issues in the use of quality of life measures in randomized controlled trials. In: Staquet MJ, Hays RD, Fayers PM, eds. Quality of life assessment in clinical trials: methods and practice. Oxford, Oxford University Press, 1998:51–67. 21. Warren KS et al. Quantification of infection with Schistosoma haematobium in relation to epidemiology and selective population chemotherapy. I. Minimal number of daily egg counts in urine necessary to establish intensity of infection. Journal of Infectious Diseases, 1978, 138:849–855.

52 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 WORKING PAPER 5. sis plays in them can only be analysed through dou- 10,11 Schistosomiasis in women ble-blind placebo-controlled trials. Through these and other studies, we now appreciate that the bur- of childbearing age, den of disease is far greater than was originally including in pregnancy suspected. In addition, we recognize particularly vulnerable groups who are at high risk for the mor- G. Richard Olds bid effects, including growing children, all women The Linda and John Mellowes Professor and Chairman, of childbearing age, and individuals with an iron Department of Medicine, Medical College of Wisconsin, deficient or nutritionally poor diet. Other high risk Milwaukee, Wisconsin, USA. groups include individuals who are already mal- nourished, and those of low social and economic status. The last quarter century has brought significant change to the field of schistosomiasis.1–3 Prior to With this as a background, it is disturbing that the 1980, the only available treatment for this helminth issue of treatment of pregnant women with PZQ infection was toxic and required injections. With remains unresolved.12,13 Despite no in vitro or ani- the introduction of praziquantel (PZQ), single-dose mal evidence for an adverse effect on either the oral treatment became a reality but the high initial pregnant mother or her unborn child, praziquan- price (2–3 US$ per dose) limited its broad applica- tel was released as a category B drug, assumed tion in endemic countries. Today, PZQ remains safe safe in animals but not tested in humans. This has and highly effective and has been used effectively almost universally been interpreted by national con- against all human schistosome species. The fall in trol programmes as a reason to withhold treatment price of PZQ (to around US cents 3 a tablet) has lead from pregnant women until after delivery. In some to growth in national control programmes based on extreme cases, this issue has lead to deworming pro- periodic mass applications to targeted populations.2 grammes being limited to pre-menarche ages for The use of PZQ in this way has reduced, but clearly women. This is a particularly disturbing result since not eliminated, morbidity induced by this parasite. most women in schistosomiasis endemic countries It has also lead to a marked reduction in intensity are at high risk for anaemia.14,15 of infection, and modest reductions in prevalence of infection, but to little impact on transmission. At least one attempt was made during the last dec- Effective control programmes in Asia and South ade to perform an appropriate double-blind pla- America, combined with the rapid development of cebo-controlled trial to resolve this issue, but it was water resources in Africa (irrigation schemes and blocked by ministry of health officials. A second dams), has changed the worldwide distribution of trial has recently been funded by the US National schistosome induced morbidity, which is now pri- Institutes of Health but has not received in-coun- marily focused in sub-Saharan Africa.2 try institutional review board approval (Kurtis, personal communication). The issue was identified Our thinking about morbidity induced by schisto- as high priority by the last WHO expert commit- somiasis has also undergone significant change over tee which published its recommendations in 2002.2 the last quarter century.4–5 Most research prior to the Based on these recommendations, a WHO informal 1980s focused on the end organ fibrotic changes in consultation on the use of PZQ during pregnancy/ the liver and urinary bladder, unique to infection lactation was convened and its recommendations with this parasite. In general, these morbid sequelae published the same year. Despite these efforts, many take years to develop and have been significantly national control programmes continue to withhold impacted by periodic treatment of populations with treatment for pregnant women. Below I will attempt PZQ. This type of thinking, however, has lead to a to outline what is currently known about women significant underestimation of the true impact that of childbearing age as a high risk group for schisto- schistosomiasis has on infected populations. This some induced morbidity, including the unique risk underestimation of DALYs has recently been out- they have during pregnancy. I will then review the lined by King et al.6 More subtle morbidity induced potential impact of infection on the unborn child. I by the parasite affects a much larger percentage of will build on the arguments outlined in an article the infected population and persists despite periodic commissioned for the WHO informal consultation12 treatment; this includes anaemia, growth stunting, and published in 2003.13 cognitive impairment, and decreases in functional work capacity.6–10 Because many infectious patho- Women historically have been thought to be at lower gens as well as micronutrient deficiencies contribute risk for schistosomiasis induced end organ morbid- to these problems, the unique role that schistosomia- ity because, epidemiologically, the prevalence and

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 53 intensity of schistosome infection was observed Anaemia is caused by a variety of factors. The associ- to be lower in women than in men. This was most ation between anaemia and schistosomiasis has been striking with S. haematobium and least obvious in strongly suggested by several cross-sectional stud- populations exposed to S. japonicum. Despite these ies and is most marked in areas in which the over- facts, women of childbearing age in Africa continue all prevalence of anaemia is high and dietary iron is to undergo significant exposure to schistosomiasis. low.15,18,19 Anaemia due to schistosomiasis is unique in that at least part of the anaemia is induced by With the introduction of national control pro- chronic inflammation.14 As a result, in the two dou- grammes, many women of childbearing age were ble-bind placebo-controlled trials using PZQ, curing not treated or had treatment delayed due to the a patient with schistosomiasis not only arrested the pregnancy/lactation issue. In a study from the fall in haemoglobin but actually resulted in a rise in Philippines, 30% of infected women between the that value, even without iron supplementation.10,11 ages of 16 and 30 went untreated over this issue.16, 13 Interestingly, treatment of hookworm infection in In a survey from Tanzania,15 less than 10% of the one of these trials did not affect serum haemoglob- infected women had been offered treatment in the ins.10 In addition, a positive effect of PZQ treat- last year while many had never been treated. ment was observed, even in individuals who were thought to be free of infection based on two stool In addition, the introduction of school-based treat- examinations.10 The authors concluded that treatment programmes has introduced school enrolment ment of even very light schistosome infections can as a potential barrier to treatment. In many coun- be beneficial to the patient’s haemoglobin. tries women are underrepresented among primary and secondary school attendees. Even when pro- Pregnancy is particularly likely to negatively impact grammes are in place to find and treat non-enrolled the nutritional status of the mother and to exacer- students, coverage is likely to be less for those who bate anaemia. Over half the pregnant women in are not enrolled. In all of these settings, women developing countries are anaemic, and many are may be suffering the classical end organ morbidity severely so.17 In a recent study in Tanzania,15 Simon induced by infection at a higher frequency. Brooker and his colleagues examined almost a thou- sand women 15–45 years of age attending a prena- When we examine populations for schistosome tal clinic in an area endemic for Schistosoma mansoni, induced subtle morbidity, women are clearly at hookworm and malaria. In this cross sectional study, significant risk for the development of anaemia S. mansoni prevalence was 64%, and hookworm 56%, compared to their male counterparts.17 This is com- while 31% had dual infections. Sixteen women had pounded in communities that are also endemic positive smears for falciparum malaria. The preva- for other diseases in which anaemia is a common lence of anaemia was 66%, with an increasing preva- sequela, such as hookworm or malaria.15 In coun- lence occurring during the course of pregnancy (72% tries with marginal nutritional resources, women for women in their last trimester). Haemoglobin may also be at greater risk for other forms of sub- concentration decreased (p = 0.02) with increasing tle morbidity including growth stunting, impaired intensity of schistosome infection. Hookworm infec- cognitive development and decreased functional tion was statistically unrelated to haemoglobin lev- work capacity. Recently several new studies have els. Women with positive malaria smears had lower started to examine this issue specifically as it relates absolute haemoglobin levels but this difference did to women. not reach statistical significance. A table of the odds ratios of the risk of anaemia in this population is Anaemia is the number one health problem of shown below (table 1). women throughout the world.17 It is estimated that there are over two billion people in the world with In an ongoing study of pregnant women infected anaemia, most of whom are iron deficient. There are with schistosomiasis (unpublished data), Friedman another 1.6 billion people who are iron deficient but and Kurtis report that pregnant women infected not yet anaemic. In developing countries almost half with S. japonicum have significantly higher trans- the women are iron deficient. Anaemic women have ferrin receptor levels and significantly lower ferritin decreased work capacity and increased absentee- levels at 32 weeks gestation than uninfected preg- ism. Anaemic pregnant women are more likely to nant controls. They have concluded that pregnant become septic and to haemorrhage, while anaemia is women infected with schistosomiasis have both iron a major cause of maternal mortality. Maternal anae- deficiency and anaemia of chronic disease. mia is a major cause of low birth weight and malnutrition in infants. Anaemic children have impaired It has been particularly hard to find studies on schis- intellectual and physical development. tosomiasis and pregnancy that look at the potential

54 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 negative impact of schistosomiasis on the unborn fully performed, double-blind placebo-controlled child. In the 1990s, it was shown that mice infected trial. This is particularly so since national control with schistosomiasis had a decreased number of via- programmes have been slow to adapt new WHO ble litters, increased maternal deaths, and increased guidelines. In addition however, we need to know spontaneous abortions. Offspring born to infected whether curative chemotherapy reverses the above mothers were stunted. In a study in Ghana, S. hae- parameters during all three trimesters of pregnancy. matobium infection during pregnancy was associated The potential link between inflammation and low with increased risk of premature birth and low birth birth weight needs to be examined carefully. I am weight. Five other studies have reported negative reminded of a phenomenon now known as ‘rebound birth outcomes attributable to schistosomiasis. In an morbidity’ in schistosomiasis.4 Infected humans unpublished ongoing study, Friedman and Kurtis dampen their inflammatory response to chronic have found, in the first 97 pregnant women stud- schistosomiasis infection over time in an attempt to ied, a 460-gram decrease in birth weight of infants limit pathology. As a consequence, curative treat- born to moderately infected women as compared to ment followed by rapid reinfection has been shown lightly or uninfected women. to induce short-term increases in schistosomiasis induced inflammation and morbidity. This takes the form of increased frequency of hepatic enlargement Table 1. Multivariate logistic regression model of sig in S. japonicum and enhanced obstruction as assessed nificant variables associated with the risk of anaemia by ultrasound in S. haematobium on re-infection in among pregnant women in north-western Tanzania* areas with very high transmission. This was demonstrated in a high transmission area of the Philippines Variable Adjusted odds P values where the pretreatment incidence of hepatic ratios (95% CI)a enlargement was 15%–20%.16,13 In this epidemio- S. mansoni infection logical setting the incidence of hepatic enlargement 0–99 epg 1.0 on re-infection is almost universal if re-treatment 100–399 epg 1.04 (0.73–1.48) 0.827 is delayed by more than a year. Superimposed on >400 epg 1.87 (1.07–3.27) 0.026 this graph is the duration of pregnancy. If excessive Age group inflammation observed on re-infection is linked to <20 years 1.0 growth stunting, then re-infection during the last 20–29 years 0.55 (0.35–0.85) 0.007 trimester of pregnancy could represent a particular >30 years 0.47 (0.29–0.74) 0.002 risk to the unborn child. Trimester First 1.0 The granulomatous inflammation found in schis- Second 2.81 (1.79–4.42) <0.001 tosomiasis lasts for several months after the adult worms have been killed since the ova persist in the Third 4.17 (2.76–6.31) <0.001 tissues. In addition, curative chemotherapy kills a. Odds ratios adjusted for age, health centre, hookworm, malaria, trimester, adult worms, which evokes a significant amount of education, and employment inflammation in the host directed at the dying adult epg: eggs per gram of faeces * Reprinted from Ajanga A et al. Schistosoma mansoni in pregnancy and worms. This short-term increase in inflammation in associations with anaemia in northwest Tanzania. Transactions of the Royal the mother could adversely affect the growth and Society of Tropical Medicine and Hygiene, 2006, 100(1):59–63, with permission from the Royal Society of Tropical Medicine and Hygiene. development of the child. I am reasonably certain that treatment is good for a mother infected with schistosomiasis. The potential benefit to the unborn Friedman and Kurtis have also demonstrated child of treatment however can only be determined higher maternal serum TNF-alpha and Il-6 levels in by a carefully carried out clinical trial. It is possible mothers with moderate infections, and found IFN- that we need to keep pregnant women completely gamma levels in the placenta to correlate with low free of infection throughout pregnancy, i.e. by treat- birth weight (Kurtis et al unpublished data). These ing them multiple times over a nine-month period. insights taken together suggest that women infected Because of the extra sensitivity involved in studies with schistosomiasis have smaller birth weight of this type, I would suggest an outside monitor for children in part because of placental inflammation such a trial. associated with schistosomiasis infection. All these studies suggest that schistosomiasis is likely to be In summary, despite several years of intensified detrimental to the unborn fetus. interest in this topic by WHO, we need more targeted studies on the impact of schistosomiasis on To resolve this issue, clearly what is needed is a care- women. These need to be longitudinal and focus on the impact of treatment on the morbid parameters.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 55 This is particularly important as it relates to anae- 8. Nokes K et al. Evidence for an improvement mia and work capacity. Anaemia is an enormous in cognitive function following treatment of problem in the developing world, but iron supple- Schistosoma japonicum infection in Chinese pri- mentation has many limitations. Aggressive chem- mary school children. American Journal of Tropical otherapy of schistosomiasis will likely significantly Medicine and Hygiene, 1999, 60(4):556–565. improve anaemia in any country endemic for this 9. Stephenson LS. The impact of schistosomiasis on disease. In addition, female children, who carry a human nutrition. Parasitology, 1993, 107:S107–S123. significant lifetime risk for anaemia, should also 10. Olds GR et al. Double-blind placebo-control- be targets for aggressive deworming programmes, led study of concurrent administration of alben- both before and after menarche. The situation with dazole and praziquantel in schoolchildren with pregnant women and schistosomiasis is a partic- schistosomiasis. Journal of Infectious Diseases, 1999, ularly sensitive issue. I feel this issue can only be 179:996–1003. addressed by a careful placebo-controlled trial which 11. McGarvey ST et al. Schistosomiasis japonica and needs to be performed now, across all three species childhood nutritional status in northeastern Leyte, and in different environmental settings. Although I The Philippines: A randomized trial of praziqu- am reasonably confident that schistosomiasis is bad antel versus placebo. American Journal of Tropical for both mother and child, the impact of treatment Medicine and Hygiene, 1996, 54(5):498–502. on the morbid parameters is less clear. It is likely 12. Report of the WHO informal consultation on the use that treatment will significantly benefit the mother of praziquantel during pregnancy/lactation and alben- at any time during pregnancy. Despite the fact that dazole/mebendazole in children under 24 months. I feel PZQ is completely safe for the unborn infant, Geneva, World Health Organization, 2002 (WHO/ recent studies on the relationship between mater- CDS/CPE/PVC/2002.4). nal inflammation and birth outcomes suggest that 13. Olds GR. Administration of praziquantel to preg- a careful study needs to be performed to assess the nant and lactating women. Acta Tropica, 2003, 86(2– true impact of treatment on schistosomiasis of the 3):185–195. unborn child. 14. Friedman JF, Kanzaria HK, McGarvey ST. Human schistosomiasis and anemia: the relationship and potential mechanisms. Trends in Parasitology, 2005, References 21(8):386–392. 1. Ross AGP et al. Schistosomiasis: a clinical per- 15. Ajanga A et al. Schistosoma mansoni in pregnan- spective. New England Journal of Medicine, 2002, cy and associations with anaemia in northwest 346(16):1212–1220. Tanzania. Transactions of the Royal Society of Tropical 2. Prevention and control of schistosomiasis and soil- Medicine and Hygiene, 2006, 100(1):59–63. transmitted helminthiasis. Report of a WHO expert 16. Olveda RM et al. Schistosomiasis japonica in the committee. Geneva, World Health Organization, Philippines: the long-term impact of population- 2002 (WHO Technical Report Series, No. 912). based chemotherapy on infection, transmission, 3. Olds GR, Dasarathy S. Recent advances in schis- and morbidity. Journal of Infectious Diseases, 1996, tosomiasis. Current Infectious Disease Reports, 2001, 174:163–172. 3(1):59–67. 17. The world health report. Geneva, World Health 4. Olds GR et al. Immunity and morbidity in schisto- Organization, 2004. somiasis japonicum infection. American Journal of 18. Kanzaria HK et al. Schistosoma japonicum and Tropical Medicine and Hygiene, 1996, 55(5):121–126. occult blood loss in endemic villages in Leyte, the 5. Olds GR, Dasarathy S. Schistosomiasis. Current Philippines. American Journal of Tropical Medicine Treatment Options in Infectious Diseases, 2000, 2:88– and Hygiene, 2005, 72(2):115–118. 99. 19. Sturrock RF et al. Schistosomiasis mansoni in 6. King CH, Dickman K, Tisch D. Reassessment of Kenya: relationship between infection and anae- the cost of chronic helmintic infection: a meta- mia in schoolchildren at the community level. analysis of disability-related outcomes in endemic Transactions of the Royal Society of Tropical Medicine schistosomiasis. The Lancet, 2005, 365:1561–1569. and Hygiene, 1996, 90(1):48–54. 7. Ezeamama A et al. Functional significance of low intensity polyparasite helminth infections in anemia. Journal of Infectious Diseases, 2005, 192(12):2160–2170.

56 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 WORKING PAPER 6. rational, effective and safe way and to develop new Measuring tools for control. schistosomiasis morbidity ASSESSMENT OF MORBIDITY Ultrasonography has proven its value as a safe, Birgitte J. Vennervald 1 and David W. Dunne 2 rapid and non-invasive technique for morbidity 1 DBL, Institute for Health, Research and Development, assessment in schistosomiasis. The technique has Charlottenlund, Denmark the invaluable advantage of directly visualizing the 2 Department of Pathology, University of Cambridge, UK organ-specific schistosomiasis-associated changes seen in the liver and urinary bladder, as well as additional disease complications such as portal hypertension and hydronephrosis (Richter, 2003; INTRODUCTION Hatz, 2001; Richter et al., 2003). Furthermore, WHO The World Health Assembly recognition of the pub- sponsored expert meetings have produced valuable lic health problems caused by schistosome infections standardized ultrasound protocols for the quantifi- promotes efforts towards schistosomiasis morbid- cation of morbidity in S. haematobium and S. mansoni ity control. The control strategy recommended by infections, and the development of standardized WHO is aimed at reducing the morbidity caused by protocols for evaluation of Asian schistosomiasis schistosomiasis. morbidity is in progress (Richter et al., 2003; Niamey Working Group, WHO, 2000). In order to make headway in the control of morbidity we must try to answer the following questions: Urinary schistosomiasis, caused by S. haematobium, what do we define as schistosomiasis related mor- affects the genitourinary tract with egg deposition bidity, how do we measure it, what is the impact in the urinary bladder wall although the reproduc- of the detected morbidity on the health of affected tive organs may also be involved. Late-stage conse- communities, what other factors might influence the quences may include hydronephrosis and possible level of morbidity in an endemic setting, and how predisposition to urinary bladder cancer. Studies can we measure the impact of treatment or interven- from different S. haematobium endemic settings in tion on morbidity? Kenya, Tanzania, Ghana and Niger using the standardized protocol have shown that reversal of urinary Another important question is what implications tract morbidity occurs within six months of treat- the ‘direct morbidity’ has at the community level ment, and that the rate of reappearance of urinary and whether we are measuring anything relevant to tract morbidity depends on the level of re-infection the health and well-being of the population. It is of (Kahama et al., 1999; Hatz et al., 1998; Wagatsuma et interest to know if people feel sick and unwell and if al., 1999; Campagne et al., 2001). there is a direct relation between what we can measure and the well-being of people. In other words can Though classical autopsy studies in Brazil unequiv- we assess the ‘feeling sick’? ocally linked the development of S. mansoni hepatosplenic schistosomiasis (HS), portal hypertension In order to control morbidity we need tools which and its severe sequelae with gross periportal fibro- can assist in monitoring the effect of an interven- sis, recent ultrasound and clinical studies in Africa tion on the level of morbidity. Preferably this should suggest that HS can also be found in S. mansoni- work both on a short-term and a long-term basis infected children in the absence of gross hepatic and be simple, non-invasive and non-expensive. It fibrosis (Vennervald et al., 2004). Many of the chil- would be an added advantage if the risk of re-devel- dren presented with evidence of increased portal oping severe morbidity after an intervention could pressure, but none had ultrasound detectable peri- be predicted. portal fibrosis. This combination does not currently feature in the diagnostic algorithm given by WHO Morbidity assessment tools are essential in control (Niamey Working Group, WHO, 2000). but it is important to keep in mind that they are also needed as research tools. We need new tools that Other studies have also reported evidence of portal can tell us more about the pathogenesis of schisto- hypertension in the absence of ultrasound detecta- somiasis including the mechanisms of both develop- ble peri-fibrosis. In a study from Kenya and Egypt ment and regression of morbidity in order to deliver involving ultrasound examination of 3954 indi- chemotherapy and other interventions in the most viduals and using the Niamey height-indexed criteria (Niamey Working Group, WHO, 2000) for

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 57 portal vein enlargement, King et al. (2003) found as a disease with important individual and public that 14% of Kenyans with a normal liver texture pat- health consequences (Leutscher et al., 1997), while S. tern met the criteria for portal vein enlargement. In haematobium eggs can be detected in semen samples Madagascar, ultrasonographic observations typical from men with S. haematobium infection indicating for portal hypertension but without any observable that the genitals are a common site of egg deposi- liver texture abnormalities or measurable peri-portal tion (Leutscher et al., 2000). Genital schistosomiasis thickening were made in 37 individuals, represent- is receiving increased attention because it is poten- ing 4.3% of the study cohort (Boisier et al., 2001). In tially a risk factor for a number of sexually trans- contrast to the study by King et al. (2003), Boisier et mitted diseases including HIV (Lawn, 2004). Genital al. (2001) used height adjusted reference values for schistosomiasis poses a problem for proper diagno- portal vein diameter obtained from a Malagasy pop- sis and it is worth noting that urine examination is ulation. Together, these observations suggest that not very valid since egg excretion in urine is often the current WHO guidelines may need revision. very low or absent in adults with genital schistosomiasis (Poggensee et al., 2000). The main problems concerning the use of ultrasonography in control programmes are the rela- In S. haematobium infection, detection of eosinophil tively high cost of the equipment, the need for well cationic protein (ECP) in urine has proven to be a trained examiners preferably with a medical, radi- valuable marker for urinary bladder inflammation ography or similar qualification, and the need for with the potential to reveal signs of early inflamma- adequate quality control procedures. tion and morbidity (Reimert et al., 2000). ECP has been evaluated as a morbidity marker for female There is still a need for simple and inexpensive genital schistosomiasis (FGS); increased levels of tools for morbidity assessment. One way of assess- ECP were detected in vaginal lavage samples from ing morbidity may be simply to ask subjects about women with FGS compared to endemic controls. the presence of signs and symptoms of morbid- However, the sensitivity of this diagnostic method ity associated with schistosomiasis. Generally this was reported to be low (Midzi et al., 2003). Studies works very well for haematuria associated with S. that assessed ECP in faecal samples as a marker haematobium infection among schoolchildren, but in of intestinal morbidity in S. mansoni infection a Tanzanian study that examined schistosomiasis- have yielded promising preliminary results (C.M. related perceptions, attitudes and treatment-seeking Reimert, personal communication). practices, it was found that the perceived causes and symptoms were incongruous with the biomedical FACTORS INFLUENCING THE LEVEL perspective. In this study, a number of respondents reported schistosomiasis to be a shameful disease OF MORBIDITY (Mwanga et al., 2004), an attitude that may lead When measuring the level of morbidity, it is impor- to underreporting of symptoms. This approach of tant to know to what extent the results can be gen- directly questioning subjects is more problematic eralized within the community as well as to a larger for intestinal schistosomiasis, where symptoms such geographical area, since a number of factors such as as diarrhoea and blood in the stool are often also degree and length of exposure (Booth et al., 2004[a]), associated with conditions other than schistosomia- intensity of infection (Kabatereine et al., 2004[a]), sis (Kabatereine et al., 2004[a]; van der Werf et al., and co-infections with malaria (Booth et al., 2004[b]), 2004). may influence both the development and the level of morbidity in an exposed population. Enlargement of the liver and/or spleen is commonly detected with schistosomiasis mansoni (Kabatereine Geographic information system (GIS) technology is et al., 2004[a]), and has recently been reported to increasingly being applied to the study of schisto- occur even in the absence of periportal fibrosis somiasis. This powerful tool for mapping the spa- (Vennervald et al., 2004). Assessment of the degree tial distribution of infection and disease is now of organ enlargement by simple clinical examination starting to generate important data for use in both may be a useful tool. A standardized method of clin- basic morbidity research and the development of ical scoring that takes organ consistency into account more effective and efficient national control pro- has recently been described (Vennervald et al., 2004) grammes (Kabatereine et al., 2004[b]; Handzel et al., and has proven useful in post-treatment assessment 2003; Clennon et al., 2004), and can provide valua- of regression of organ enlargement (Vennervald et ble information about risk of exposure and co-infec- al., 2005). tion on a micro-geographical scale. This is important in view of the very focal nature of schistosomiasis Genital schistosomiasis in women is now viewed infection and disease.

58 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Malaria and schistosomiasis are often geographi- PZQ on the severe consequences of schistosomiasis cally co-endemic in sub-Saharan Africa, and co-infec- mansoni such as portal hypertension and oesopha- tions with these parasites are common in school-age geal varices. children, the main target group for schistosomiasis control programmes. Both infections may cause CONCLUSIONS enlargement of the liver and/or spleen, and an exac- erbating effect of relatively high exposure to both The increased focus on conditions such as malaria, malaria and S. mansoni infections on splenomeg- AIDS and tuberculosis, that cause either severe acute aly has been demonstrated in a study in which GIS disease or high levels of mortality, has resulted in spatial analysis was combined with detailed clinical relative neglect of infections such as schistosomia- and ultrasound examination (Booth et al., 2004[b]). sis. With the Schistosomiasis Control Initiative, focus IgG3 responses to malaria schizont antigen, a proxy has been redirected towards schistosomiasis control. for exposure to malaria, were higher in Kenyan chil- However, control strategies should be evidence- dren with S. mansoni infection and hepatosplenom- based and field research is necessary to determine egaly compared with infected controls (Mwatha et the impact of an intervention on the morbidity level. al., 2003), and results from a study in Kenya indi- Scientific evidence that allows accurate evaluation cate that the benefits of treating hepatosplenome- of what works, what does not work, and the reasons galy with praziquantel (PZQ) will depend on the why, is crucial for the development of efficient and level of exposure to malaria (Booth et al., 2004[c]). cost-effective strategies to ensure long-term reduction in disease levels in target populations. POST-INTERVENTION ASSESSMENT Significant advances have been achieved in our The key tool in schistosomiasis morbidity control is understanding of the epidemiology of schistosomia- treatment with PZQ, and, with the major ongoing sis and the various factors that may influence the control initiatives (Fenwick et al., 2003), this drug morbidity level. However, there is need for greater will be used extensively in many schistosomiasis understanding of the morbidity mechanisms and for endemic countries in the coming years. In a com- better tools for morbidity assessment. Good research prehensive review, Utzinger and Keiser (Utzinger is vital to sustainable disease control, and advances and Keiser, 2004) described the current drugs avail- in the laboratory, even if not immediately applicable able for morbidity control and covered aspects of to control efforts, are needed to improve our under- therapeutic efficacy and adverse events in clinical standing of the disease and develop new tools for schistosomiasis. morbidity assessment and control.

Several studies have examined the effect of treat- It is also important to strengthen research capacity ment on S. mansoni related organomegaly, periportal in endemic countries and to support the many good fibrosis and other ultrasound detectable parame- scientists from these countries. One of the advances ters (Boisier et al., 1998; Doehring-Schwerdtfeger et in morbidity assessment has been the increase in al.,1992; Frenzel et al., 1999), and one study has number of ultrasonographers from endemic coun- compared ultrasonography and detailed clini- tries trained in assessment of schistosomiasis mor- cal examination in measuring morbidity regres- bidity. It is vital for the sustainability of control sion (Vennervald et al., 2005). In this study a steady efforts that local capacity is created, and that this decrease of the organomegaly among children with capacity participates in the control programmes and HS was demonstrated up to three years after treat- assists in the training of new people. Any support ment with PZQ. There was however a significant for further training and exchange between ultra- difference in the rate of organ regression between sonographers from endemic areas would be very children who became egg negative after treatment valuable. as compared to children who remained egg positive, but where intensity of infection decreased markedly MAIN POINTS AND CONCLUSIONS (own unpublished results). • The absence of gross or ultrasound detectable Most previous studies have assessed the effect of fibrosis does not exclude the possible presence of treatment over a relatively short follow-up period severe morbidity in S. mansoni infected patients. and often among children only. It is therefore impor- • Chronic co-exposure to schistosomiasis mansoni tant to assess the long-term effect of PZQ treatment and malaria may influence both the level of mor- with follow-up studies more than five years after bidity and the measurement of morbidity: treatment among populations living in areas of – by affecting the severity of HS morbidity intense transmission in order to assess the impact of

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 59 – by affecting the regression of morbidity after Campagne G et al. Continued ultrasonic follow-up of PZQ treatment children infected with Schistosoma haematobium after – by confounding the assessment of morbidity. treatment with praziquantel. Tropical Medicine and • There is geographical variation (at the macro International Health, 2001, 6:24–30. and micro-geographical levels) in the severity of Clennon JA et al. Spatial patterns of urinary schisto- schistosomiasis associated morbidity, and it is somiasis infection in a highly endemic area of coast- likely that many external environmental factors al Kenya. American Journal of Tropical Medicine and have important roles in determining the severity Hygiene, 2004, 70:443–448. of morbidity associated with schistosomiasis. • Inflammatory markers may prove to be impor- Doehring-Schwerdtfeger E et al. Ultrasound versus tant parameters for the assessment of a variety of clinical examination as indication for Schistosoma man- schistosomiasis associated morbidities. soni associated morbidity in children. Tropical Medicine • Ultrasonography is useful as a tool for morbid- and Parasitology, 1992, 43(4):245–248. ity assessment of several different schistosomia- Fenwick A et al. Drugs for the control of parasitic dis- sis-associated conditions. However, the capacity eases: current status and development in schisto- to apply this technique locally in schistosomia- somiasis. Trends in Parasitology, 2003, 19:509–515. sis endemic countries needs to be developed as a priority in order to make full use of its potential. Frenzel K, et al. Evidence for a long-term effect of a • Other types of pathology may be of significance single dose of praziquantel on Schistosoma mansoni- in populations living in endemic areas, e.g. intes- induced hepatosplenic lesions in northern Uganda. tinal morbidity associated with schistosomiasis American Journal of Tropical Medicine and Hygiene, 1999, mansoni and japonicum remains almost com- 60(6):927–931. pletely unstudied and is likely to be of signif- Handzel T et al. Geographic distribution of schisto- icance, particularly in situations where other somiasis and soil-transmitted helminths in Western factors such as co-exposure to intestinal parasites Kenya: implications for anthelminthic mass treatment. and/or malnutrition are present. American Journal of Tropical Medicine and Hygiene, 2003, 69:318–323. Hatz CF et al. Evolution of Schistosoma haematobium- References related pathology over 24 months after treatment with Boisier P et al. Geographic differences in hepat- praziquantel among school children in southeast- osplenic complications of schistosomiasis mansoni ern Tanzania. American Journal of Tropical Medicine and and explanatory factors of morbidity. Tropical Medicine Hygiene, 1998, 59:775–781. and International Health, 2001, 6:699–706. Hatz CFR. The use of ultrasound in schistosomiasis. Boisier P, et al. Reversibility of Schistosoma mansoni- Advances in Parasitology, 2001, 48:225–284. associated morbidity after yearly mass praziquantel Kabatereine NB et al. Epidemiology and morbidity therapy: ultrasonographic assessment. Transactions of of Schistosoma mansoni infection in a fishing commu- the Royal Society of Tropical Medicine and Hygiene, 1998, nity along Lake Albert in Uganda. Transactions of the 92(4):451–453. Royal Society of Tropical Medicine and Hygiene, 2004[a], Booth M et al. Hepatosplenic morbidity in two neigh- 98:711–718. bouring communities in Uganda with high levels of Kabatereine NB et al. Epidemiology and geography of Schistosoma mansoni infection but very different dura- Schistosoma mansoni in Uganda: implications for plan- tions of residence. Transactions of the Royal Society of ning control. Tropical Medicine and International Health, Tropical Medicine and Hygiene, 2004[a], 98:125–136. 2004[b], 9:372–380. Booth M et al. Micro-geographical variation in expo- Kahama AI et al. Urine circulating soluble egg anti- sure to Schistosoma mansoni and malaria, and exac- gen in relation to egg counts, hematuria, and urinary erbation of splenomegaly in Kenyan school-aged tract pathology before and after treatment in chil- children. BMC Infectious Diseases, 2004[b], 4:13. dren infected with Schistosoma haematobium in Kenya. Booth M et al. Exposure to malaria affects the regres- American Journal of Tropical Medicine and Hygiene, 1999, sion of hepatosplenomegaly after treatment for 61:215–219. Schistosoma mansoni infection in Kenyan children. BMC Medicine, 2004[c], 2:36.

60 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 King C H et al. Measuring morbidity in schistosomia- Utzinger J, Keiser J. Schistosomiasis and soil-trans- sis mansoni: relationship between image pattern, mitted helminthiasis: common drugs for treatment portal vein diameter and portal branch thickness in and control. Expert Opinion on Pharmacotherapy, 2004, large-scale surveys using new WHO coding guide- 5:263–285. lines for ultrasound in schistosomiasis. Tropical van der Werf MJ et al. Measuring schistosomiasis Medicine and International Health, 2003, 8:109–117. case management of the health services in Ghana and Lawn SD. AIDS in Africa: the impact of coinfections Mali. Tropical Medicine and International Health, 2004, on the pathogenesis of HIV-1 infection. Journal of 9(1):149–157. Infection, 2004, 48:1–12. Vennervald BJ et al. Detailed clinical and ultra- Leutscher P et al. Clinical findings in female genital sound examination of children and adolescents in a schistosomiasis in Madagascar. Tropical Medicine and Schistosoma mansoni endemic area in Kenya: hepat- International Health, 1997, 3:327–332. osplenic disease in the absence of portal fibrosis. Tropical Medicine and International Health, 2004, 9:461– Leutscher P et al. Community-based study of genital 470. schistosomiasis in men from Madagascar. Lancet, 2000, 355(9198):117–118. Vennervald BJ et al. Regression of hepatosplenomegaly in Kenyan school-aged children after praziqu- Midzi N et al. Assessment of eosinophil cationic pro- antel treatment and in the absence of re-infection by tein as a possible diagnostic marker for female geni- Schistosoma mansoni. Transactions of the Royal Society of tal schistosomiasis in women living in a Schistosoma Tropical Medicine and Hygiene, 2005, 99:150–160. haematobium endemic area. Parasite Immunology, 2003, 25:581–588. Wagatsuma Y et al. Resolution and resurgence of Schistosoma haematobium-induced pathology after com- Mwanga JR et al. Schistosomiasis-related perceptions, munity-based chemotherapy in Ghana as detect- attitudes and treatment-seeking practices in Magu ed by ultrasound. Journal of Infectious Diseases, 1999, district, Tanzania: public health implications. Journal of 179:1515–1522. Biosocial Science, 2004, 36:63–81. Mwatha JK et al. Associations between anti- Schistosoma mansoni and anti-Plasmodium falciparum antibody responses and hepatosplenomegaly, in Kenyan schoolchildren. Journal of Infectious Diseases, 2003, 187:1337–1341. Niamey Working Group. Ultrasound in schistosomiasis: a practical guide to the standardized use of ultrasonography for 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 of the lower genital tract: prevalence and disease-associated morbidity in Northern Tanzania. Journal of Infectious Diseases, 2000, 181:1210–1213. Reimert CM et al. Quantitative assessment of eosi- nophiluria in Schistosoma haematobium infections: a new marker of infections and bladder morbidity. American Journal of Tropical Medicine and Hygiene, 2000, 62:19–28. Richter J. The impact of chemotherapy on morbidity due to schistosomiasis. Acta Tropica, 2003, 86:161–183. Richter J, Hatz C, Haussinger D. Ultrasound in tropical and parasitic diseases. The Lancet, 2003, 362:900– 902.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 61 WORKING PAPER 7. • Definition or development of a serologic test for Clinical schistosomiasis diagnosis. • Definition of a histologic pattern of granuloma in the liver characteristic of the acute phase of José Roberto Lambertucci schistosomiasis. Universidade Federal de Minas Gerais, Estudos de • Definition of the best approach to treatment Medicina Experimental, Núcleo de Estudos Sobre (schistosomicides plus steroids). Esquistos, Belo Horizonte, Brazil

Table 1. Clinical classification of schistosomiasis mansoni The clinical aspects of Schistosoma mansoni infection in humans are outlined in table 1. Stage of invasion Acute schistosomiasis (apparent and non-apparent)

THE STAGE OF INVASION Chronic schistosomiasis • Hepatointestinal The stage of invasion starts with cercarial dermatitis • Hepatosplenic and evolves with the migration and development of the schistosomes. Symptoms may commence with Complications fever as early as two or three days after infection. • Pulmonary hypertension • Neuroschistosomiasis Pulmonary involvement may be heralded by cough • Association with bacteria (Salmonella, Staphylococcus aureus) and pulmonary infiltrates in chest X-ray. Wheezing, • Glomerulonephritis myalgia, abdominal pain, eosinophilia and moder- • Schistosomiasis in the immunocompromised host ate splenomegaly may compose the clinical picture. • Ectopic schistosomiasis

The diagnosis of schistosomiasis at this stage is quite Table 2. Clinical and laboratory findings in acute difficult. Experimental work in mice suggests that schistosomiasis mansoni either praziquantel or oxamniquine, when given during the first week of infection in the usual doses, • A history of contact with stream waters in endemic areas in the is efficient in aborting development of the worms. last 60 days • Fever, diarrhoea, hepatosplenomegaly, dry cough, urticaria • Similar clinical picture in other members of the group who Research needs bathed together • Eosinophilia • Earlier diagnosis and treatment: • Ultrasound: hepatosplenomegaly, periportal lymph nodes – presumptive diagnosis followed by treatment • Computed tomography (CT) scan of the lungs: micronodules in of cercarial dermatitis in endemic areas with both lungs praziquantel, or with artesunate after the sec- • Eggs of S. mansoni in the stools • Liver biopsy: huge necrotic-exudative granulomas in portal tracts ond week. • Serology (enzyme-linked immunosorbent assay [ELISA] using keyhole limpet haemocyanin [KLH] antigen) ACUTE SCHISTOSOMIASIS The acute phase of schistosomiasis is usually asymp- INTESTINAL/HEPATOINTESTINAL tomatic but clinical signs of varying intensity may SCHISTOSOMIASIS occur. Those living in endemic areas may develop the syndrome after having contact for the first time After the acute phase manifestations recede, the with water contaminated by S. mansoni cercariae. infection progresses to the chronic phase. This is the The most common manifestations are fever, chills, stage of infection usually observed in endemic areas, weakness, weight loss, headache, nausea, vomit- but most individuals are asymptomatic. Intermittent ing, diarrhoea, hepatomegaly, splenomegaly, and diarrhoea is the most common symptom in patients marked eosinophilia (table 2). In patients with acute with intestinal/hepatointestinal schistosomiasis schistosomiasis admitted to hospital because of without polyps. Episodes of diarrhoea alternate with intensity of symptoms, treatment should be started periods of normal bowel movement or constipation, with corticosteroids, followed by schistosomicides. and faeces may contain blood and mucus. On palpation, the abdomen may be tender, particularly along Research needs the descending colon and sigmoid. The liver may be enlarged and hardened but hepatic function tests are • Recognition of the importance of acute schisto- invariably normal. Sigmoidoscopy may show areas somiasis in endemic areas. of granular inflammation with hyperaemic pinpoint elevations, 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, is Table 3. Characteristics of compensated hepatosplenic a common complication of intestinal schistosomia- schistosomiasis mansoni sis in Egyptian farmers. Clinical findings Higher prevalence in the age range 10–30 years Research needs General aspect: good Hepatosplenomegaly (exclude other causes) • A clinical and ultrasonographic definition of Variceal bleeding hepatointestinal schistosomiasis. No signs or symptoms of liver failure Somatic underdevelopment in the young HEPATOSPLENIC SCHISTOSOMIASIS Biochemical and haematologic findings Normal liver function tests (alanine aminotransferase [ALT], It is not difficult to identify and confirm a diagnosis of alkaline phosphatase, gamma-glutamyltransferase [GGT], advanced hepatosplenic schistosomiasis in patients bilirubin, albumin, prothrombin time) admitted to a reference hospital (see tables 3 and 4), Hypergammaglobulinaemia (increase of the IgG fraction) although it can be difficult to disclose individuals Anaemia, leukopenia, thrombocytopenia with hepatosplenic schistosomiasis in field-based Haemodynamic aspects studies. These individuals can be distinguished from Normal liver sinusoidal pressure others with hepatointestinal schistosomiasis basically Portal and splenic hypertension by the presence of splenomegaly, and this has been Peculiar alterations of the intra-hepatic vasculature Normal liver flow attempted by abdominal palpation. In areas endemic for malaria and visceral leishmaniasis, or in the pres- Ultrasound ence of other diseases which evolve with splenome- Characteristic periportal thickening galy (mononucleosis-like syndromes, for example), a Gall bladder wall thickening in the absence of calculous cholecystitis Increased left liver lobe palpable spleen may not help in the identification of Increased diameter of the splenic and portal veins patients with hepatosplenic schistosomiasis. Identification of portal collateral veins (e.g. left gastric vein)

Magnetic resonance imaging In Brazil, hepatosplenic schistosomiasis was found Increase in the intensity of signal in portal tracts more frequently in white people than in black peo- Splenomegaly ple with similar levels of infection. Easy identification of portal and collateral vessels

Pathologic aspects With portable ultrasound, it is possible to improve Moderate inflammatory activity the accuracy of clinical examination. A combined Intense Symmers’ fibrosis clinical and ultrasonographic classification of schis- Liver cells preserved tosomiasis in endemic areas has been proposed: Lobular structure of the liver preserved (1) Palpable spleen, severe periportal thickening and portal hypertension (a group usually found in general hospitals – see table 3). Table 4. Characteristics of decompensated hepatosplenic (2) Severe periportal thickening, portal hyper- schistosomiasis tension and a non palpable spleen (hepatic schistosomiasis). > 30 years of age (3) Palpable spleen with light to moderate peripor- Liver atrophy when compared to the compensated form of tal thickening. hepatosplenic schistosomiasis (4) Palpable spleen with a normal liver on ultrasound. Co-morbidities: hepatitis B, hepatitis C, alcohol abuse, a history of previous variceal bleeding Abdominal scar (post-splenectomy) The meaning and importance of groups 3 and 4 in Signs and symptoms of liver failure: ascites, jaundice, vascular the natural history of schistosomiasis remain to be spiders, mental confusion, slurred speech, coma, gynecomastia appraised. Poor general appearance, muscle wasting Biochemical alterations: hypoalbuminemia, hyperbilirubinemia, Research needs hyperammonemia • A clinical and ultrasonographic definition of Portal thrombosis is commonly described hepatosplenic schistosomiasis. Reduced hepatic flow • Definition of the best surgical approach to Periportal fibrosis and proliferation of biliary ducts variceal bleeding in patients with hepatosplenic Focal post-necrotic cirrhosis schistosomiasis. • Comparison of the serum markers of fibrosis with histology of the liver, and with imaging techniques.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 63 ULTRASOUND vs. MAGNETIC (FDA) for this indication under the trade name RESONANCE IMAGING IN THE Revatio. DIAGNOSIS OF PERIPORTAL FIBROSIS Sildenafil inhibits phosphodiesterase type 5, the main phosphodiesterase in the pulmonary vascu- Lately, periportal thickening on ultrasound has lature; inhibiting it maintains high levels of cGMP, been considered as evidence of Symmers’ fibrosis. which promotes the vasodilation effects of endog- In a recent study in Brazil comparing ultrasound enous nitric oxide. The drug may also have an anti- (US) with magnetic resonance imaging (MRI), in proliferative effect on pulmonary artery smooth a group of 20 patients with periportal thickening muscle cells. diagnosed by US and assumed to have liver fibrosis caused by S. mansoni infection, 20% where found In a preliminary study on the course of hepat- by MRI to have fat infiltration of the portal tracts of osplenic schistosomiasis in 13 patients with pul- the liver. If these findings are confirmed, a limit for monary hypertension in Brazil, sildenafil showed the use of ultrasound in schistosomiasis should be promising results. established. Research needs Research needs • Well designed studies using sildenafil are neces- • Studies addressing the value of MRI in evalua- sary to confirm these data. tion of periportal thickening in schistosomiasis. NEUROSCHISTOSOMIASIS PULMONARY HYPERTENSION Schistosomal myeloradiculopathy (SMR) is the most Clinical and radiological findings are similar to common neurological form of S. mansoni infection. those associated with other causes of pulmonary In 2004, a study in Brazil found that 5.6% of inflam- hypertension. Symptoms are fatigue, palpitations, matory myelopathies seen at a tertiary Brazilian dyspnea on exertion, cough with occasional haemo- hospital were due to SMR. In a hospital in Tanzania, ptysis, signs of right ventricular hypertrophy, and a prevalence of 6% has been estimated. dilation of the pulmonary artery. Echocardiography helps the diagnosis, but cardiac catheterization is Ninety five per cent of untreated patients die or do more informative: pulmonary hypertension is not show any improvement. Frequently, physicians present when a pulmonary pressure of 20 mm Hg are not aware of the existence of schistosomal mye- or higher is registered. The patient may ultimately loradiculopathy, and when they are, they do not progress to decompensation with congestive heart have the means to investigate schistosomiasis and to failure. Sudden death with cardiovascular collapse exclude other diseases. has been reported. The clinical picture includes: lumbar and/or lower Pulmonary hypertension has been described in limb pain, lower limb hypoesthesia/anesthesia, 13% of patients with advanced hepatosplenic schis- lower limb paresthesias, lower limb weakness, uri- tosomiasis, and cor pulmonale in 2.1%. Standard nary dysfunction, intestinal dysfunction, sexual treatment of patients with pulmonary arterial hyper- dysfunction. Diagnosis of SMR is based on the fol- tension (PAH) includes anticoagulant therapy with lowing criteria: evidence of low spinal cord lesion, warfarin (anticoagulant agent) and a diuretic such as demonstration of exposure to schistosomal infection furosemide for fluid retention caused by right-sided by microscopic or serological techniques, and exclu- heart failure. In selected patients, a calcium-channel sion of other causes of transverse myelitis. MRI of blocking agent may be helpful. Some patients with the spine should be used in all cases. Biopsy of the PAH in whom medical management has failed have spinal cord should be considered in special cases. undergone lung transplantation. Cerebrospinal fluid (CSF) examination will add to In a recent randomized clinical trial, 277 patients information on diagnosis when it shows the presence with symptomatic PAH were randomized to placebo of eosinophils, hyperproteinorraquia, lymphocyto- or sildenafil orally three times daily for 12 weeks. sis, and, in some cases, a positive immunological The authors conclude that sildenafil in doses of 20 test for schistosomiasis in the spinal fluid. mg three times a day is effective for treatment of pulmonary arterial hypertension. The drug has been Exclusion of other diseases of the spinal cord should approved by the US Food and Drug Administration be 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 the Research needs spinal cord, B12 deficiency, diabetes, systemic lupus • Studies in endemic areas on the association of erythemathosus, anti-phospholipid syndrome, schistosomiasis with gram-negative bacteria: syphilis, HIV and HTLV-1 infection, auto-immune – what is the prevalence in endemic areas? vasculitis, herpes simplex myelitis, tuberculosis, – definition of treatment. hepatitis B and C, multiple sclerosis, neurocysticer- cosis, syringomyelitis. GLOMERULONEPHRITIS Treatment includes the use of ivermectin to treat Chronic glomerulonephritis appears in 12%–15% of strongyloidiasis, followed by praziquantel (60 mg/ patients with hepatosplenic schistosomiasis man- kg body weight, single dose) and high doses of soni admitted to general hospitals in Brazil. The methylprednisolone (15 mg/kg a day, iv; maximum nephrotic syndrome is the most frequent form of dose, 1 g a day) for 5 days, followed by prednisone clinical presentation of schistosomal nephropathy. (1 mg/kg a day per os) for 6 months. There is evidence that renal manifestations develop slowly, perhaps ten or more years after the onset of Epidemiological surveillance includes: a) training hepatosplenic disease. of health personnel to develop a high index of sus- picion for schistosomal myeloradiculopathy (for The outcome of treatment of the nephrotic syndrome example, the clinical triad of low back pain, lower associated with hepatosplenic schistosomiasis with limb weakness and urinary dysfunction should alert antischistosomal drugs, corticosteroids and immu- the local physician that this patient needs further nodepressors has been disappointing. Some authors investigation); b) notification of a regional reference have shown that when patients present with neph- centre and provision of neurological examination; rotic syndrome, the disease is too far advanced and c) stool examination for S. mansoni eggs, lumbar tap is therefore irreversible. with CSF examination, and radiological examination. Any obstacle to the above procedures should be Research needs communicated to the state health authorities, who will provide alternatives to support those patients in • Recognition of glomerulonephritis as a severe need of more sophisticated investigation. complication of hepatosplenic schistosomiasis: – definition of the prevalence in endemic areas. Research needs – research on treatment. • Recognition of the importance of neuroschistosomiasis in endemic areas. SCHISTOSOMIASIS IN THE • Definition of parameters for diagnosis and treat- IMMUNOCOMPROMISED HOST ment (when, how and for how long). The number of people immunosuppressed by drugs (cytotoxic chemotherapy or other immunosuppres- ASSOCIATION WITH BACTERIA sive agents including steroids and irradiation), or affected by diseases that cause immunodepression The association of schistosomiasis with Salmonella (AIDS, neoplasia, malnutrition, chronic renal fail- and other gram-negative organisms is well docu- ure), is growing fast. In the immunocompromised mented. The most common characteristics of the host there have been changes in the clinical presenta- clinical syndrome are: 1) a long history (from several tion, pathological aspects and therapeutic approach weeks to a few years) of febrile disease; 2) bacterae- to most associated infectious diseases. mia with one of many species of the genus Salmonella or other gram-negatives; 3) chronic active schisto- Data on the behaviour of schistosomiasis mansoni somiasis. The number of cases reported in Brazil for in the immunosuppressed host are scarce. Even so, this association has decreased during the last ten it is possible to draw out some areas of clinical inter- years, which has been attributed to mass chemo- est concerning this particular scenario: therapy with schistosomicides. • Depression of cell-mediated immune response in the host diminishes granulomatous response The association of schistosomiasis and Staphylococcus to S. mansoni eggs. Without granuloma for- aureus causing pyogenic liver abscesses has been mation, destruction of hepatic cells is to be described in Brazil in the murine model of schisto- expected, causing varying degrees of hepatitis somiasis and in humans. The development of liver (depending on the worm load and the level of abscesses in experimental schistosomiasis in mice immunosuppression). has been confirmed in Egypt.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 65 • Egg output decreases sharply in mice experimen- TREATMENT OF SCHISTOSOMIASIS tally infected with S. mansoni and immunosup- Although schistosomiasis chemotherapy prima- pressed by drugs or thymectomy. A well formed rily relies on praziquantel, the present arsenal also granuloma facilitates the migration of eggs in the includes oxamniquine and artemisinin derivatives. host tissues. Without granuloma formation, S. mansoni eggs do not reach (or reach only in small numbers) the gut lumen. Diagnosis of schisto- Research needs somiasis based on parasitological stool examina- • Development of novel antischistosomal agents. tion should be re-evaluated in this context. • Development of combinations of schistosomi- • The efficacy of schistosomicides is also cides (praziquantel and oxamniquine; praziquan- expected to decrease in such cases, since the tel and artesunate). action of oxamniquine and praziquantel is • Studies on increasing the dosage of praziquantel immunodependent. in use today. • Schistosomal infection is expected to interfere • Studies on repeat treatment with praziquan- with the course of diseases responsible for immu- tel once every 2 to 4 weeks for periods of up to 6 nosuppression. For instance, in patients with months. acquired immunodeficiency syndrome, schistosomiasis may aggravate the clinical picture by decreasing the T CD4+ cell count thus carrying References on which this text is based an increased risk for concomitant infection with bacteria (e.g. Salmonella), viruses or fungi. The Medical Letters. Sildenafil for pulmonary arterial hypertension. The Medical Letter on Drugs and Research needs Therapeutics, 2005, 47:65–67. Lambertucci JR et al. Schistosoma mansoni: assessment • Definition of the role of schistosomiasis in the of morbidity before and after control. Acta Tropica, natural history of acquired immunodeficiency 2000, 77:101–109. syndrome. • Definition of the behaviour of schistosomiasis in Silva LCS et al. Treatment of schistosomal myeloradic- the immunocompromised host. ulopathy with praziquantel and corticosteroids and evaluation by magnetic resonance imaging: a longitudinal study. Clinical Infectious Disease, 2004, 39:1618– ECTOPIC SCHISTOSOMIASIS 1624. MANSONI Utzinger J et al. Combination chemotherapy of When periovular granulomas form outside the por- schistosomiasis in laboratory and clinical trials. tal and pulmonary circulations, it is considered to Antimicrobial Agents and Chemotherapy, 2003, 47:1487– be ectopic schistosomiasis. Most of the time this rep- 1495. resents a curiosity. Periovular granulomas can be found in such strange sites as the thyroid, kidneys, pancreas, testicles, ovary, uterus, adrenals, lymph nodes, heart, prostate and central nervous system. Ectopic cutaneous lesions usually affect the perineal area or trunk, but involvement of other areas of the skin has also been reported. Rarely is ectopic egg deposition sufficient to suggest a clinical syndrome.

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. populations live on less than US$ 2 a day (United Progress towards Nations Statistics Division, 2005**) and have very limited access to health care and schooling. the detection of schistosomiasis The current strategy to achieve this PPC goal is to involve governments and the public health sector Ana Rabello and Martin Enk in implementing community-based programmes Centro de Pesquisas René Rachou, Fiocruz, for school-age populations. This activity should Belo Horizonte, Brazil ideally be part of integrated programmes requir- ing the engagement of local, often poorly trained, health care workers who deal with the different What progress has been made and what are the challenges on a minimum budget. A useful guide current priorities in research towards the detec- for planners and programme managers provides tion of schistosome infections? Any comprehensive direction for collecting baseline parasitological data approach to address this matter requires a frame- (Montresor et al., 2002) through questionnaire sur- work: diagnosing schistosomiasis to do what, where, veys for urinary schistosomiasis in all schools and, to/by whom? in areas likely to be endemic for urinary or intestinal schistosomiasis, urine and stool surveys in a random sample of schools. The Kato-Katz method is SOCIO-POLITICO-ECONOMIC recommended for stool examination, and a filtration REQUIREMENTS FOR MORBIDITY technique (or reagent strip) for detection of eggs (or CONTROL blood) in urine. Is the scientific community capa- In the context of Goal 1 of the Millenium Development ble of offering simpler and more effective diagnostic Goals, which is to eradicate extreme poverty and tools to the deworming programme than those pres- hunger, the 54th World Health Assembly (in 2001) ently available? Is there any progress? Is anything recognized that tools are available to treat para- coming out of the pipeline? sitic infections that deprive the poorest of the poor of their health and well-being, slow economic Questionnaires and reagent strips progress, and contribute to social marginalization. When urgent intervention is required to prevent A resolution was put forward to start to seriously death and liver or bladder damage, often in an envi- tackle worm infections, specifically soil-transmit- ronment of civil unrest or man-made or natural ted helminths and schistosomiasis. Accordingly, the disaster, any extra labour and costs needed are prob- World Health Organization launched the Partners lematic. Although no new alternative, simple, fast for Parasitic Control (PPC) initiative, the global tar- screening method has been produced, during the get of which is to treat at least 75% of all school-age last decade, scientific efforts have validated the use- children who are at risk of morbidity from soil-trans- fulness of the questionnaire and the reagent strip mitted parasites and schistosomiasis by the year as simple tools to estimate Schistosoma haematobium 2010 (Resolution WHA54.19. WHO, 2001). infection. Consistently in studies performed in different geographic areas, strong positive associa- Because schistosomiasis has focal distribution, tion has been found between reported haematuria, and in order to ensure the safe, efficient and eco- micro-haematuria and eggs in urine (Ansell et al., nomic use of praziquantel, tools are required that 1999; Stothard et al., 2002; van der Werf, Borsboom will allow simple, rapid and inexpensive identifi- and de Vlas, 2003; van der Werf and de Vlas, 2004). cation of communities at highest risk of morbidity. Therefore a simple questionnaire asking “Did you The PPC calls for a diagnostic method that targets have blood in urine during the last month?” and reduction of morbidity. More than 80% of individ- “Did you suffer from schistosomiasis during the last uals infected with schistosomes live in sub-Saharan month?” is a validated tool that allows for a deci- Africa (Chistulo et al., 2000), where 106 million sion to be taken – the decision to treat all school-age present with bladder wall pathology and 14.8 mil- children when 30% of them report gross haema- lion with liver/spleen enlargement (van der Werf, turia, indicating that 50% have detectable eggs in 2003), and where more than 800 million are at risk urine (Guyatt et al., 1999). Lower predictive values of infection. In this context it is worth mentioning are observed for the entire population, especially that, in least developed countries, people in exposed for 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/07 67 ing conditions such as menstruation, pregnancy and tion or Kato-Katz) cost about 10 US cents; although genitourinary infections (Utzinger et al., 1998). This these relatively cheap and simple methods have aspect must be taken into consideration when plan- been available for decades, electricity, microscopes ning the complementary strategy of the deworming and trained microscopists may be very few or not programme which is based on community action available. and treatment of groups at high risk of infection. A matter of concern is that the efficiency of the ques- In this case again, the best scientific contributions tionnaire and strip test decreases as the prevalence and progress over the last decades have resulted not and intensity of infection decrease. in the development of new methods but in better understanding of the advantages, limitations and The situation is far more difficult regarding the utility of available methods. A recent example is detection of S. mansoni and S. japonicum eggs in stool the use of computer simulation to investigate the because using questionnaires for intestinal symp- validity and cost-effectiveness of different screen- toms has proved less promising. Repeated and ing and control strategies for S. mansoni infection in extensive studies aimed at developing and validat- Uganda. In identifying schools with a prevalence of ing a questionnaire for rapid screening of S. man- S. mansoni higher or equal to 50%, a sampling com- soni infection have addressed a variety of possible puterized method provided sensitivity and specifi- specific symptoms. The questions “Did you have city of >90% at sample sizes of less than 20 children blood in stool during the last month?” and “Did (Brooker et al., 2005). you have bloody diarrhoea during the last month?” were significantly associated with the prevalence of THE SCIENTIFIC AND S. mansoni infection, but the diagnostic performance of these symptoms was only moderate. In different TECHNOLOGICAL REQUIREMENTS districts of sub-Saharan countries, the sensitivity of FOR TRANSMISSION CONTROL information on the perception of blood in stools var- In many countries such as Saudi Arabia, The ied from 47% to 88.2%, the specificity varied from Philippines, Morocco, China, Venezuela, and in 57.7% to 76%, the positive predictive values varied regions of Egypt and Brazil, significant progress in from 66% to 73.2%, and the negative predictive val- the control of schistosomiasis and other diseases has ues from 60% to 78.9% (Utzinger et al., 1998, 2002). been achieved by the national control programmes due to considerable increases in resource capabili- Less information is available on the efficiency of the ties, health educational activities, and environmen- questionnaire in estimating S. japonicum infection. tal sanitation. Use of large-scale chemotherapy has In China, a six-question (on episodes of diarrhoea, allowed prevalence to decrease dramatically and be frequency of water contact, school grade attained, kept at low levels. weakness, past history of S. japonicum infection, and previous treatment for schistosomiasis, if any) In this strikingly diverse framework, in which relia- form showed sensitivity of 93.7% and specificity of ble and accurate diagnostic tools are needed as a key 91.9% (Zhou et al., 1998). The use of multi-question element for schistosomiasis elimination, the health questionnaires and their analysis by logistic regres- services are generally prepared and resources, sion resulted in an area below the receiver-operat- though limited, are on hand. However, the window ing characteristic curve of 0.90 (Tan et al., 2004), but of opportunity to switch from morbidity control to these are complex approaches that require skilled transmission control in these areas is only partially personnel. opened because of the lack of diagnostic tools for reliable, simple and inexpensive identification of Egg detection the relatively small number of individuals who harbour just a few worms. Can the scientific commu- One of the drawbacks of the questionnaire and nity offer more effective diagnostics tools than those urinary strip test is that neither provides baseline presently available? Is there any progress? information on the intensity of infection. There is no need to re-confirm that the urine filtration and Unfortunately, the results of research on improved Kato-Katz stool examination methods offer good diagnostic techniques are still unsatisfactory bear- sensitivity in highly endemic areas; these are highly ing in mind the ideal technique and the financial and studied methods and their usefulness for morbid- infrastructural difficulties of most endemic coun- ity control is well defined. Urine is easily collected tries. Repeated parasitological examinations of urine but, due to the circadian pattern of egg excretion, or stool associated with different methods of anti- specimens should ideally be collected between 10 body detection remain the validated instruments. To am and 2 pm. Parasitological methods (urine filtra- overcome the lack of sensitivity in situations of low

68 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 worm burden (as found in low prevalence areas) for estimation of infection intensity. Moreover, circu- and in evaluation after treatment, it is necessary to lating schistosome antigens disappear rapidly after increase the number of stool samples. This approach treatment and can therefore be used for assessment reduces the operational advantages of the technique of cure. However, the sensitivity of antigen detection by increasing the costs, hampering the screen-and- varies from 55% to 100%, being low in low endemic treat operations, and reducing compliance. In moni- areas (van Lieshout, 2000) with no advantage over toring the control programmes, parasitological data stool and urine examination. must be considered with caution since treatment may reduce the egg elimination rate by 90% in those DNA detection patients who remain infected. Recently, a DNA detection assay was developed and evaluated in a pilot field study. The polymerase Antibody detection chain reaction (PCR) indicated a prevalence of 38.1%, Although the efficiency of antibody detection var- while triple Kato-Katz testing indicated 30.9% prev- ies according to the antigen system or method, the alence in the same samples (Pontes et al., 2003). The techniques usually present high sensitivity but low DNA amplification assay may constitute an alterna- specificity. Most commonly used is the enzyme- tive to available diagnostic techniques for the detec- linked immunosorbent assay (ELISA). The search tion of S. mansoni infection, but still needs further for antigens of higher specificity than the soluble validation. The PCR may, in particular, constitute a crude egg (SEA) or worm antigens (SWAP) resulted tool for the diagnosis of Schistosoma sp. infection in in purified preparations such as cathionic fraction special situations when high sensitivity and specifi- 6 (CEF6) (Doenhoff et al., 1993), adult microsomal city are required and where infrastructure, financial antigen for S. mansoni, japonicum and haematobium resources and skilled personnel are available. (MAMA, JAMA, HAMA) (Tsang et al., 1983), gut associated antigen 31/32 (Klinkert et al., 1991), and Combined approach the alkaline phosphatase immunocapture assay As long as there is no simple diagnostic test for mass (Pujol and Cesari et al., 1990). Variable results with screening in areas of low prevalence, one strategy is these purified preparations were observed in dif- to combine different methods to identify the small ferent settings. They may be useful in specific sit- number of infected people. One possibility is to use uations (Doenhoff et al., 2004), but in general, the antibody detection, and to confirm actual infec- antibody-based methods offer low specificity, per- tion with multiple parasitological examinations. sistence after chemotherapy, cross reactivity, poor The goal of this approach is to reduce the chances correlation with egg output, complex handling, and of under-diagnosis and at the same time to reduce high costs. unnecessary treatment. The implementation of a schistosomiasis surveillance system, run by local Although some progress has been reported in the public health centres and based on geographical research and development of rapid tests for anti- distribution, water contact patterns, and the map- body detection, no validated resilient novel tool is ping and registration of individual cases, can help to available. Rapid tests for antibody detection in new define the target population. Here again, inter and assay formats have been reported for S. japonicum: trans-disciplinary (bio-science, mathematics, epi- the dot immunogold filtration assay (Wen et al., demiology, programme management) research is 2005), and the silver-enhanced colloidal gold met- needed in order to provide the basis for decisions on alloimmunoassay (Chu et al., 2005). A western blot the most cost-effective approach. assay has also been evaluated for anti-S. mansoni antibody detection (Sulahian et al., 2005). These new Various control strategies have been defined by dif- formats use crude antigens and still need to be vali- ferent national control programmes. Unequivocal dated in large-scale field trials. benefits are expected in the above-mentioned high morbidity areas as praziquantel is a safe drug even Antigen detection during pregnancy and breastfeeding (Adam et al., Similarly, a number of assays to detect circulating 2005). The same strategy may not be proper in low antigen have been described. Most experience has endemic areas, where severe morbidity is rare, but been obtained with the detection of anodic (CAA) the lack of a useful and simple diagnostics method and cathodic (CCA) schistosome antigens in serum combined with the low price of chemotherapeutic and urine using the ELISA or dipstick platforms, intervention has shifted the control strategy from and antigen capture with monoclonal antibodies. individual diagnosis and treatment to selective pop- The main advantages are high specificity, positive ulation mass drug distribution. In an endemic area correlation with worm burden, and the possibility where less than 10% of children present with eggs in

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 69 stool or urine, the targeted treatment of all school- For the two scenarios discussed above (morbidity age children twice during their school years is rec- control and transmission control), it is clear that the ommended (Montresor et al., 2002). Expressing this priorities are to develop tests for rapid assessment approach in numbers, in a community with 1000 of intestinal schistosomiasis in areas of high ende- school-age children and an estimated prevalence of micity and to develop more sensitive and specific 8%, the drug will unnecessarily be administered to diagnostic tools for use in areas of low transmis- approximately 900 students. sion, as was defined by TDR in 2001.*** In addition, improved diagnostics tools are needed to assist in This policy has potential implications: chemotherapy, in the monitoring and evaluation of 1) The risk of increasing drug resistance. control programmes and of drug resistance, and in 2) The possible high costs and difficult sustain- clinical trials of vaccine candidates and new drugs. ability when compared to individual diagnosis and treatment integrated into the primary Importantly, the diminishing focus on schistosomia- health care system. The cost of a strategy based sis has reduced the number of involved research on ‘passive chemotherapy’ and health education groups. The decline in funding for schistosomia- proved to be about half that of mass drug dis- sis and diagnostics has led to this lack of notable tribution in two villages in China, with 11% and advances. As a final note, and most importantly, dis- 12.3% prevalence of S. mansoni infection, with ease-endemic countries’ research capacity and local similar treatment coverage (Guo et al., 2005). autonomy are essential in carrying out and main- On the other hand, in Ghana and Mali, only taining realistic, collaborative and self-sustained half of the patients reporting blood in stool or control programmes. urine would receive treatment in a passive case detection health care system (van der Werf et al., 2004). The different experiences are certainly References the result of health education and a strength- Adam I, Elwasila E, Homeida M. Praziquantel for the ened primary health care service in China. Such treatment of schistosomiasis mansoni during pregnan- a comprehensive approach brings benefits that cy. Annals of Tropical Medicine and Parasitology, 2005, go far beyond the targeted disease. 99:37–40. 3) The ethical aspects. In respect to individual autonomy, whenever a drug is to be adminis- Ansell J et al. The reliability of self-reported blood in tered unnecessarily to a person, he/she must be urine and schistosomiasis as indicators of Schistosoma informed of the risks and benefits, and the alter- haematobium infection in school children: a study native approaches must be debated. Moreover, in Muheza District, Tanzania. Tropical Medicine and residents in endemic areas must have the right International Health, 1997, 2:1180–1189. to refuse to take the drug in the absence of an Brooker S et al. Rapid assessment of Schistosoma man- individual positive diagnosis. soni: the validity, applicability and cost-effectiveness of the Lot Quality Assurance Sampling method The lack of notable development in Uganda. Tropical Medicine and International Health, In conclusion, this review reflects the limited invest- 2005, 10:647–658. ment of both public and private sectors in research Chitsulo L et al. The global status of schistosomiasis and product development for diagnostics for schis- and its control. Acta Tropica, 2000, 77:41–51. tosome infections. Despite the fact that research has yielded breakthroughs in molecular biology, chem- Chu X et al. Silver-enhanced colloidal gold metalloim- istry and engineering, no advances have been taken munoassay for Schistosoma japonicum antibody detec- up by industry and applied to diagnostics develop- tion. Journal of Immunological Methods, 2005, 301:77–88. ment for a growing range of illnesses and conditions Doenhoff MJ et al. Seroepidemiology and serodiagno- including schistosomiasis. There is urgent need sis of schistosomiasis in Kenya using crude and puri- for an extended public-private partnership model fied egg antigens of Schistosoma mansoni in ELISA. to target research and development from genome Transactions of the Royal Society of Tropical Medicine and sequencing to regulatory approval, including mak- Hygiene, 1993, 87:42–48. ing available newly registered products to the public sector at affordable prices.

*** http://www.who.int/tdr/diseases/schisto/direction.htm

70 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Doenhoff MJ, Chiodini PL, Hamilton JV. Specific and van der Werf MJ, Borsboom GJ, de Vlas SJ. No effect sensitive diagnosis of schistosome infection: can it of recall period length on prevalence of self-reported be done with antibodies? Trends in Parasitology, 2004, haematuria in Schistosoma haematobium-endemic areas. 20:35–39. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2003, 97:373–374. Guo JG et al. The role of ‘passive chemotherapy’ plus health education for schistosomiasis control in China van der Werf MJ et al. Quantification of clinical mor- during maintenance and consolidation phase. Acta bidity associated with schistosome infection in sub- Tropica, 2005, 96:177–183. Saharan Africa. Acta Tropica, 2003, 86:125–139. Guyatt H et al. The performance of school-based van der Werf MJ et al. Measuring schistosomiasis questionnaires of reported blood in urine in diagnos- case management of the health services in Ghana and ing Schistosoma haematobium infection: patterns by Mali. Tropical Medicine and International Health, 2004, age and sex. Tropical Medicine and International Health, 9:149–157. 1999, 4:751–757. van der Werf MJ, de Vlas SJ. Diagnosis of urinary Klinkert MQ et al. Immunological analysis of cloned schistosomiasis: a novel approach to compare blad- Schistosoma mansoni antigens Sm31 and Sm32 with der pathology measured by ultrasound and three sera of schistosomiasis patients. Tropical Medicine and methods for hematuria detection. American Journal of Parasitology, 1991, 42:319–324. Tropical Medicine and Hygiene, 2004, 71:98–106. Montresor A et al. Helminth control in school-age van Lieshout L, Polderman AM, Deelder AM. children. A guide for managers of control programmes. Immunodiagnosis of schistosomiasis by determina- Geneva, World heath Organization, 2002. tion of the circulating antigens CAA and CCA, in particular in individuals with recent or light infections. Pontes LA et al. Comparison of a polymerase chain Acta Tropica, 2000, 77:69–80. reaction and the Kato-Katz technique for diagnosing infection with Schistosoma mansoni. American Journal of Wen LY et al. Evaluation on the applied value of the Tropical Medicine and Hygiene, 2003, 68:652–656. dot immunogold filtration assay (DIGFA) for rapid detection of anti-Schistosoma japonicum antibody. Acta Pujol FH, Cesari IM. Antigenicity of adult Schistosoma Tropica, 2005, 96:142–147. mansoni alkaline phosphatase. Parasite Immunology, 1990, 12:189–198. Zhou H et al. Diagnosis of schistosomiasis japonica in Chinese schoolchildren by administration of a ques- Stothard JR et al. Urinary schistosomiasis in school- tionnaire. Transactions of the Royal Society of Tropical children on Zanzibar Island (Unguja), Tanzania: a par- Medicine and Hygiene, 1998, 92:245–250. asitological survey supplemented with questionnaires. Transactions of the Royal Society of Tropical Medicine and Hygiene, 2002, 96:507–514. Sulahian A et al. Development and evaluation of a Western blot kit for diagnosis of schistosomiasis. Clinical and Diagnostic Laboratory Immunology, 2005, 12:548–551. Tan H et al. Rapid screening method for Schistosoma japonicum infection using questionnaires in flood area of the People’s Republic of China. Acta Tropica, 2004, 90:1–9. Tsang VC et al. Schistosoma mansoni adult microsomal antigens, a serologic reagent. II. Specificity of antibody responses to the S. mansoni microsomal antigen (MAMA). Journal of Immunology, 1983, 130:1366–1370. Utzinger J et al. Schistosoma mansoni, intestinal parasites and perceived morbidity indicators in schoolchildren in a rural endemic area of western Cote d’Ivoire. Tropical Medicine and International Health, 1998, 3:711– 720. Utzinger J, Tanner M. Screening for schistosomiasis with questionnaires. Trends in Parasitology, 2002, 18:375–377.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 71 WORKING PAPER 9. Research mission areas, where the probability of recent infec- 2 towards new treatments tions at the time of treatment is relatively high. for schistosomiasis Another problem is the existence of schistosomes that show decreased sensitivity to PZQ. The fact that Donato Cioli different PZQ susceptibilities exist has been docu- Institute of Cell Biology, National Research Council mented both in field and laboratory-derived schis- (CNR), Italy tosomes, but the relevance of these differences must be evaluated quite carefully. Differences are invariably small (about 3x in terms of the median effec-

A single drug, praziquantel (PZQ), is currently tive dose [ED50]) and do not increase upon exposure available for the treatment of infections due to of repeated parasite generations to drug pressure.3

Schistosoma haematobium (the most frequent species), Some technical details of the ED50 determination S. japonicum, S. mekongi, S. intercalatum and the so- (i.e. the time of treatment after infection) may con- called minor schistosomes. For S. mansoni infections, tribute to overestimation of PZQ refractoriness. A oxamniquine is still commercially available but its recent report from an area of Egypt where schisto- price discourages use and procurement is often dif- somes with decreased PZQ susceptibility had been ficult. Thus, PZQ is practically the only drug availa- isolated ten years ago, showed no indication of drug ble for an infection that concerns 200 million people. resistance in the population.4 Thus, it is likely that It is clear that we are living dangerously, since theory the limited variability of PZQ efficacy observed so and experience strongly suggest that drug resistance far reflects, as with any drug, a certain genetic heter- is a virtually unavoidable phenomenon for any anti- ogeneity of schistosome populations, but is unlikely infective compound; if resistance were to under- to represent, as of today, a serious problem in terms mine the usefulness of PZQ, it could take several of public health. This should be taken as an incen- years to develop an adequate substitute. In view of tive to exert continuous monitoring of PZQ efficacy, the fact that several million PZQ doses are adminis- since the risk is still pending that serious and rapidly tered every year and the number is going to rise in spreading drug failure may appear in the future. the immediate future – increasing the risk of development of resistance – it should be apparent that it As administered today, PZQ is a 50/50 racemic mix- is now time to start looking for new drugs against ture of two stereoisomers, one of which is totally schistosomiasis. inactive as a schistosomicide but is contributing to produce side effects. This goes against the increasing PRAZIQUANTEL demand of drug regulatory agencies to develop single-enantiomer compounds for all modern drugs.5 PZQ has proved to be a excellent drug, but is far from perfect. Its main asset is efficacy, which can Finally, the mechanism of action of PZQ has not be roughly summarized in the notion that a sin- been unequivocally established, which is an obsta- gle oral dose usually gives cure rates of 70%–90% cle to any rational development of better analogues and reductions in egg excretion of 85%–95%. The and an impediment to interpreting phenomena of other important feature, as already mentioned, is decreased drug sensitivity. the wide spectrum of efficacy, encompassing all known human schistosomes as well as other trem- It is apparent from the above that several areas of atodes and cestodes. Side effects are rarely serious research could be directed towards better use of and are usually of short duration, so that treatments PZQ. To begin with, drug efficacy is usually meas- can be administered without direct medical supervi- ured by counting parasite eggs at follow-up, but sion.1 The widespread use has promoted large-scale the timing of examination after treatment is highly production and commercial competition, which has variable and this prevents meaningful comparisons resulted in very reasonable prices (about US$ 0.24 between different treatments. The optimal timing per average treatment). of follow-up should be determined in such a way that full deployment of drug effects is allowed while The main problem with PZQ is that it is practically minimizing ‘false failures’ due to reinfection or to inactive against immature schistosomes, its full maturation of immature worms. Also, laboratory activity being displayed only 6–8 weeks after infec- determination of PZQ ED50s in the mouse should tion. This is the cause of many treatment ‘failures’ be adapted to take into account the possibility that and a serious limitation to the overall drug efficacy. some schistosome isolates may reach full matura- The problem is particularly serious in high trans- tion, and full drug sensitivity, at very late times after infection.

72 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 An experimentally standardized protocol of PZQ tosome genes in heterologous systems and needs administration has still to be adopted. The 40 mg/kg direct confirmation in the parasite. Also, a compre- vs. 60 mg/kg choice is likely to depend on the local hensive description of schistosome calcium chan- parasite characteristics, but parameters e.g. the asso- nels is still lacking and no attempt has been made ciation with food or drinks could probably be stand- to fit the insensitivity of immature worms into the ardized. Combinations with other drugs may have model. the goal of prolonging the bioavailability of PZQ in some special circumstances (e.g. using cimetidine) or OXAMNIQUINE of increasing the effectiveness of PZQ by associating it with compounds with different antischistosomal In over thirty years of intensive use, mainly on the modes of action. In principle, a combination of PZQ American continent, oxamniquine has proved to be and artemisinin derivatives sounds extremely attrac- a very safe and effective drug for S. mansoni infective since the latter compounds are especially active tion. It would be an absolute loss if commercial rea- against immature schistosomes, but a number of sons were to cause its disappearance. Every effort problems need to be tackled experimentally (as dis- should be made to keep it on the market, as it is the cussed below). For S. mansoni infections, a combina- only valid, albeit partial, alternative to PZQ. tion with oxamniquine has been tested with mixed results; it doesn’t seem very promising since both The major drawback of oxamniquine (limited spec- drugs are ineffective against immature worms.6 trum of activity) is somewhat counterbalanced by the existence of a reasonable model regarding its Efforts should be made to produce PZQ consisting mechanism of action. It has been shown that oxam- only of the active stereoisomer. Incidentally, this niquine acts like a pro-drug, being transformed would also reduce by half the size of the PZQ tab- into the active compound by a schistosome enzyme lets that are often difficult to swallow, especially for that catalyses its conversion to a reactive ester. The children. oxamniquine ester spontaneously dissociates giving rise to an alkylating agent capable of forming Continuous monitoring of PZQ effectiveness should covalent bonds with parasite DNA and other mac- be established for early detection of any possible romolecules. Lack of the esterifying enzyme – a sul- appearance of drug resistance. Large chemother- fotransferase – leads to drug inactivity.8 Since S. apy programmes should include follow-up exami- japonicum and S. haematobium appear to possess the nations performed at least on samples of the treated enzyme, but presumably with critical changes in the population, and any repeated, widespread or sus- oxamniquine binding site, it is in principle feasible picious failures should be followed by parasite to determine the structure of their binding sites and isolation and laboratory determination of drug sen- then to modify the oxamniquine molecule in such a sitivity in experimental animals. way that it could bind to the enzymes of the other species. If successful, this would recuperate a pre- Operational research is needed to examine current cious weapon for the armamentarium of antischis- PZQ delivery systems, and to determine how PZQ tosomal drugs. treatment and delivery can significantly reduce schistosomiasis morbidity and enhance sustain- ARTEMISININ DERIVATIVES ability of control. For example, the frequency of treatment campaigns is a key element in the optimi- These compounds, currently among the most potent zation of economic resources in relation to morbid- antimalarials available, are also active against all ity reduction in the population. Association of PZQ major human schistosome species.9 They are of spe- with anthelminthic drugs targeted at different par- cial interest because their activity is exactly comple- asites is quite common in the case of albendazole, mentary to the activity of PZQ, i.e. it is especially and additional combinations may be investigated. directed against immature worms, while adult schistosomes are only partially sensitive. Thus combina- As already mentioned, elucidation of the mech- tion therapy would be in principle very attractive, anism of action of PZQ would be of paramount but there are a number of practical issues that make importance. An attractive hypothesis has been put the proposition rather problematic. Artemisinin forward which implicates the beta subunit of volt- derivatives have to be administered in multiple age-gated calcium channels as a key molecule in the doses, are relatively expensive, and may interfere observed massive calcium influx in the parasite and with antimalarial chemotherapy if used against in the subsequent tegumental alterations caused by schistosomiasis in areas where both diseases are PZQ.7 The evidence collected so far is quite convinc- present. Artemisinins by themselves have been suc- ing but is mainly based on the expression of schis- cessfully used as antischistosomals in some special

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 73 circumstances, e.g. in people exposed to the infec- antagonist is of short duration compared to that of tion at a defined time because of a flood, but cannot Ro 11-3128 so that repeated administrations would be considered as a possible alternative to PZQ due be needed.13 Further development of the drug was to their limited activity against adult worms. abandoned, but some similarities with the mode of action of PZQ may be of interest: both compounds cause a rapid calcium influx, muscular contraction RESEARCH ON NEW and tegument disruption; both display stereoselec- ANTISCHISTOSOMAL DRUGS tive activities; both emerged from a screening of In principle, new antischistosomals can be searched compounds active on the nervous system. It was out either by high throughput screening of large shown, however, that PZQ does not compete for the chemical collections or by focusing on existing leads binding site of Ro 11-3128. and more promising potential targets. The first approach is currently supported by TDR (through Plant derivatives its drug discovery unit), but screening for antischis- A long list of plant-derived substances have been tosomals in vitro or in vivo is a rather expensive shown to be more or less active against various process and the funds available have not permitted, stages of the schistosome life cycle. Such substances so far, the large-scale operation that is desirable. As are often quite appealing for their ‘natural’ origin to the second approach, brief mention will be made and for their possibly inexpensive production in here of some examples of existing leads that might the same areas where schistosomiasis is endemic. be the object of further exploration. In many cases, however, these plant extracts are hardly acceptable mixtures of hundreds of unde- Acridanone hydrazones fined compounds, are quite variable in composition, A series of acridine derivatives synthesized by and would require elaborate processes for isolation Hoffmann La Roche (among them Ro 15-5458) have and identification of the active principle. Toxicity shown promising activity against the three major is often a problem that limits the use of such ‘nat- human schistosomes and, most importantly, against ural’ products. A systematic and rigorous study of both mature and immature stages.10,11 A single oral natural substances, however, remains one of the dose gave practically complete cure in mice, rabbits most promising sources of new drugs, including and primates. At least two members of the series antischistosomals. were active even after epicutaneous application on the skin of hairless mice. In addition, they are rela- Other potential drug targets tively simple chemicals that could probably be syn- A large number of potential drug targets exist that, thesized rather inexpensively. The major problem although not experimentally shown to be applica- with these acridine compounds is that they are typ- ble in antischistosomal chemotherapy, are neverthe- ical DNA-intercalating agents and may therefore less attractive because they have been exploited in possess mutagenic and carcinogenic properties. The other systems or against different pathogens. This bacterial tests performed so far have failed to show is a field of enormous interest, especially since the mutagenicity, but much more extensive toxicological progress of genomics is opening a number of schis- trials are clearly needed for this type of compound. tosome molecules to direct experimental testing.

Benzodiazepines Last but not least, it is quite possible that new drugs Several benzodiazepines have been shown to pos- against schistosomiasis may not come from efforts sess antischistosomal properties, among them the aimed directly at this specific goal, but may well be anticonvulsant clonazepam and its methyl deriva- the result of basic research on the biology of schisto- tive designated Ro 11-3128.12 The latter compound somes. Needless to say, investments in this area are was very effective in animals as well as in a prelim- never wasted. inary human study, but activity was confined to S. mansoni and S. haematobium, while S. japonicum was not affected. Immature schistosomes are also sensitive to Ro 11-3128. The problem is that, not surprisingly for a benzodiazepine, the drug causes severe and long-lasting sedation, accompanied by ataxia and muscle relaxation. This could be prevented by administering the benzodiazepine antagonist Ro 15-1788, which does not block the antischistosomal activity, but unfortunately the effect of the

74 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 References 1 Cioli D, Pica-Mattoccia L. Praziquantel. Parasitology Research, 2003, 90(Suppl 1):3–9. 2 Gryseels B et al. Are poor responses to praziquantel for the treatment of Schistosoma mansoni infections in Senegal due to resistance? An overview of the evidence. Tropical Medicine and International Health, 2001, 6:864–873. 3 Cioli D et al. Determination of ED50 values for praziquantel in praziquantel-resistant and -susceptible Schistosoma mansoni isolates. International Journal of Parasitology, 2004, 34:979–987. 4 Botros S et al. Current status of sensitivity to praziquantel in a focus of potential drug resistance in Egypt. International Journal of Parasitology, 2005, 35:787–791. 5 Triggle DJ. Stereoselectivity of drug action. Drug Discovery Today, 1997, 2:138–147. 6 Utzinger J et al. Combination chemotherapy of schistosomiasis in laboratory studies and clinical trials. Antimicrobial Agents and Chemotherapy, 2003, 47:1487–1495. 7 Greenberg RM. Are Ca2+ channels targets of praziquantel action? 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 studies of 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-hydrazones in Cebus monkeys experimentally infected. Revista do 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, against Schistosoma haematobium. Arzneimittel-Forschung, 2003, 53(1):57–61. 12 Stohler HR. Ro 11-3128, a novel schistosomicidal compound. In: Siegenthaler W, Luethy R, eds. Current Chemotherapy, Proceedings of the 10th International Congress of Chemotherapy, American Society of Microbiology, Washington DC, 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/07 75 WORKING PAPER 10. But vulnerability is not only a matter of individu- The sociocultural als’ risk behaviour. At the level of national and international socioeconomic processes, endemic areas context of schistosomiasis are ‘produced’ and maintained by water resources control: current development, by the dynamics of population move- knowledge and future ment (e.g. migration and tourism), by unplanned research needs urbanization, and also by the structures that mar- ginalize certain groups of people (e.g. women, certain ethnic groups, refugees). These larger scale Birgitte Bruun and Jens Aagaard-Hansen socioeconomic processes contribute systematically DBL – Institute for Health Research and Development, to increased vulnerability (Saker et al., 2004). Denmark, and Schistosomiasis Research Programme (SRP) Activities to control the infection can also be regarded as a specific sub-set of social processes, which condition access to diagnosis and informa- INTRODUCTION tion, and involvement in decision-making regarding health programmes. These issues have become par- The first initiatives to control schistosomiasis were ticularly prominent since the global control strategy implemented in Egypt around the First World War shifted from vector control to morbidity control and and have continued in various countries around the the human definitive host became the focus of inter- world ever since. Thus, for almost a hundred years ventions. Control programmes do not operate in a we have accumulated knowledge about the control sociocultural or political vacuum, but interact with of schistosomiasis. However, in spite of these efforts, national health systems that are influenced by a host the latest figures indicate that the number of infected of sociocultural and economic factors, including the people has risen. Since the first estimation almost 60 agendas set by the Millennium Development Goals years ago of 114 million people infected (Stoll, 1947), (MDGs), sector-wide approaches (SWAps), decen- today 200 million are thought to be infected (Engels tralization policies and poverty reduction strategies et al., 2002; Chitsulo et al., 2000). (PRS).

This rise can be partly explained by population As we move from a look at day-to-day activities, growth in some of the endemic areas, but this fact through the larger scale social dynamics that influ- does not diminish the challenge to public health, ence vulnerability, to the operations of control pro- particularly since the infection is increasingly found grammes and health systems, we gradually move in the poorest areas of the world where resources for away from a specific focus on schistosomiasis control are very limited. The challenge is of a tech- towards the underlying dynamics that determine nical nature in terms of the need for improved diag- (unequal) vulnerability to ill health. These dynam- nostics and treatment regimens, but it is also very ics are formed by political, economic, social and cul- much of a social and political nature. The process tural factors, or ‘the social determinants of health’, of making treatment available to the infected and, which is an illuminating conceptual framework indeed, of preventing people getting infected in the for understanding and addressing disease, includ- first place, is inextricably linked to specific socio- ing schistosomiasis. Research on the social deter- cultural, behavioural, political and economic factors minants offers quantifiable insights into important and processes at local, national and international variables, but also has the capacity to embrace anal- levels. yses of social processes, which can illuminate how vulnerability emerges in interaction with shifting The sociocultural factors and processes are many. policies and programmes for control (see working At the level of local day-to-day activities, transmis- paper 11 of this publication on: The social determi- sion dynamics are influenced by changing patterns nants of schistosomiasis). of water contact which are related to sociocultural expressions of age, gender role and occupation. The social sciences can provide insight into the social Cultural factors play a role in the identification of dynamics at local, national and international levels signs and symptoms, and when the severity of the that influence transmission and control. Social sci- disease is negotiated among other pressing concerns ence is an umbrella term for a host of very diverse in the household. These factors have implications for disciplines, of which economics, political science, the way people select and use possible alternatives cultural geography, communication, education, to unsafe water contact and for the way health edu- sociology and anthropology have contributed spe- cation and treatment options should be developed. cifically to knowledge regarding schistosomiasis.

76 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 This paper will mainly summarize selected research spective, consequences for willingness to partic- findings from the latter two disciplines regarding ipate in surveys, ethics, and the validity of data schistosomiasis control and point to future areas for (Goncalves et al., 2005; Hatz, 2001; Feldmeier et research on control activities. The paper is based al., 1993:162). on an ongoing comprehensive literature search, • Case detection and case management, which are including English, French, Chinese and Portuguese important in passive control strategies, depend articles, on sociocultural aspects of both the trans- on health personnel skills, capacity and moti- mission and control of schistosomiasis. It is our aim vation as well as on the income generating pos- to publish an annotated bibliography in 2006 under sibilities of health facilities (Bian et al., 2004; de the auspices of TDR. The compilation of the bibli- Vlas et al., 2004; van der Werf et al., 2004; van der ography is funded by the Schistosomiasis Research Werf et al., 2002; Sayed et al., 2000). Program (SRP) under the Schistosomiasis Control • Although the existence of genital schistosomiasis Initiative (SCI) funded by the Bill and Melinda Gates in women has been known since the beginning Foundation. of the 20th century, and much more recently has also become known in men, these forms of schistosomiasis appear to be seriously under-diag- CURRENT KNOWLEDGE AND nosed (Talaat et al., 2004; Leutscher et al., 2000; TOPICS FOR FURTHER RESEARCH Poggensee et al., 1999; Feldmeier et al., 1995). The REGARDING THE SOCIOCULTURAL extent of genital schistosomiasis is of particular ASPECTS OF SCHISTOSOMIASIS concern since this form of schistosomiasis may CONTROL interact with the spread of sexually transmitted As mentioned above, social science has explored infections, including HIV (Leutscher et al., 2003; transmission dynamics at local, national, and inter- Poggensee et al., 2001). national levels. This paper will, however, focus on studies of schistosomiasis control, which can largely Since survey data have essential implications be grouped into four main topics: for policy development and priority-setting, the • Diagnosis and case management observations above invite scrutiny with regard to • Health education the representativeness of data, specifically as to • Community involvement whether there is unbiased inclusion of marginal- • Schistosomiasis control in a broader health sys- ized groups. In this regard it should also be noted tems perspective. that the unknown extent of genital schistosomiasis means that its status as a public health issue remains The sections below will summarize selected findings unclear (Poggensee et al., 1999). under each topic and point to gaps in our knowledge. It should be emphasized that the findings and Topics for future research suggested topics for future research listed below • How can the social aspects of diagnosis, such as are localized and may not account for all endemic under-representation of women or the poorest, areas. be addressed in screening and surveillance? • How can the need for ethically and individually Diagnosis and case management acceptable methods of control that are also effec- Diagnosis and case management are often seen as tive at the community level be addressed? purely technical enterprises, but they can also be • What are the social and technical barriers to bet- perceived more broadly as ‘interfaces’ between the ter diagnosis of genital schistosomiasis in both infected individual, the afflicted community and the men and women? health care system represented by different types of health service, health care worker and researcher. Health education The literature related to schistosomiasis is very In schistosomiasis control, health education is seen limited in this field, but the following have been as instrumental in improving awareness of the infec- observed: tion and increasing knowledge about its transmis- • The acceptability of diagnostic tools and thereby sion. It is also seen to motivate behaviour change data on prevalence levels can be influenced by and to create an enabling environment where other social and cultural factors, including gender interventions, such as treatment and the instalment biases and economic constraints of the poorest of water supply and sanitation, are accepted. Finally, to join screenings and surveys. Only scarce data health education is sometimes intended to maintain are available on the links between acceptability sustainability of programme results and to build cit- of various diagnostic methods from the local per- izenship by engaging local stakeholders politically

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 77 in their local environment. The latter purpose is par- TB programmes, where active involvement of local ticularly prominent in studies from Brazil (Massara people is often at the core of the work (but where et al., 2004). success is rare in the lowest income countries). The next section will describe community involvement, In sociological and anthropological research related but first, a few research needs specifically related to to schistosomiasis, studies on health education are health education in schistosomiasis are: the most numerous. Such studies present various health education models for different target groups Topics for future research or they evaluate the impact of health education inter- • What are the factors involved when men, women ventions on perceptions, behaviour and/or levels of and children actually do change behaviour to prevalence. Findings are often similar to health edu- reduce the risk of schistosomiasis infection? cation initiatives for other ailments. Selected obser- • What is the experience when health education vations are: campaigns on schistosomiasis are combined with • Health education does not work if people have other health promoting campaigns? no (attractive) alternatives to unsafe water con- • How do people navigate between various per- tact. This observation applies equally to domes- ceived health risks and how can knowledge of tic, occupational, religious and recreational these strategies be incorporated into the design activities (Ekeh et al., 1988). and indicators of control programmes? • Health education messages are often conveyed in a way that appears irrelevant to local stakehold- Community participation ers’ experience, priorities and routines (Kloos, 1995). Many studies have looked at community participa- • Many health education initiatives do have an tion. The literature observes that community par- impact on knowledge. However, improved ticipation or involvement is sometimes understood knowledge does not necessarily lead to changed as an intervention along with health education and practice in order to avoid risk. In other words, sanitation, and more rarely it is understood as it was there is no linear connection between knowledge originally intended: as an approach to planning, and behaviour (as is also well known from many implementation and evaluation. It is a term with other diseases) (Kloos, 1995). a very wide range of uses, from mere rhetorics in • Health education is not a matter of pouring programme documents to actual partnerships and information into empty vessels. Health infor- action research (Espino et al., 2004; El Katsha et al., mation is always re-interpreted in the light of 1998). A critique observes how community participa- previous experience and translated into action tion is sometimes reduced to a matter of using vol- depending on what is socially, economically and unteers to reduce expenses and using local leaders practically possible and desirable for the indi- to ease acceptance of the programme. Furthermore, vidual and the household. Unfortunately, much local representatives are rarely included in decision- health education in control programmes does not making forums (Loureiro, 1989). However, it is a reflect this insight (El Katsha et al., 1994). misconception to believe that community partici- • Health education components of control pro- pation makes programmes less demanding in terms grammes are rarely systematically evaluated for of material and human resources (Kloos, 1995:1499). impact, and the few impact studies there have Furthermore, official representations of commu- been have produced varying results (Lucien et nity participation tend to down-play the ‘political’ al., 2003; Sow et al., 2003; Lansdown et al., 2002; aspects of the process, but in practice any interven- Nsowah-Nuamah et al., 2001; Garba et al., 2001; tion is ‘political’, whether it is labelled participatory Guanghan et al., 2000). or not. Especially studies from Brazil have high- • The possibility of developing a standard script lighted this particular aspect of schistosomiasis con- for effective health education is doubtful due to trol (Acioli et al., 1998; Dias, 1998; Barbosa, 1995). local variations. So far, health education on schis- Selected observations from studies on community tosomiasis has taken a myriad forms, involving participation in relation to schistosomiasis include: mass media, theatre, posters and brochures, elab- • Many policy-makers and implementers agree orate interactive education projects in schools, that communities can and should be involved and the animation of local educators. This com- in various aspects of control (e.g. snail control plicates any attempt to conduct comparative and environmental management). However, the analyses of impact (Kloos, 1995). translation of involvement into action is sometimes reduced to an issue of making people Many lessons about the more effective strategies for cooperate, partly due to the institutional logic of health education can be learned from HIV/AIDS and the 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-setting to contribute to control measures? What indica- are rare (Alves, 1998). tors of equity should be defined? • In many cases the term ‘community participa- • If women are more engaged in local control tion’ has lost its original meaning. A new term, activities, what is their motivation? What would ‘community-directed intervention’, has emerged make men become more engaged? How can we in onchocerciasis control programmes in Nigeria engage children both in and out of school? (that are now integrated with schistosomiasis • What are the conducive and constraining fac- and other intestinal helminth control) to indicate tors involved in letting local stakeholders take a higher degree of community responsibility for more control of programmes? To what extent are distribution of drugs and other aspects of control. programmers and health authorities at all lev- Studies have shown how this approach out-per- els ready to let go of control? What would the formed more conventional programme-designed institutional implications be, also in sectors other systems in effectiveness, acceptance, and cover- than the health sector? age (Katabarwa et al., 2005). • If capacity building is needed in this regard, • Few studies in schistosomiasis control have how can we avoid it becoming another and more assessed the relationship between the type of sophisticated way of vertical control with limited community participation and the impact and/ sustainability? or sustainability of prevention and control measures over time. Even fewer have looked into the Schistosomiasis control in a broader health social processes involved in community partici- systems perspective pation with the aim of generating more general There is a growing sense that advances in drugs, conclusions about the dynamics of social change vaccines and diagnostics are not enough to improve (Espino et al., 2004). health on their own, but that the systems by which • The concept of ‘community’ evokes the image these means are distributed need scrutiny. In malaria of a uniform organism with shared interests, control some voices claim that failure to control the but community representatives cannot always disease is not due to lack of tools but to failures at the be taken to act in the interests of all community societal and organizational levels (Heggenhougen et members (women, the poorest, ethnic or polit- al., 2003). Does this observation perhaps apply to ical groups, etc.). No community is completely schistosomiasis control efforts as well? homogeneous (Espino et al., 2004). • There are very few studies on how mobile pop- Apart from economic, political and governance ulations, or communities cut through by social, issues, there are also social and cultural aspects of economic and political divisions, can be involved schistosomiasis control at this level. Very few stud- in control activities, if at all (Espino et al., 2004). ies address these themes, but some of the observa- • Women generally maintain a higher and more tions and issues raised are: constant level of enthusiasm in surveys and con- • Understanding health-seeking behaviour and trol projects than men (Feldmeier et al., 1993:165). factors influencing the decision to self-report is • There is no single, universal way to moti- relevant for health planners (Danso-Appiah et al., vate community participation. Success largely 2004:785). Whether people seek treatment is not depends on factors that differ from village to vil- only a matter of their knowledge of the infection. lage, e.g. the authority of the village chief, the Perceived quality of health care, the cost of med- internal cohesion of the village community, the icine, and user fees are among the socioeconomic general economic situation and economic stratifi- and cultural factors that influence whether peo- cation (Hielscher and Sommerfeld, 1985:481). ple prioritize treatment (e.g. Uchoa et al., 2000) Topics for future research or seek alternatives within a pluralistic system (Muela et al., 2000). • What are the links between successful involve- • The exact dynamics of social development (bet- ment of local stakeholders in planning, imple- ter education, living conditions, sanitation, etc.) mentation and evaluation on the one hand and and schistosomiasis are unclear, but the infec- improved sustainability in different endemic set- tion tends to appear among the poorest and most tings on the other hand? underprivileged (Watts, 2005; Dias, 1998; Liese, • How can we best address the fact that schisto- 1986). somiasis is often found among the poorest and • Health workers and facilities are, most often, nei- most mobile groups who have the least resources ther equipped nor motivated for passive control (in terms of time, manpower and social relations) and case management (as mentioned above).

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 79 • User fees can skew case finding. If schistosomia- programmatic support in different settings? How sis control structures are vertical and situated to create synergy between local control efforts in a health system that is in the process of intro- and global initiatives? ducing user fees, there is a risk that “reducing • What are the social and political barriers to the the prevalence and incidence of schistosomia- necessary intersectoral collaboration and to pub- sis would be irrational behaviour from a short lic–private partnerships in schistosomiasis con- and medium-term profit perspective” (Bian et al., trol, which are absolutely paramount in water 2004:91–92). resources development and urbanization proc- • In relation to priority-setting, the measurement esses, not to mention general initiatives to reduce of burden of disease has been contested. The few poverty? disability measurements of cognitive development, working ability and income generation are FUTURE DIRECTIONS FOR even more controversial (King, 2005; Michaud et al., 2004; Parker, 1992). SOCIAL SCIENCE RESEARCH ON • Even if there was consensus on the burden of SCHISTOSOMIASIS CONTROL disease related to schistosomiasis, it might not The history of schistosomiasis control has fluctuated be the only factor in priority-setting. The bursts between control measures focused on one-dimen- of global attention paid to polio, malaria and TB sional, technical ‘quick-fix’ interventions on the one were not only the result of rational assessments hand and the application of multiple approaches of burden of disease and the availability of cost- on the other hand. This fluctuation occurred as the effective interventions. Their emergence on the ‘quick fixes’ seemed not to work (Reich, 1988) and global health agenda was driven not only by as new understanding of how the social dimensions the risk they posed to the North, but also by the in disease causation interact with technical innova- symbols and emotionally engaging images of dis- tions and changes in organizational/managerial set- ease threats, and by the role that various actors ups became available. There has been a tendency to and technologies could have in combating them focus on biological rather than social factors in the (Shiffman et al., 2002:231). transmission of schistosomiasis, except for brief periods in the 1930s and late 1960s (Sandbach, 1976:275). The issues raised above are similar to many other Today, for good reasons, treatment with praziqu- health concerns in developing countries and inex- antel is the backbone of control interventions, with tricably linked to the lack of political understand- increasingly refined ways of targeting populations ing and commitment, and financial and human due to increased attention to the cost–effectiveness resources. Thus, some of the proposed topics for of disease specific interventions. The long-term sus- future research below are not specific to schisto- tainability of this approach is, however, questionable somiasis control alone but could be part of a more due to the costs of repeated treatment, the possibil- generic research agenda. ity that the parasite will develop drug resistance, and the many practical challenges that control pro- Topics for future research grammes meet during implementation in complex • How will user fees for diagnosis and treatment sociocultural settings involving a variety of health affect equity in access to relevant medical serv- and non-health stakeholders. ices in different local settings? • How can the measurement of burden of disease If control efforts are to become more effective and and disability related to schistosomiasis be fur- sustainable, it is also necessary to work towards ther improved to strengthen priority-setting in better use of the available economic, technical and the health sector? human resources – and this implies (behaviour) • What is the evidence for the effectiveness, effi- change not only for the people who live on the ciency and sustainability of standardized control banks of lakes, rivers and streams but also for pro- programmes vs. programmes that adapt to local grammers and policy-makers at national and inter- concerns and conditions? national levels (e.g. Porter et al., 1999). Researchers • To what extent does the health sector have need to complement technical solutions with criti- the authority and capacity to explore innova- cal insights into the social and intervention manage- tive approaches and linkages to other health ment dynamics at all levels in order to strengthen promoting activities that are made to fit local the interventions. Further insight will be needed on conditions? modes of delivering various combinations of inter- • What would be the optimal mix between hori- ventions and on how local stakeholders can best be zontal implementation and vertical technical or involved in the processes of priority-setting. Such ‘grounding’ of the process might point to ways

80 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 that schistosomiasis control could ‘piggy-back’ on de Vlas SJ et al. Quantitative evaluation of integrated other interventions in the interests of local stake- schistosomiasis control: the example of passive case holders, whose health needs are already integrated. finding in Ghana. Tropical Medicine and International Whether such a process could lead to more appro- Health, 2004, 9(6):A16–A21. priate health service delivery if different control and Dias JC. [Community participation and control of prevention programme components were combined endemic diseases in Brazil: problems and possibili- in new ways should also be explored. The inclusion ties]. Cadernos de Saúde Pública, 1998, 14(Suppl 2):19– of social science perspectives will not make control 37. of schistosomiasis any simpler – but then again, it never was simple, as is evident from the perpetually Ekeh HE, Adeniyi JD. Health education strategies for high global numbers of infected people. tropical disease control in school children. The Journal of Tropical Medicine and Hygiene, 1988, 91(2):55–59. Acknowledgements El Katsha S, Watts S. A model for health education. The authors would like to thank the Schistosomiasis World Health Forum, 1994, 15(1):29–33. Research Program (SRP) for funding the work for El Katsha S, Watts S. Schistosomiasis screening and the forthcoming bibliography on the Social-cultural health education for children: action research in context of schistosomiasis transmission and control. Nile delta villages. Tropical Medicine and International Furthermore, we thank the following people for val- Health, 1998, 3(8):654–660. uable comments to the draft versions of this paper: Engels D et al. The global epidemiological situation Dr Susan Watts, Senior Research Associate, Social of schistosomiasis and new approaches to control and Research Center, American University in Cairo, research. Acta Tropica, 2002, 82(2):139–146. and Social Determinants of Health, WHO Eastern Mediterranean Regional Office, Cairo; Drs Pascal Espino F, Koops V, Manderson L. Community participa- Magnussen, Jens Byskov, and Niels Ornbjerg at the tion and tropical disease control in resource-poor settings. DBL – Institute of Health Research and Development, Geneva, UNICEF/UNDP/World Bank/WHO Special Denmark, and others. Programme for Research and Training in Tropical Diseases (TDR), 2004 (TDR/STR/SEB/ST/04.1 ). Feldmeier H, Poggensee G, Krantz I. A synoptic References inventory of needs for research on women and tropi- Acioli MD, de Carvalho EF. [Discourses and practices cal parasitic diseases. II. Gender-related biases in the concerning the social participation process in health diagnosis and morbidity assessment of schistosomia- education activities: community mobilization in the sis in women. Acta Tropica, 1993, 55(3):139–169. PCDEN/PE. Programa de Controle das Doencas Feldmeier H, Krantz I. A synoptic inventory of needs Endemicas do Nordeste/Pernambuco]. Cadernos de for research on women and tropical parasitic diseases. Saúde Pública, 1998, 14(Suppl 2):59–68. I. Application to urinary and intestinal schistosomia- Alves PC et al. [Schistosomiasis and the challenge of sis. Acta Tropica, 1993, 55(3):117–138. community participation]. Cadernos de Saúde Pública, Feldmeier H et al. Female genital schistosomiasis. 1998, 14(Suppl 2):79–90. New challenges from a gender perspective. Tropical Barbosa FS. Determination and control of schisto- and Geographical Medicine, 1995, 47(Suppl 2):S2–15. somiasis. Memórias do Instituto Oswaldo Cruz, 1995, Garba A et al. [Impact of health education programs 90(2):155–159. on the control of urinary bilharziasis in Niger]. Santé, Bian Y et al. Market reform: a challenge to pub- 2001, 11(1):35–42. lic health – the case of schistosomiasis control in Goncalves MM et al. [Sociocultural and ethical fac- China. The International Journal of Health Planning and tors involved in the diagnosis of schistosomiasis man- Management, 2004, 19(Suppl 1):S79–S94. soni in an area of low endemicity]. Cadernos de Saúde Chitsulo L et al. The global status of schistosomiasis Pública, 2005, 21(1):92–100. and its control. Acta Tropica, 2000, 77(1):41–51. Guanghan H et al. The role of health education for Danso-Appiah A et al. Determinants of health-seek- schistosomiasis control in heavy endemic area of ing behaviour for schistosomiasis-related symptoms Poyang Lake region, People’s Republic of China. The in the context of integrating schistosomiasis control Southeast Asian Journal of Tropical Medicine and Public within the regular health services in Ghana. Tropical Health, 2000, 31(3):467–472. Medicine and International Health, 2004, 9(7):784–794.

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Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 83 WORKING PAPER 11. The as an equity issue, as the disease is most common social determinants among poor, marginal populations. Moreover, it is now recognized as being associated with nutri- of schistosomiasis tional deficiencies that are a major barrier to social development. Susan Watts Social Research Center, American University in Cairo, PO Box 2511, Cairo 11511, Egypt. THE CHANGING EMPHASIS ON THE SOCIAL DETERMINANTS OF SCHISTOSOMIASIS The Commission on the Social Determinants of The importance of the social determinants of schis- Health (SDH) was launched by WHO in March tosomiasis for researchers and policy-makers is 2005. Its mandate is to trace the pathways by which reflected in the various constituent strategies of social determinants affect health status and out- control programmes. These have changed with the comes. Of these determinants, poverty is the key. development of new tools, new (measurable) objec- The Commission is also to recommend policies to tives, and new perspectives on what it is possible to tackle inequalities originating from the social deter- achieve through social action and public policies. minants. The concern for inequalities, and for ineq- In the era before praziquantel, the social context of uities, ‘unfair and remediable inequality’ (Feachem, treatment was largely ignored in the mass treatment 2000), is central to WHO’s mandate, harking back programmes carried out by authoritarian colonial to the original definition of health in the WHO regimes and their successors. Research on the social Constitution and in Health for All. determinants of transmission focused on water contact behaviour. With the introduction of praziquan- The SDH approach goes beyond a biomedical under- tel as an effective treatment in the 1980s, it became standing of schistosomiasis as it affects individu- important to identify social/demographic groups als to consider the social and behavioural setting to be targeted for treatment through the primary within which the infection is transmitted and has health care system. Programme objectives focused its impact. It encompasses every aspect of schisto- on the control of transmission, prioritizing, among somiasis transmission and control: diagnosis, treat- others, school-age children, who experienced the ment and care, preventive activities such as health largest number of infections and shed the largest education, vector control, and the provision of safe number of schistosomes. water and sanitation. Currently however, the core strategy of provid- In this paper, I will present a preliminary explora- ing treatment with praziquantel has as its objec- tion of the current challenges social determinants tive the control of morbidity. Risk groups have been present to schistosomiasis research, and how these re-defined as those vulnerable to infection and/or may affect plans for future research and control less likely to receive treatment through routine pri- activities in some of the poorest countries of the mary health care services. This approach echoes world. These challenges can be explored by way of the emphasis in the SDH on equity and reaching the knowledge networks WHO identified for the those in society who are most vulnerable. Three risk consideration of the Commission. They include: groups have been identified in the literature: measurement, health systems, employment condi- 1. Those engaging in certain occupations – espe- tions, globalization, early child development, urban cially fishing, and agricultural activities associ- settings, priority public health conditions, gender ated with irrigation. and social exclusion (Lee, 2005; Marmot, 2005; for 2. Women – during pregnancy, and exposure dur- more information on SDH see CSDH 2005[a] and ing domestic activities. 2005[b]). 3. Children of school age.

For the Commission, schistosomiasis is not likely to This change in focus occurred when research iden- be identified as a priority public health condition. tified previously hidden morbidity due to schis- However, some of the Commission’s concerns for tosomiasis. School-age children are of particular priority health conditions are relevant for schisto- concern, not only because of the high rates of rein- somiasis. These include the integration of SDH pol- fection, but mainly because of the association icies and actions into general health programmes; between schistosomiasis and stunting, vitamin A equitable access to public services; intersectoral deficiency and developmental and cognitive prob- action; and promoting equitable access to health lems. For pregnant women, deliberately omitted care. It is essential that schistosomiasis be regarded in earlier treatment programmes, treatment could

84 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 also help to limit nutritional deficiencies which are society. Because of this, poverty is often hidden, and exacerbated by schistosomiasis, especially iron defi- its extent underestimated. ciency anaemia. The UNDP Human Development Indicators (HDI) Attention among researchers and public health spe- are generalized measures of well-being. These indi- cialists is now shifting to sub-Saharan Africa, where cators are aggregated into a composite index and endemic countries are among the poorest in the ranked for each country. Those listed in table 1 are world. Here, schistosomiasis programmes will be relevant for the social determinants of schistosomia- operating in very different social and political envi- sis, and give an indication of the relative standing ronments from countries such as Egypt, Morocco, of various countries. However, because these fig- Brazil, the Philippines and China, which recently ures are averages, they do not identify the extent of claimed to have achieved successful morbidity con- inequality in a country, the gap between the aver- trol. These last mentioned countries are considered age and those at the bottom of the heap. Intensity of as being within the range of medium (rather than infection, morbidity and disease risk are likely to be low) human development. highest in the poorest sector.

All countries in the Low Human Development cat- SCHISTOSOMIASIS AS A DISEASE OF egory listed above are targeted for schistosomia- POVERTY sis treatment interventions. Except for Nigeria, the As of 2005, 85% of all schistosomiasis infections are most populous country in Africa, they have recently found in sub-Saharan Africa, mostly among poor been added to the list of countries covered by the people who live in remote areas, without access to Schistosomiasis Control Initiative (SCI). The poorest health services, safe water, sanitation, and educa- country, Niger, is at the bottom of the human devel- tion. We now need to give more attention to schis- opment league, 177th of 177 countries for which tosomiasis as a disease of poverty. Indeed, because records are available. of the particular dynamics of schistosomiasis transmission, and the need for treatment, it is possible Many of these countries have inadequate health sys- to argue that the presence of schistosomiasis can tems. It is difficult to provide meaningful figures be used as an indicator of poverty. What difference that capture the many aspects of access to health does this recognition of the link between poverty care. The proportion of births attended by skilled and schistosomiasis make to our research agenda, health personnel has been shown to be related to and to the way we present our findings to those child and maternal survival. This indicator can with the power to take action? also stand as a proxy indicator for general access to health care. For these reasons it is used as a key indi- The social determinants of schistosomiasis in cator for the Millennium Development Goals. Data sub-Saharan Africa for these countries on skilled birth attendants also show a large discrepancy between top and bottom Among the characteristics of poor people and poor wealth quintiles, with at least one third fewer births households relevant for schistosomiasis research in attended by skilled personnel in the poorest 20% sub-Saharan Africa are: of households compared to the richest 20% (UNDP, • Lack of access to resources, especially health 2005:table 8). services, safe water and sanitation, and education. • Poor people suffer poorer health than those who MEASURING THE SOCIAL are better off. They need more health care, but DETERMINANTS often get less. The poor are defined as ‘hard to Exploration of the social determinants of health reach’: care is more expensive and difficult to raises a number of methodological issues, chiefly deliver. related to measurement, that are not experienced in • Poor people are more likely to have an inade- the more quantitatively oriented discipline of epi- quate diet than the better off. demiology. Epidemiological studies can, often in a • Many poor areas and individuals have limited matter of weeks, measure the impact of treatment social capital, and limited access to social net- by comparing the levels of infection before and after works essential to obtain resources and overcome treatment. But it is likely to take much longer for periodic domestic crises. the impact of social determinants, be they changes in behaviour, in wealth status, or in access to water The result of these accumulated disadvantages is and sanitation, to show up in SDH evaluation stud- marginalization and social exclusion from the larger ies. Also the methods, definitions and scale of oper-

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 85 Table 1: Human Development Indicators

HDI Rank HDI index 1. 2. 3. 4. 5. 6.

Medium Human Development Ghana 138 0.520 21 42 26 45 59 44 Uganda 144 0.508 44 59 39 na na 39 Low Human Development Nigeria 158 0.453 40 62 25 70 67 35 Tanzania 164 0.418 27 54 44 20 82 36 Zambia 166 0.394 45 55 47 64 68 43 Mali 174 0.333 55 52 38 72 45 41 Burkina Faso 175 0.317 49 88 34 45 36 31 Niger 177 0.281 54 88 40 61 38 16

Definitions: 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-flush latrine, 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 nutritional deficiency). 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 those a daily basis; they become habitual activities that used in epidemiology. are handed down to children during socialization (Curtis and Cairncross, 2003). Community-based research is essential in SDH research to provide a view of schistosomiasis at the In the context of local conditions, many terms used local level, in the setting in which interventions actu- in discussions of the social determinants of schis- ally have an impact on health. Concern for the social tosomiasis take on specific significance. For exam- determinants of schistosomiasis involves coming ple, with the recent emphasis on occupation and to an understanding not only of what local people vulnerability to infection, survey questions need to do, but why. These ‘why’ questions illustrate ‘proc- be re-evaluated. Many survey questions focus on ess’, linkages between behaviour and what local the major occupation. However, surveys should people consider is feasible and appropriate, given include a full range of work-related activities, by their knowledge, priorities and skills. Processes are women and men, as these affect such things as the difficult to measure objectively, but the dynamics time available to visit health centres for treatment, of change can be analysed rigorously. Information and exposure to infection during farming. Poor peo- on topics such as water use and treatment-seeking ple need to engage in a multiplicity of activities to behaviour can be used for health messages and for ensure household survival. Women’s activities are planning improvements in access to safe water and especially likely to be missed as they occur in the sanitation. informal sector. They include preparing and sell- ing food, looking after cattle and poultry, and work- In tropical Africa, detailed studies of handwashing alongside their husbands in the fields. Women’s ing, a critical hygiene behaviour in the prevention domestic roles can also be seen as contributing to of diarrhoeal disease, have been carried out in rural work-related activities, as they support household settings with poor access to safe water and sani- members engaged in income-generating activities. tation. These studies have been used to develop Domestic water management (collection, storage, hygiene education and rapid assessment protocols use and disposal of water) can consume many hours for use at the community level. Changes in daily a day when there is no water, or no adequate drain- water use (relevant for schistosomiasis control) and age for waste water within the house (Watts, 2004; handwashing have a high likelihood of being sus- El Katsha and Watts, 2002:22–28). tainable once established, as they are repeated on

* 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 to schistosomiasis (Feldmeier et al., 1999; Leutscher et access resources, is a vital resource for people in all al., 2005). societies. Horizontal networks, mostly involving kin and neighbours, help people respond to domestic The impact of globalization on crises, while vertical networks link them to those schistosomiasis with more ‘social power’ and help them gain access Globalization can be briefly defined as a long- to education, health care, subsidized food, etc. term process of increasing global connectivity and Although people in poor communities often have change. It is often associated with increasing pov- little social capital, some have good social networks, erty, as poor people are vulnerable to loss of employ- which, because they operate informally, are outside ment (due to changing global market structures) and the purview of official observers who belong to a rights to health care (due to failing health systems, different social class. These local variations must be regulated by structural adjustment programmes). recognized (Szreter and Woolcock, 2004). Globalization means, in most cases, that control of the financial affairs of a country resides beyond its RESEARCH IMPLICATIONS borders. (See also the TDR publication on globali- Researching gender zation and infectious diseases [Saker et al., 2003], which reviews the changes in disease distribution, The term ‘gender’ refers to the social roles, respon- transmission rate, and disease management). sibilities and activities of males and females. Gender is socially determined, while the term ‘sex’ is biolog- Population movements are increasingly due to glo- ically determined; therefore it is not enough to sim- balization. Non-immune populations can be exposed ply replace the term ‘sex’ with the term ‘gender’ in to infection in new areas; infected people can move epidemiological studies. The need to disaggregate to new areas taking schistosomes with them. Poor data according to gender is well known. Aspects people moving to new areas often fail to escape the of gender relevant to schistosomiasis include: gen- poverty that drove them to move in the first place. dered tasks, gendered spaces, and gendered treat- Forced population movements are associated with ment-seeking behavior (El Katsha and Watts, 2002: extreme vulnerability to disease, especially due to chapter 9). malnutrition and the absence of safe water and sanitation. Sub-Saharan Africa has the largest number of Current treatment strategies, which focus on vul- refugees of any world region, around 2 700 000. The nerable women, need to take a holistic view of the data on those who have been internally displaced status of women, and their lack of social power, are less reliable, but suggest far larger numbers, contrasted with the social and economic priority overall, than those officially recognized as refugees granted by the wider society to men. Pregnant and (UNDP, 2005:table 23). lactating women, neglected until recently in treatment programmes, need treatment for schistosomia- Researchers need to update the earlier assessments sis and nutritional deficiencies that affect their own of how water resources development affects the sta- health and the health of their unborn children. How tus of schistosomiasis (Hunter et al., 1993). The eco- can such treatment reach those who need it most, logical and social disruptions caused by large dams and to what extent can it be combined with other are now better understood than they were ten years programmes that involve women and their young ago. Current concern about the Three Gorges Dam children, such as nutritional supplements and on the Yangtze River in China appears to focus on vaccination? ecological change (the movement of vector snails), but construction also involves a vast forced and vol- Community-based studies of female genital schis- untary movement of millions of people, carrying tosomiasis (FGS) are needed. These require gen- with them their diseases, culture and behaviour. Is der sensitivity in working with local populations, it still sufficient to call for intersectoral collaboration and health staff, as the infection has symptoms that in planning and in disease impact assessment? What mimic sexually transmitted diseases (STDs). They role, if any, do international agencies, donors and also require a detailed knowledge of local gender other interested parties have in protecting the health dynamics, and reaching out to men as well as to of people affected by such projects? women (Talaat et al., 2004). We need more community studies on FGS associated with S. haematobium; Urbanization is also an aspect of globalization, with there are none as yet on FGS due to S. mansoni. There the push/pull pressures of rural poverty and urban have been few community studies of male genital opportunity resulting in movement to towns. Many impoverished people move to shanty towns on

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 87 the peri-urban fringes of large population centres, national organizations and donors. It is directed where infrastructure for health, water and sanita- primarily at streamlining management, upgrading tion has not yet been established. Assumptions that facilities and training health personnel. Its involve- schistosomiasis is a rural disease need to be revised ment in actual health interventions is limited to the because: effective delivery of a package of essential services. 1. Rural people bring their diseases with them to Relevant essential services for an endemic area may the rapidly expanding population centres. include schistosomiasis surveillance and treatment. 2. Unsafe sanitation and water supplies, plus HSR planners pay lip service to equity in access unchanged behaviour, will facilitate the estab- to health care. However, in practice, HSR policies, lishment of disease transmission in urban focusing on management-related issues and cost slums. effectiveness, do not leave much room for equity 3. Migration and globalization have broken down considerations. Even among uniformly poor popula- established ideas of what constitutes ‘rural’ and tions, the very poor may not be reached (Armstrong ‘urban’. These definitions are not consistent et al., 2003). from country to country. Definitions reflect past cultural and social realities, and administrative Children of school age convenience. In the Nile delta, water and sanita- A major SDH knowledge area is early child devel- tion conditions in villages with a population of opment. However, many health problems faced 10 000 or more may be similar to those in poor by older, school-age children are similar to those urban areas. In Brazil, metropolitan regions are of younger children. They are also rooted in social defined as urban but appear to include small determinants such as poverty, malnutrition, and scattered settlements in which conditions are poor hygiene that are linked to the lack of safe very similar to those in rural areas. water and sanitation. New research approaches are needed on the nutritional vulnerability of school- Governance is a globalization issue, as today, more age children who suffer from schistosomiasis and than ever before, many decisions made by a gov- other intestinal parasites. ernment are limited, or controlled, by international institutions, multinational businesses and regulatory In poor endemic countries in sub-Saharan Africa, frameworks; some have a positive impact, many are up to one-third of the children under five may be negative. Governance can be defined as ‘a set of stunted, indicating long-term nutritional defi- traditions and institutions by which authority in a ciency. Most attention focuses on growth deficit country is exercised’. The main areas of concern for among young children but it is likely to continue governance are: voice and accountability, political as polyparasitism, which impedes the absorp- stability, government effectiveness, the rule of law tion of nutrients, and children face added nutri- and corruption (Kaufmann et al., 2003). Corruption ent demands during puberty. Studies among older is facilitated as corrupt local nationals take advan- children have found a correlation between schisto- tage of international financial facilities to siphon off somiasis and childhood stunting. Assis et al. (2004) vast sums of money that could have been used for pioneered a new approach by including food intake social programmes. Indicators of good governance when looking at nutritional status and S. mansoni are subjective, and depend on the preconceptions infection in the poor north-eastern Brazilian state and objectives of those making the assessments. of Bahia. They found that children aged 7–14 who They can provide a general indication of the extent were heavily infected or had an inadequate intake of to which governments can provide services to their lipids (fats) were at higher risk of stunting than non- people that are affordable and equitably distributed. infected children. They are often used by donor agencies to determine whether debt can be forgiven, and if aid should be This research suggests possibilities for further explo- provided, and if so, how much. Especially in poor ration of the link between inadequate nutritional countries that are heavily aid dependent, coordina- intake and schistosomiasis, drawing on findings in tion by donors at the national level now strongly local settings, and incorporating considerations of supports intersectoral planning. This offers intrigu- local dietary preferences and food availability and ing new possibilities for health ministries to think affordability. Such research could also strengthen outside their usual parameters, and for disease con- the argument for delivering schistosomiasis treat- trol programmes to become more closely integrated ment alongside treatments for other locally endemic with other health initiatives. diseases, and nutritional supplements. This would be cost effective, as treatment would target the same Within ministries of health, health sector reform groups. (HSR) is heavily influenced (and financed) by inter-

88 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 More research is needed on locally appropriate strat- activities encouraged (or dictated) by new globaliz- egies to treat out-of-school children as less than half ing forces, including multinational companies and of the children in endemic countries in Africa may international health programmes. Schistosomiasis be enrolled in school. While many children with- programmes should now be identified as networks: draw or attend school irregularly because they are a web of relationships that links organizations and needed to work or live far from school, only a small individuals across organizations (Reich, 2002). proportion will attend regularly enough to be covered in school-based programmes. However, out- The health priorities of poor countries in sub- of-school children are more likely to be at risk of Saharan Africa, especially those being devastated infection. A study in a poor rural area of Egypt by the HIV/AIDS epidemic, also need to be recog- found that out-of-school children, especially girls, nized by researchers. Providing basic health care in had far higher rates of infection than did those in low income countries costs around US$ 30–40 per school. The research team designed a protocol for capita, yet most poor countries spend less than US$ reaching these children within the existing school- 6 per capita on health (UNDP, 2005:63). People liv- based framework (Husein et al., 1999). ing on less than US$ 1 a day cannot be expected to pay for health care. In such a context, the concept of In poor countries in Africa, the deworming pro- cost recovery is a non-starter that can only succeed gramme supported by Partnership for Child in shutting out the poor from health care. Just over Development (which includes treatment for schis- one-third of the people in sub-Saharan Africa live tosomiasis) is being delivered through schools, on in countries that have experienced a decline in HDI the grounds that schools are more ubiquitous than since 1990 because of the combined impact of HIV/ health centres, and that teachers can be trained to AIDS and structural adjustment policies (UNDP, give out the drugs. Little research appears to have 2005:21). Even if current attempts to relieve debt use been done on delivering treatment to out-of-school the money to restructure health and education, the children in these countries through the school sys- challenge for the poorest countries to provide effec- tem. Given the focus on school-age children, and the tive and sustainable schistosomiasis control is for- proven role of education in fostering social devel- midable. Where should schistosomiasis research opment and health, such health programmes could position itself in this new context? form part of an overall strategy to encourage school attendance by children from poor families by pro- CONCLUSIONS: NEW DIRECTIONS viding free meals, health care and small payments to children who attended regularly. If a school sys- FOR RESEARCH ON THE SOCIAL tem is not deemed suitable for the delivery of such DETERMINANTS OF HEALTH programmes, alternative strategies for reaching Research on the social determinants of schistosomia- school-age children could be modelled on commu- sis is now focusing on the poorest populations in nity-based strategies such as those used in Uganda sub-Saharan Africa, where governments and house- to deliver treatment for schistosomiasis, onchocer- holds have very limited resources. The poorest peo- ciasis and intestinal helminths, and in Nigeria for ple, those least likely to be able to pay for health schistosomiasis, lymphatic filariasis and onchocer- care even if it is provided nearby, are those most ciasis (Ndyomugyenyi et al., 2003) likely to be at risk from schistosomiasis. A research agenda needs to incorporate the following specific The challenge of new strategies and areas of research that reflect the current realities in competing health priorities poor countries in sub-Saharan Africa: • The impact of population movements on schisto- Today schistosomiasis control has moved away from somiasis control. its earlier focus on integrated projects incorporating • A new look at gender and schistosomiasis: wom- specific schistosomiasis-related interventions such en’s vulnerability; pregnant women; female (and as diagnosis, treatment, health education, vector male) schistosomiasis; the structural underpin- control, and coordination with programmes to pro- nings of women’s low status that result in their vide safe water and sanitation. At the present time, marginalization in the control programmes of schistosomiasis is more often seen as an element in various countries and localities. broader programmes that combine schistosomiasis • Strategies for reaching school-age children control with other health interventions. At the same that take account of local conditions, feasibility, time the distinction between top-down vertical dis- sustainability. ease-specific programmes and local-level horizon- • The role of urbanization, including the extent to tal programmes may no longer be relevant. The new which schistosomiasis is an urban or rural prob- emphasis is on intersectoral programmes and other lem, and whether these terms are still relevant.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 89 Some of these conclusions are not specific to schisto- Lee JW. Public health is a social issue. The Lancet, 2005, somiasis. They are the unavoidable consequence of 365:1005–1006. linking the disease to poverty, and of looking at the Leutscher PD et al. Increased prevalence of leuko- situation from a vantage point largely outside schis- cytes and elevated cytokine levels in semen from tosomiasis research. Within this framework, equity Schistosoma haematobium-infected individuals. Journal becomes a central issue. Technical topics, such as the of Infectious Diseases, 2005, 191(10):1639–1647. social aspects of diagnostics and morbidity measurement, may appear less important but they, too, El Katsha S, Watts S. Gender, behavior, and health: schis- can be filtered through the lens of equity. In terms tosomiasis transmission and control in rural Egypt. New of schistosomiasis research and methodology, an York and Cairo, American University in Cairo Press, approach to schistosomiasis via its social determi- 2002. nants requires some new definition for once stand- Kaufman D, Kraay A, Mastruzzi M. Governance mat- ard concepts, and a methodology for appropriate ters III: governance indicators for 1996–2002. World Bank locally oriented research. working paper, 2003 (http://worldbank.org/wbi/ governance/pubs/govmatters3.html).

Marmot M. Social determinants of health inequalities. Acknowledgements Lancet, 2005, 365:1099–1104. I am grateful for comments and encouragement Ndyomugyenyi R, Kabatereine N. Integrated commu- from Jans Aagaard-Hansen, Birgitte Bruun and nity-directed treatment for the control of onchocercia- Sheldon Watts. Susan Watts alone is responsible for sis, schistosomiasis and intestinal helminths infections the views expressed in this publication. in Uganda: advantages and disadvantages. Tropical Medicine and International Health, 2003, 8(11):997–1004. References Reich MR. Reshaping the state from above, from within, from below: implications for public health. Social Armstrong J et al. Inequities among the very poor: Science and Medicine, 2002, 54:1669–1675. health care for children in rural southern Tanzania. The Lancet, 2003, 361(9357):561–566. Saker L et al. Globalization and infectious diseases: a review of the linkages. Geneva, UNICEF, UNDP, World CSDH (Commission on Social Determinants of Bank, WHO Special Programme for Research and Health). Towards a conceptual framework for analysis and Training in Tropical Diseases, 2004 (Social, Economic action on the social determinants of health. Draft discus- and Behavioural Research, Special Topics no. 3 [TDR/ sion paper for the CSDH, May 2005. Geneva, World STR/SEB/ST/04.2]). Health Organization, 2005[a]. Szreter S, Woolcock M. Health by association? Social CSDH. Action on the social determinants of health: capital, social theory, and the political economy of learning from previous experience. Background paper public health. International Journal of Epidemiology, for the CSDH, March 2005. Geneva, World Health 2004, 33(4):650–667. Organization, 2005[b]. Talaat M et al. The social context of reproductive Curtis V, Cairncross, S. Effect of washing hands with health in an Egyptian hamlet: a pilot study to iden- soap on diarrhoea risk in the community: a systematic tify female genital schistosomiasis. Social Science and review. Lancet Infectious Diseases, 2003, 3(5):275–281. Medicine, 2004, 58:515–524. Feachem RGA. Poverty and inequity: a proper focus UNDP. Human Development Report 2005. New York, for the new century. Bulletin of the World Health UNDP, 2005. Organization, 2000, 78(1):1–2. Watts S. Women, water management, and health. Feldmeier H et al. Male genital schistosomiasis and Emerging Infectious Diseases, 2004, 10:2025–2026. haemospermia. Tropical Medicine and International Health, 1999, 4:791–793. Hunter JM et al. Parasitic diseases in water resources development: the need for intersectoral negotiation. Geneva, World Health Organization, 1993. Husein MH et al. Who misses out with school-based health programmes? A study of schistosomiasis control in Egypt. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1996, 90:362–365.

90 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 WORKING PAPER 12. the influence of certain parameters on the overall Ecological and other conclusions can be assessed by varying one parameter at a time or using stochastic methods. Finally, factors related to they are useful for comparing the potential cost schistosomiasis effectiveness of alternative control strategies, information that is important in the decision-making Stephen T. McGarvey process when only scarce resources are available. International Health Institute Brown University, These models are however limited because they do Providence, RI 02912, USA not include individual contact rate and assume that all individuals of a given age acquire infection and contaminate the environment at the same rate.

INTRODUCTION AND For the case of S. japonicum, building transmission BACKGROUND models may require inclusion of domestic and wild Schistosomiasis infection and disease control pro- animals’ infection parameters. A review of non- grammes using praziquantel have generally been experimental studies in China that we published successful in reducing intensity of infection and several years ago indicated reductions in human associated severe morbidities. But transmission infection in communities over time after changes remains active in many areas of the world with a in handling of animals and animal faecal disposal likely increase in the proportion of individuals practices. More recent work in press by D. McManus infected at low intensity levels. There is increasing and colleagues indicates that bovines, especially evidence that low intensity of infection appears to buffaloes, may be responsible for the persistence of be associated with level of malnutrition, assessed by human schistosomiasis transmission in the Poyang anthropometry and anaemia, as well as cognition. Lake region of Jiangxi Province. Their experimental Recent work by our group at Brown University also study tested the hypothesis that buffalo are major suggests that morbidity increases in schistosomia- reservoirs for human infection in marshland/lake sis patients co-infected with geohelminths. Thus, areas. After establishing similar characteristics in the further reduction of schistosomiasis transmission is study villages, they compared human and buffalo desirable. This follows from one of the WHO goals infection intensity and prevalence over several years to develop strategies for sustainable control. in an intervention village where humans and buffaloes were treated with praziquantel, and in a control One approach to sustainable control is to develop village where only humans were treated. Over the mathematical models of schistosomiasis transmis- four-year study, human schistosomiasis incidence in sion. Such models may provide useful insights for the intervention village decreased, but in the control predicting what effect chemotherapy control strate- village it increased. Buffalo chemotherapy resulted gies might have on the transmission dynamics of the in a decrease in buffalo infection rate in the inter- infection, and can measure effectiveness in terms vention village, which coincided with the reduction of number of cases of infection prevented. Models in human infection rate in the last two years of the may also test the effects of other interventions such study. Mathematical modelling predicted that buffa- as snail control, and, in the case of Schistoma japon- loes are responsible for 75% of human transmission icum, infection control in other mammalian defini- in Jishan. This experimental study not only shows tive hosts. the importance of bovines for transmission in China but suggests that mathematical models may be use- Age-structured population dynamic models for S. ful for providing estimates of the health and eco- mansoni and S. haematobium, useful for predicting the nomic impacts of human and animal chemotherapy development of early and late disease in humans, and environmental modifications to reduce schisto- have been developed and validated with field data somiasis transmission in China. by M.S. Chan and colleagues. This group also made models for the development of early and late dis- Related work on S. japonicum transmission model- ease due to S. japonicum but these did not include ling has been done by R. Spear and colleagues in animal hosts. These models assume that the larval Sichuan, China. These very detailed studies of trans- stage of the parasite is always at equilibrium (due to mission and associated factors focus on the develop- its very short life expectancy). Therefore they do not ment of mathematical models and pay close attention include parameters associated with changes in the to uncertainty in estimations, using Bayesian meth- snail and/or larval populations. ods to more accurately calibrate diverse data such as snail population biology, ambient air and water These models do allow sensitivity analysis where temperature, rainfall, spatial data and indices, S.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 91 japonicum infection parameters, including eggs and chemotherapy, snail control and environmental mod- estimated worms, and chemotherapy. Evidence ifications on human or animal infection. Our goal in indicates that focal snail control, egg control, and working on S. japonicum ecology and transmission crop type have a strong influence on infection trans- in The Philippines is to develop an age-structured mission. Based on data from 20 villages, the evi- dynamic model, using field data, that includes the dence shows that transmission is higher with use snail host, mammalian hosts, and parameters that of human and animal manure-based fertilizer for could represent the effect of anthropogenic environ- growing tobacco and vegetables compared to chem- mental changes due to farming, irrigation and live- ical fertilizers used for rice farming. They suggest stock management on the transmission dynamics. that composting and/or waste treatment of manure To our knowledge, no model has yet incorporated may reduce transmission. the whole ecology of the S. japonicum transmission cycle, including the animal, human and snail Another recent set of studies on schistosomiasis hosts. The mathematical model will help our under- transmission conducted by C. King and colleagues standing of the transmission dynamics of S. japon- focused on snail distribution and focality of trans- icum infection and help in predicting the effects of mission of S. haematobium in Kenya. Their anal- control strategies. Field data from a site where the yses focused on heterogeneities of S. haematobium disease has been in a state of equilibrium for sev- transmission across time and space on a sub-vil- eral years are needed to validate such a model and lage scale. They found significant clustering of infec- to assess the impact of rice farming techniques and tion intensity (density) around specific water sites, animal husbandry on the transmission dynamics of with the significance radius varying by age group. infection and disease in humans. Once the pattern The region of influence for a given site appears to of infection has been well described in a model, the be 500m–1000m. Further work on survival analy- parameters of mathematical models can be modi- sis of adjusted risk for reinfection by village is in fied, based on field data, to explain the dynamics of progress by this group and shows that village loca- transmission in other areas. tion remains most significant. Median time to reinfection varied from three years to well over eight We proposed the following specific aims: 1) to deter- years in villages situated right next to each other. mine the effects of variation and changes in irriga- The studies suggest that very local effects should be tion and rice farming methods on transmission of S. taken into consideration when establishing a control japonicum to snails and to human and animal defin- programme. itive hosts; 2) to determine the effect of variation in S. japonicum infection in animals, and of animal Related work by this group on treatment allocation behaviour and management practices, on S. japoni- strategies was aided by the development of a trans- cum transmission; 3) to develop a generalizable pre- mission model. This model assumed fairly constant dictive model of the ecology and transmission of S. transmission factors across the years, with some sites japonicum based on temporal and spatial variation being worse than others and distance effects similar in rice farming practices, human infection parame- to those observed in the field. For targeted efforts, it ters, and animal numbers and infection parameters; was clear that treatment of the subset of all children 4) to compare the predicted effect of anthropo- across the area was much more effective than treat- genic environmental change on human and animal ing the subset of 2–3 worst villages, either alone or S. japonicum infection using three different analytic several at a time. This was because of the interlock- approaches: a) a Bayesian hierarchical model; b) an ing transmission pathways between villages that age-structured population dynamic model; and c) a share water sites. In the latest ongoing modelling geographic information systems model. studies, the impact of treating one or more snail sites either alone or in combination with the delivery of The research uses a longitudinal observational human medication is being pursued. It is intended to design. At baseline we collected transmission take into account evidence of the seasonality of parameters for humans, other mammals and snails. infected snails, and thus design the optimal timing We also collected water contact data on humans and of possible snail control. socio-demographic information. The longitudinal follow-up interval was 12 months after baseline and mass treatment of all village residents. The major ECOLOGY AND TRANSMISSION OF outcome concerns human incidence of infection. S. JAPONICUM IN THE PHILIPPINES The major design contrast was irrigated villages vs. The brief summary above indicates that several non-irrigated villages to enable interpretation of dif- schistosomiasis research groups have developed ferences in infection transmission to humans that population dynamic models to assess the impact of are based on irrigation, after adjustment for other

92 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 aspects of S. japonicum transmission such as animal valid test could contribute to more effective public infection and management. health control programmes.

Hierarchical cluster sampling was used so that we Using this validated diagnostic test for animal infec- could estimate and adjust the effects of clustering tion, we estimated the S. japonicum infection pro- at different levels: individual, household, farm, and portions in 2178 dogs, 2379 cats, 4310 pigs, 1900 village. This is based on the fact that units of obser- water buffaloes and 1399 rats from which we col- vation in such an ecological study are not independ- lected faecal specimens for one to three days. The ent but clustered. proportion of S. japonicum infection over all 50 villages was 61.33% for rats, 30.30% for dogs, 4.24% for We chose 50 villages, 25 with water management cats, 1.93% for pigs, and 1.63% for carabao (water and 25 without water management. In each village buffalo). There was substantial inter-village varia- we randomly recruited 35 households and in each tion in animal prevalence. household we asked 4–6 members to participate. In each village we attempted to study 35 animals of The baseline human S. japonicum prevalence was each of five species: water buffalo, pigs, dogs, cats based on 1427 households and 6917 individuals and rice field rats. We made geocoded maps of all from 50 villages. A total of 5624 (81.3%) participants villages with water courses, water management and provided at least one stool sample. Using Bayesian rice fields included. Snail sampling was based on techniques to adjust for measurement error, the ocular survey of all water courses, and then sam- prevalences of those lightly and at least moderately pling at sites based on vegetation and flow charac- infected varied, respectively, from 0% (0%–3.1%) teristics that are usual for presence of Oncomelania to 45.22% (36.5%–53.9%), and from 0% (0%–1.6%) snails. A smaller pilot study to assess genetic differ- to 22.95% (16.39%–31.15%), from village to village. ences in S. japonicum across the several mammalian Using the 0–7 year old group as a reference category, hosts and in the snails is also under way. the odds ratio (OR) of being infected among males and females aged 17–40 years was 8.76 (6.03–12.47) Our results to date include the development and and among 11–16 year olds 8.59 (4.74–14.28). People publication of Bayesian modelling techniques to who did not work on a rice farm had a lower preva- estimate uncertainty of infection parameters by age, lence of infection than those working full time on a sex and village. These estimates were then used to rice farm. There was no difference in human infec- develop an age structured dynamic transmission tion intensity or prevalence between the irrigated model based on equilibrium transmission condi- villages and non-irrigated villages. tions in three Leyte villages in 1981 before praziquantel use. The model showed quite reasonable To estimate the association of animal and human results with mass treatment of humans and other infection at baseline, we used faecal samples for control measures on scenarios of snail reduction. The 5623 humans, 2178 dogs, 2379 cats, 4310 pigs, 1900 model structure will be refined as we integrate more water buffaloes and 1399 rats collected for one to detailed data from the ongoing data collection. three days. A Bayesian hierarchical cumulative logit model with adjustments for age, gender, occupation We developed and standardized animal parasitology and measurement error in the Kato-Katz method methods for assessment of animal infection inten- was used. The average eggs per gram of faeces (epg) sity, including adjustments for uncertainty. This is in dogs was strongly correlated with that of cats, based on an adaptation of the Danish Bilharziasis pigs and rats. The average epg in cats was associ- Laboratory (DBL) method. Faecal samples from all ated with that in dogs and pigs. The average epg animals were collected for one to five days in four in water buffaloes was not strongly associated with villages. For all species, the sensitivity estimates of that in any other animals. In univariate models, the only one stool sample were less than 80%. However, human infection ORs of a unit increase in the vil- the sensitivity improved to more than 96% in all lage-level average epg of cats and dogs were 1.98 species when three or more faecal samples were col- (1.25–3.22) and 1.15 (1.06–1.26), respectively. In mul- lected on three separate days. The specificity was tivariate models, intensity in dogs and cats was also estimated to be above 92% across all species, even if positively associated with the OR of human inten- just a single sample is used. Our results suggest that sity of infection. the DBL-technique is valid for the detection of infection with S. japonicum in animals, and that sensitiv- Unlike the suggestion from China, we did not find ity estimates are excellent when faecal samples are any association between the intensity of infection collected on at least three different days. Monitoring in water buffaloes and humans. This may be due to S. japonicum infection in animal reservoirs with a the low prevalence of infection, of less than 2%, in

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 93 water buffaloes and to the aggregation of two-thirds Financial Support of these infected animals in one village. This sug- The USA National Institutes of Health and National gests the epidemiology of S. japonicum in mammals Science Foundation, Ecology of Infectious Disease and its link to human infection is different in Samar Program: NIH Fogarty International Center Grant Province from that reported in China. no. TW01582. We are actively working in several areas, including: Collaborators • Estimating and testing an age structured dynamic transmission model with the baseline ST McGarvey, Brown University, USA. data. This includes spatial modelling. H Carabin, University of Oklahoma, USA. • The one-year follow-up after mass treatment, which was completed in December 2005. R Olveda, E Balolong Jr, V Tallo, R Gonzalez, P Alday, Analysis of follow-up infection rates will focus G Aligui on estimating the impact of human, animal, snail, Research Institute for Tropical Medicine (RITM), farming, geospatial and other characteristics at Manila, The Philippines. baseline and follow-up. • Development of an age-structured dynamic AL Willingham III, Danish Centre for Experimental transmission model using the longitudinal infec- Parasitology, Frederiksberg, Denmark. tion data and all relevant factors associated with T Fernandez Jr , Leyte State University, Baybay, The transmission in the regression models. Philippines. • Looking for the association between different S Riley, Hong Kong University, Hong Kong. spatial layers and infection incidence, to determine if any spatial associations with transmission J Webster, Imperial College, London, UK. are true effects or the result of failure to under- L Joseph, McGill University, Montreal, Canada. stand the different scales or levels, i.e. the ecological fallacy. H Madsen, Danish Bilharziasis Laboratory, Charlottenlund, Denmark.

94 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 WORKING PAPER 13. increased pollution of water bodies with human Research on the wastes might favour transmission, but pollution with agricultural or industrial wastes may have the molluscan intermediate beneficial impact of eliminating transmission, but hosts for schistosomiasis: for all the wrong reasons. Because schistosomes by what are the priorities? necessity follow the snails, we must not ignore the snails as they will ultimately dictate where in the Eric S. Loker world schistosomiasis can occur, and likely at what Department of Biology, University of New Mexico, level of prevalence it can occur. Albuquerque, New Mexico 87131, USA. Having said this, snails should not be viewed as the enemy – or the target. Indeed, they are, like us, unwitting participants in the life cycles of schisto- Abstract somes and other helminths of medical and/or veter- Human-infecting schistosomes and the snails that support inary significance. Snails are an integral part of the their life cycles remain all too common in today’s world, and biosphere and attempts to eradicate them are not we must remain diligent in funding studies related to these only misguided from a conservation point of view organisms. Dramatic changes in the distribution and abun- (Kristensen and Brown, 1999), but unlikely to be dance of snails hosting schistosomes are under way or can be successful (Lardans and Dissous, 1998). Given the anticipated, so we must closely monitor such changes because pervasive problems of pollution and introduction where the appropriate snails go, the schistosomes typically follow. We also need to continue to develop modern tools to of exotics (Pointier, David and Jarne, 2005), the day gain a deeper basic understanding of snail biology, and to bet- will likely come when the presence of indigenous ter comprehend the interactions between schistosomes and schistosome-transmitting snails in an aquatic habi- snails, particularly in real-life field settings. We need to apply tat will be considered a sign of environmental health modern techniques to learn more about the unseen natural and something about which to be happy. Rather it enemies of both snails and schistosome sporocysts, and to is the parasites that depend on snails and humans learn more about other relevant snail-transmitted pathogens, for their survival that must be controlled. This is including the species of non-human schistosomes that cause cercarial dermatitis. We must improve the dissemination of somewhat different from contemplating the control relevant information to workers in endemic areas who often of a typical arthropod-borne pathogen like malaria suffer from poor access to new knowledge. Finally, there is an where the vector, such as a mosquito, is also obnox- important need to maintain a critical mass of malacologists, ious and harmful to people in its own right. Snails both to capitalize on the promise offered by exciting tools are by contrast innocent bystanders. now or soon to be available, and to avoid losing our accumulated practical knowledge of medically important snails and their role in transmission of schistosomiasis. So, if snails are not the enemy, is there any real imperative to learn more about their biology? The answer is unequivocally ‘yes’ because the more we know about the intricacies of the parasite–snail rela- INTRODUCTION tionship (Lockyer et al., 2004), the broader is our conceptual base from which to draw unique solu- Without snails, there can be no schistosomiasis. tions regarding parasite control. Furthermore, as Because schistosome-transmitting snails occur in noted above, conditions in the developing tropics very particular ecological circumstances that are will favour massive changes in the distribution and subject to rapid change in an increasingly human- abundance of snails of medical or veterinary signifi- dominated world, one of the greatest challenges to cance. We need to be able to anticipate and respond understanding the future of this neglected yet per- to such changes. sistent human disease is to try to understand how snails will be affected by global changes in climate, increased pollution of aquatic habitats, continued MONITORING AND PREVENTING transport of exotic and invasive species, construction CHANGES IN SNAIL DISTRIBUTION of dams and irrigation systems, mass movements of AND ABUNDANCE humans, and changes in human population density and standards of living. Some of these factors such The aquarium and aquatic plant trade, the inces- as continued high levels of poverty and civil unrest sant movement of people and their goods, and even will have more predictable effects on transmission, natural dispersal events, all conspire to move snails but others, like climate change, pollution of aquatic from one location to another (Pointier, David and habitats or movement of exotic species, will have Jarne, 2005). The hermaphroditic or parthenoge- impacts that are far harder to predict. For example, netic reproductive habits of many snails (Jarne and Stadler, 1995) favour their successful introduction

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 95 into new locations. Thus a Biomphalaria glabrata-like is that such habitats will increasingly be colonized snail was dispersed naturally to Africa within the by globe-trotting snails with high levels of tolerance past five million years creating dramatic new oppor- for pollution, such as physids (Dillon et al., 2002). tunities for schistosome parasites there (Woodruff Fortunately, although physids do transmit derma- and Mulvey, 1997; Campbell et al., 2000; DeJong et titis-causing avian schistosomes, they do not play al., 2001). Through the activities of humans, ironically a role in the transmission of other parasites of med- likely those involved in schistosomiasis research, the ical or veterinary significance, although the likeli- ‘second coming’ of B. glabrata to Africa, to the Nile hood of them acquiring such a capability cannot Delta, was accomplished in the last 50 years (Lotfy be discounted. The uncertainties regarding where et al., 2005). The neotropical Biomphalaria tenagophila and when new situations will arise with respect to has appeared in central Africa (Pointier et al., 2005), snails is further compounded by the impact of glo- and B. straminea, a particularly invasive exotic, now bal climate change (Martens et al., 1997; Sutherst, thrives in Asia and many other parts of the world 2004) and the construction of massive water devel- (Pointier, David and Jarne, 2005). The latter two spe- opment projects such as dams that influence snail cies can both host S. mansoni. Indoplanorbis exustus, habitats across huge areas (Zheng et al., 2002; Sow the host for three schistosome species of ruminants et al., 2002). in southern Asia, has also appeared in Africa and the Caribbean region (Pointier, David and Jarne, 2005). WHO has a role to play with respect to encouraging Fortunately, other introductions, such as of Bulinus regulations that make it less likely for snails to be species to the neotropics, have not to our knowledge accidentally distributed, for providing updates about yet been effected, and all measures should be used where and when new introductions have occurred, to prevent this from occurring. and possibly assisting focal control programmes where feasible to eradicate newly-introduced exot- At the same time as potential schistosome hosts are ics of medical significance. It is also imperative to being redistributed, other snails such as Melanoides highlight the global degradation of freshwater hab- tuberculata or Helisoma duryi are also being widely itats and the host of public health problems associ- introduced around the globe, including to the ated with this degradation. It is sobering and ironic neotropics. Although these introductions may to imagine that WHO could some day announce the have beneficial impacts on schistosome transmis- eradication of schistosomiasis from the Nile delta, sion, as observed particularly on the Caribbean but any excitement would potentially be muted islands, they ultimately have many unfavourable by the realization that the eradication was because aspects (Kinzelbach, 1995), such as displacement the aquatic habitats there were so fouled as to pre- of native (often endangered) snails and poten- vent any self-respecting macroinvertebrate such as a tial to introduce associated trematodes (Scholz and snail from surviving. Salgado-Maldonado, 2000), that may also threaten endangered native vertebrate species. Because of the massive scale of anticipated environmental change, studies to understand the basic Less dramatic range extensions, such as of B. glabrata ecology and ecological preferences of schistosome- into southern Brazil (Graeff-Teixeira et al, 2004) or of transmitting snails remain critical. In particular, B. alexandrina down the course of the Nile (Lotfy studies that help to define the nature of competitive et al., 2005), also bear scrutiny. As noted recently interactions with invasive snails such as Melanoides in Nature (Marshall, 2005), and as seen all too com- (Giovanelli, Vieira, and da Silva, 2002; 2005), or that monly in snail habitats in both the neotropics and help to define the tolerances of snails with respect Africa, many of the aquatic habitats in which schis- to different categories of pollutants, are particu- tosome-transmitting snails occur are now incredi- larly important. Also helpful for understanding bly fouled by pollution. It is often necessary to kick the impact of changing habitats across broad geo- away the refuse to get to the water to find snails graphic scales are remote sensing techniques (Seto which are nonetheless there and even thriving. The et al., 2002). impact that such rampant pollution will have on schistosomiasis will be significant. For example, The highest priority for the WHO with respect to what is causing the change in distribution of schisto- molluscan aspects of schistosomiasis is to recognize somiasis along the course of the Nile (Abdel Wahab that snail and parasite faunas are in a state of rapid et al., 1993), with sharply falling prevalence of S. flux and that this may create surprising new oppor- haematobium and a rise in the relative abundance of tunities for transmission in some places, may pre- S. mansoni? Among the many possibilities that must vent transmission in others, and may serve as a bell be considered is the role of pollution, now extensive weather for detecting even more profound environ- in the canals of the delta. A reasonable expectation

96 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 mental and health changes associated with degrada- invaluable to have microarrays so that the transcription of aquatic environments around the world. tional activity of snail genes, such as in response to schistosome infection or changing environmental circumstances, can be monitored. cDNA micro- DEVELOPING A MODERN TOOLKIT arrays with over 2000 non-redundant features have TO STUDY THE BASIC BIOLOGY already been developed in the UK (C.S. Jones, per- OF SNAILS AND ASSOCIATED sonal communication), and oligo-based arrays are PARASITES under construction in the US. The microarrays can At the same time as maintaining a global overview be updated and enlarged as we obtain information of the biogeography of snails and associated para- about more snail genes. Going hand in hand with sites, it is also necessary to ‘turn inward’ and gain the development of microarrays is the development a greater appreciation of the basic biology of snails, of expressed sequence tag (EST) libraries, both by trematode larval stages, and their interactions. For individual investigators (C. M. Adema, personal this, a modern toolkit is required. Given the enor- communication; Mitta et al., 2005; Davison and mous impact that modern approaches have had on Blaxter, 2005) and through the assistance of sequenc- furthering our understanding of mosquitoes and ing centres. The Sanger Centre, for example, is likely their parasites (Heckel, 2003; Christophides et al., to provide 100 000 ESTs to complement the B. gla- 2004), no less should be sought for the snails that brata genome sequencing effort. transmit schistosomes and other parasites. The first paper using RNA interference (RNAi) One of the most prominent model organisms among to facilitate functional studies of snail gene prod- snails is Biomphalaria glabrata: it is relatively easy to ucts has recently been published (Jiang, Loker and rear in the laboratory, as is its associated parasite, Zhang, 2006). The FREP2 gene, normally expressed Schistosoma mansoni. One disadvantage of the wide- at increased levels following exposure to dige- spread study of B. glabrata is the possibility that it netic trematode parasites such as S. mansoni or will be accidentally introduced into new locations. Echinostoma paraensei, was targeted for knockdown. Studies with B. glabrata have already shown the Double-stranded RNA (dsRNA), corresponding to potential to illuminate general principles of inverte- specific regions of the FREP2 gene, was introduced brate immunobiology (Zhang et al., 2004) and host- into snails by direct injection into hemolymph. parasite interactions (Lockyer et al., 2004), so the Knockdown efficiency was examined at the tran- impact of these studies is important on a broader script level using quantitative polymerase chain stage as well. reaction(PCR) (qPCR) and Northern blot analysis, and expression levels were shown to be significantly Development of modern tools for use with B. glabrata reduced (~70%–80% knockdown). The establish- is well under way, with the support and encouragement of RNAi techniques in B. glabrata will enable ment of a consortium of biologists working with us to elucidate the function of genes that we believe snails, and several funding organizations includ- play a role in defence against pathogens such as S. ing WHO. The National Human Genome Research mansoni. Institute (NHGRI) has supported the construction of a high quality bacterial artificial chromosome Proteomics is yet another important approach to be (BAC) library that is now available to the pub- developed with respect to snail–schistosome stud- lic. Furthermore, B. glabrata has been selected by ies. Automated mass spectrometry approaches the NHGRI to be the subject of a genome sequenc- offer the promise of providing enormous quantities ing project,** which will likely be completed before of information regarding the protein and peptide the decade is over. Both BAC library and genome composition of individual snail organs or tissues. sequencing projects feature the BB02 strain of B. gla- Having information about the snail proteome will brata, an S. mansoni-susceptible isolate recently col- prove to be useful in providing annotation to the lected from Minas Gerais in Brazil.*** This will be huge amount of snail genome sequence anticipated among the first molluscan genome sequences to be to be forthcoming. Another valuable tool already completed. available for use is the ability to culture trematode larvae in the presence of cells of the Biomphalaria gla- Other important tools are already being developed. brata embryonic cell line (Bge cells) (Coustau and To go along with the genome sequence, it will be Yoshino, 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.html

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 97 raising the potential for eventual routine culture of destroyed. The low prevalence of infection noted schistosome sporocysts without the need to main- following exposure to low doses of miracidia in nat- tain snail colonies. ural snail–schistosome combinations suggests that such mismatches regularly occur in the field, and can Although the first priority will be to develop the play an important role in diminishing the number of toolkit to support studies of B. glabrata as a model, patent infections achieved. Having better tools to thus enabling us to gain deeper insights into snail– assess the early fate of sporocysts in snails would schistosome interactions, we should most emphati- help us to understand the role of this phenomenon cally not lose sight of the fact that most human cases in nature. For example, using a PCR-based assay of schistosomiasis still occur in Africa, and probably to monitor the presence of S. haematobium larvae always will. Thus it will be relevant to learn more in bulinid snails, Hamburger et al. (2004) showed about species such as Biomphalaria pfeifferi, Bulinus that many more snails had been exposed to para- truncatus, and Bulinus globosus which play important sites than had actually developed cercariae-produc- roles in transmission in tropical Africa. Transferral of ing infections. An explanation consistent with the much of the technology to these species should then data is that miracidium–snail encounters are more be possible and should be encouraged because it common than realized, but that a failure of some should not be assumed that the fundamental nature sporocysts to develop in some snails keeps patent of all schistosome–snail relationships is the same. infection rates low. This has fundamental implica- This might be particularly true for the Asian schis- tions with respect to schistosome transmission. tosomes transmitted by pomatiopsid snails which have generally been little studied. Other practical tools for the study of schistosomes in snails have already been devised, such as the use of hybridization of Southern blots to a polymorphic SOME ADDITIONAL TOOLS TO repetitive DNA element (Minchella et al., 1995) to FACILITATE OUR UNDERSTANDING provide insight into how many different schisto- OF SCHISTOSOME–SNAIL some genotypes are present within a given snail. INTERACTIONS IN THE FIELD Additional techniques, such as an ability to quan- Additional tools and approaches are also needed tify the amount of schistosome biomass in a particu- to better understand schistosomes and snails in the lar snail, would also be useful for understanding the field. For example, one useful approach to serve as epidemiology of snail infections in the field. an alternative to classical methods for determining prevalence of schistosome infection among With respect to the snails themselves, one of the long- snail hosts is PCR-based methodology to detect the standing needs for schistosomiasis workers in the presence of even minute amounts of schistosome field has been to have reliable means to determine DNA in snails, including cryptic prepatent infec- which species of snails they are working on. The tions (Hanelt et al., 1997; Jannotti-Passos et al., 1997; application of molecular techniques to both amplify Hamburger et al., 1998, 2004). and provide sequence data for key reference genes like ITS 1 and 2, 18S, 28S, 16S, ND1 and CO I is prov- One important phenomenon of direct relevance to ing to be extremely helpful, not only with respect transmission is the degree of compatibility between to providing a more reliable yardstick for species local snails and schistosomes. Although much of determinations (Vidigal et al., 2002, 2004; Lotfy et the recent work on schistosome–snail compatibility al., 2005), but also for development of robust phyl- has focused on the differences between isolates or ogenies that have allowed us to gain a much greater inbred snail lines that are either fully susceptible or appreciation of the evolutionary history of schisto- strongly resistant to schistosome infection (Coelho some-transmitting snails (DeJong et al., 2001; Jones et al., 2004; Lockyer et al., 2004; Carton et al., 2005), et al., 2001; Morgan et al., 2002; Atwood et al., 2004). evidence from the field suggests that absolute resist- By application of molecular methods, two species of ance is rare, and that that the “success or failure of bulinid snail differing in susceptibility to S. haema- an infection does not depend on the snail suscep- tobium have been identified on Zanzibar, thus con- tibility/resistance status, but on the ‘matched’ or siderably clarifying where transmission is possible ‘mismatched’ status of the host and parasite phe- and directing control efforts (Stothard et al., 2002). notypes” (Théron and Coustau, 2005). The basic This provides a good example of the importance of idea here is that if a particular schistosome mira- accurate snail identification and the value of medi- cidium has a genetic constitution that appropriately cal malacology for eventual control efforts. matches a snail of a particular genetic constitution, a successful encounter will occur. If such a match does not occur, then the parasite will be recognized and

98 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 STUDIES OF THE NATURAL ENEMIES may routinely kill snails in the field for all we know. AND SYMBIONTS OF SNAILS Furthermore, many of the tools needed to characterize snail viruses are already in hand, most notably Except in a focal or insular context, it is difficult to the Bge snail cell line. Extracts of snails from natural imagine how populations of snails would ever be populations could be readily prepared and plated controlled at a level sufficient to interrupt transmis- onto Bge monolayers. Then any plaques revealed sion in a sustainable, cost-effective, environmentally could be subjected to further study in search of viral acceptable way. Snails transmitting schistosomia- particles. Snail viruses could be useful as control sis often have considerable abilities to aestivate, to agents, may adversely affect schistosome develop- be passively dispersed, or to quickly re-populate ment, or may be convenient agents for generating areas because of their rapid rates of reproduction. transgenic snails. Virtually nothing is known about Attempts to control snails through the application how snails defend themselves from viruses. It is of molluscicidal chemicals derived from either the conceivable that RNAi-related mechanisms are chemical industry or from local indigenous plants used to discourage viral infections, and if so, then would seem to face a severe uphill battle given the the study of molluscan viruses may offer valuable increasingly strong public resistance to the wide- clues for how to better exploit RNAi to knockdown spread application of chemicals to the environment. snail genes, potentially including those required for The evidence that such chemicals have specific effects snails to nurture larval trematodes. on target snails is often equivocal (Monkiedje et al., 1991; Oliveira and Paumgartten, 2000; Giovanelli et Also poorly known are the bacterial associates of al., 2002). schistosome-transmitting snails. Although some studies of culturable bacteria have been undertaken Also likely to be of limited potential for future con- using Biomphalaria, including snails from natural trol efforts on a continental scale are most meth- habitats (Ducklow et al., 1979, 1981), no studies using ods of biological control that have been proposed, PCR-based methods to survey the bacterial diver- including the use of exotic generalist predators/ sity associated with snails have been undertaken. competitors that carry unacceptable ecological risks Thus it is not at all clear if snails have a bacterial (Cowie, 2001). It seems unlikely that indigenous flora that simply mimics the aquatic environment in predatory/competitor molluscs can be counted on which they live, is typical of other aquatic inverte- to achieve sustainable control, otherwise we would brates, or if they harbour specialized and uncultura- already see ample evidence of their effectiveness. ble species. Knowing more about the bacterial flora Even the introduction of indigenous species into of snails is important because such bacteria may environments where they do not already occur may offer specific opportunities for control, or for intro- carry hazards, especially with respect to rice-grow- ducing exotic genes into snails. Also, bacterial asso- ing or creating new opportunities for disease trans- ciates with snails may influence the susceptibility of mission (Yousif and Lämmler, 1975; Teo, 2001). snails to schistosomes or other trematodes.

Here it is argued that even though sustainable, Two final examples of poorly known symbionts of environmentally-acceptable snail control may be a freshwater snails deserving of study are nematodes near-impossible goal, it is nonetheless important to and chaetogasters. Some nematodes from terrestrial continue to learn more about the natural enemies or snails, like their entomopathogenic relatives from symbionts of snails, particularly the ones that are insects, carry potentially lethal bacteria into snails at present either poorly characterized or unknown. (Glenn and Wilson, 1997; Grewal et al., 2003). It is When snail symbionts have been examined with not known if freshwater snails have similar coun- modern molecular-based methods, some surprising terparts, or if molluscopathogenic nematodes of ter- results have emerged. Thus snails and other mol- restrial snails could be adapted to freshwater snails. luscs have been shown to harbour members of a Also unknown is the impact such nematodes and poorly known clade of eukaryotic symbionts lying their bacterial associates might have on develop- close to the divergence between fungi and animals, ing larval trematodes. Chaetogasters are ectosymbi- the Mesomycetozoea (Hertel et al., 2002). otic oligochaetes of snails and are of interest because they can consume both schistosome miracidia and As an example of our ignorance with respect to cercariae, and may play a role in protecting snails snail symbionts, not a single virus from any snail from infection (Rodgers et al., 2005). There is much of medical significance, or to my knowledge from to learn about snail symbionts, and it seems cer- any gastropod, has ever been isolated. Such viruses tain that some of these associates will prove to be almost certainly exist – it would be unusual for any biologically unique and may have useful proper- group of organisms to be devoid of viruses. They

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 99 ties with respect to controlling snails or their larval Oncomelania. The significance of this is that these trematodes. other trematodes, by virtue of competing with, or preying upon, the larvae of schistosomes, may exert a larger measure of natural control than we would SPOROCYSTS AS THE TRUE TARGETS otherwise suspect (Esch et al., 2001). Thus ecologi- OF CONTROL EFFORTS: THE NEED cal simplification could potentially have the effect TO DEVELOP NEW APPROACHES of intensifying schistosome transmission in some As noted above, with respect to controlling schisto- areas. somiasis at the level of the molluscan host, the true enemy is not the snail that is hosting the parasite but NOT PARASITES OF HUMANS BUT the schistosome sporocysts that colonize the snail. STILL IN NEED OF STUDY: THE It is these sporocysts that will eventually produce SCHISTOSOMES THAT CAUSE the infective stages – cercariae – that infect humans. In general, especially with the advent of a host of CERCARIAL DERMATITIS molecular techniques, particularly PCR, there are Throughout the world, the cercariae of schistosomes now new opportunities to look for, identify, and to of animals, especially those from birds, cause der- potentially manipulate natural enemies or symbi- matitis when they penetrate the skin of people in onts of sporocysts. Since the molecular era began, contact with waters of natural habitats (Verbrugge et there has been virtually no attempt to follow up on al., 2004). Although it has generally been considered promising studies of the microsporidian hyperpar- that such cercariae die in the skin, recent work sug- asites of trematode larvae (Canning, 1981). How gests that this is not always the case, and that some common are these in nature? How many different parasites from such infections may persist and cause taxa are capable of infecting trematode, including neurological problems (Hradkova and Horak, 2002). schistosome, larvae? Can these be grown in vitro There is ample evidence that outbreaks of dermatitis (for example in cultures of Bge cells) and then be occur continually around the world, both in marine introduced into natural populations of schistosome- and freshwater habitats (Larsen et al., 2004), in some transmitting snails? cases involving exotic species of gastropods as hosts (Cohen, personal communication). We currently Some trematodes are well-known hosts for rickett- have only a hazy picture of the diversity of schis- sial parasites, most notably Neorickettsia helminth- tosome species involved in dermatitis outbreaks, a oeca transmitted by Nanophyetus salmincola in the picture rendered all the more hazy by the complica- Pacific Northwest. There is now evidence, based on tions of interpreting the classical literature. Again, the use of PCR amplifications, to indicate that rick- with the advent of molecular methods for identifica- ettsiae may be more commonly associated with lar- tion of dermatitis-causing cercariae and correspond- val trematodes than previously thought (Park et al., ing adults (Brant et al., 2006), and of the associated 2003; Chae et al., 2003; Pusterla et al., 2003; Gibson snails, we have significant new opportunities to et al., 2005). Do rickettsiae infect the intramolluscan learn more about this entire phenomenon. Studies of stages of human or animal-infecting schistosomes? the basic biology of dermatitis, including the poten- We don’t know. tial for prolonged human infection with non-human schistosome cercariae, should be undertaken. Other groups of symbionts of larval trematodes very well might come to light, including viruses or potentially members of the Mesomycetozoea. In THE NEED FOR RELIABLE general, it would be helpful for funding agencies to INFORMATION TRANSFER TO encourage exploration, using modern approaches, DEVELOPING COUNTRIES AND FOR for novel associates of larval trematodes that may MAINTAINING A CRITICAL MASS IN have considerable control potential, including with MEDICAL MALACOLOGY something typically lacking, the possibility of spe- One of the ongoing ironies of schistosomiasis cificity with respect to controlling sporocysts. research is that much of the necessary background information and literature, and many of the new A final consideration with respect to larval schis- tools and techniques, are far more readily availa- tosome population dynamics is the ultimate effect ble in developed countries than in endemic areas. of human-mediated ecological simplification. This Some programmes like the education of budding will also have the effect of eliminating other verte- African malacologists by the Danish Bilharziasis brates and invertebrates that serve as hosts for met- Laboratory, have done much to improve not only acercariae or adults of trematode species that also the level of training of scientists from developing cycle through snails like Biomphalaria, Bulinus or

100 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 countries but also the flow of relevant information • Better facilitation for transfer of relevant informa- to them. Primarily through the use of the world- tion to scientists in developing countries. wide web, potentially through the central organiza- • Continued support for a critical mass of medical tion of the WHO, there should be a renewed attempt malacologists, including centres to support train- to provide schistosomiasis field workers in developing of scientists from developing countries and ing countries with as many opportunities as possi- support for scientists from developed countries ble to get accurate and practical updates regarding willing to work in the often difficult field condi- various aspects of medical malacology. Provision tions where schistosomiasis transmission occurs. of techniques to collect and identify snails using both classical and modern techniques, along with copies of the supporting references, would be very Acknowledgments appropriate. Attention to regional differences in the The author thanks the members of the ‘Parasites and snail fauna would also be very helpful. Additional Hosts’ reading group at the University of New Mexico topics worthy of inclusion would be outlining the for their helpful feedback. This work was supported techniques for separating and isolating snails, iden- by NIH Grant Number RR-1P20RR18754 from the tification of the types of cercariae that are produced International Development Award (IDeA) program by snails, again with the supporting original refer- of the National Center for Research Resources, and ences, and protocols for how to apply some of the by NIH grants AI24340 and AI44913. newer molecular methods for determining if snails are infected with schistosomes.

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104 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 WORKING PAPER 14. former method, focusing especially on immunity- Schistosomiasis related genes such as those for human leukocyte antigen (HLA), cytokines, and adhesion molecules. and immunity HLA genes are highly polymorphic and their alleles are well characterized at the DNA sequence level. Kenji Hirayama For example, the HLA-DRB1 gene has over 100 alle- Department of Molecular Immunogenetics, Institute les in the human population. In particular, HLA- of Tropical Medicine, Nagasaki University, 1-12-4 DR, -DQ, -DP, -A, -B, and -C are believed to function Sakamoto, Nagasaki 852-8523, Japan. as immune-response proteins directed against exog- enous pathogens. Cytokines are also believed to play important roles in controlling the intensity ABSTRACT and duration of immune response. Recently, single nucleotide polymorphisms (SNPs) have been Genetic predisposition to severe forms of observed very commonly in the promoter regions schistosomiasis japonica of some cytokines, including tumour necrosis fac- In China, we have identified two major genes related to tor (TNF), interleukin (IL)-4, IL-13, and interferon-γ. the severity of liver fibrosis of chronic schistosomiasis, one Several studies have demonstrated that these poly- an HLA class II gene and the other the IL-13 gene. The fre- morphisms directly affect promoter activity. quency of the HLA-DRB5*0101 (B1*1501) allele and that of the IL-13 promoter A/A (IL-13P A/A) genotype was elevated in fibrotic patients, although the two genes are located on dif- Polymorphisms in HLA class II genes and ferent chromosomes, chromosomes 6p and 5q, respectively. the IL-13 promoter and schistosomal liver Subjects with both genotypes had odds ratios (OR) of 24.5, fibrosis much higher than the sum of the ratios for each individual genotype (OR = 5.1 for HLA-DRB5*0101, OR = 3.7 for IL-13P Schistosomiasis japonica is a chronic helminthic A/A). That the effects of the two susceptibility markers are infectious disease that affected at least 860 000 indi- synergistic rather than additive strongly suggests that the viduals in China in 1995. Morbidity and mortality pathogenic Th2 response directly influences the prognosis of are dependent on its chronic sequela, post-schisto- post-schistosomal liver fibrosis. somal hepatosplenic disease, which is characterized by liver fibrosis, portal hypertension, ascites accu- Miniature pig is a unique model for human mulation, oesophageal varices, and eventual death. schistosomiasis The liver fibrosis seen in these patients is induced CLAWN mini-pig was infected with a Chinese strain of by a granulomatous immune response against Schistosoma japonicum by skin penetration of 200 cercariae. the eggs that are deposited in the periportal area. The recovery rate of adult worms in the portal vein was Schistosomal egg-antigen-specific CD4+ T cells play almost 50% and they completely matured to excrete eggs 9 weeks after the challenge infection. Although they showed a major role in the formation of granuloma through a naturally healing pattern of infection after 20 weeks of Th2-type cytokine production in experimental schis- infection, the miniature pig was revealed to be a permissive tosomiasis mansoni. However, in humans, little is host. We established this model system and tried to use it for known about the immunological response during vaccine development. Hopefully this model will be appli- the chronic phase of hepatosplenic disease. Because cable to studies on the prevention and treatment of chronic only 5%–10% of patients with chronic schistosomia- schistosomiasis. sis japonica develop hepatosplenic disease, and because the granulomatous response is initiated by CD4+ T cells reactive to schistosomal antigen, pol- GENETIC PREDISPOSITION ymorphisms of the HLA class II antigens, which TO SEVERE FORMS OF control the reactivity of the CD4+ T cells, may be asso- SCHISTOSOMIASIS JAPONICA ciated with susceptibility to hepatosplenic disease. Indeed, associations between schistosomal hepat- Our recent findings clearly indicate the presence osplenic disease and HLA alleles have been reported of genetic factors that can predict the prognosis of for schistosomiasis mansoni and for schistosomiasis schistosomiasis japonica. The identification of genes japonica. Recently, more objective diagnostic meth- associated with susceptibility or resistance to the ods using ultrasonography have become popular severe forms will help us to understand its patho- and have been standardized to measure changes in genesis, and finally to devise new treatments. liver morphology. Therefore, we used this method to categorize the patients into a ‘fibrotic’ group and To identify the genes responsible, two different a ‘non-fibrotic’ group, and examined their genetic approaches are generally undertaken: targeted gene characteristics by analysing the polymorphisms of analysis and genome-wide survey. We adopted the

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 105 candidate genes encoding HLA class II and class I sis, whereas the HLA-DRB1*1501–DRB5*0101 hap- antigens, TNF-α and cytokines. lotype (P < 0.02) increases this susceptibility. If we assume that these genetic associations arise from the A total of 230 current or former patients with functions of the HLA molecules themselves, then the chronic schistosomiasis japonica were examined for critical question is: how do these molecules present liver changes. All patients were from the agricul- antigens to CD4+ T cells to initiate the immunolog- tural village of Beishan, in Yushan county, China, ical processes leading to fibrosis? We have not yet and had their first episode of infection and treat- identified the antigen(s) responsible for the stimula- ment at least ten years before this study began. The tion of pathogenic or protective T cells via such HLA mean age of the subjects was 52.6 ± 10.5 years and molecules. the mean time since their initial treatment was 27.4 ± 8.8 years. Ultrasonographic diagnosis was car- TNF-α promoter polymorphism ried out according to the WHO standard for diagno- A 1042-bp DNA fragment spanning the 5’-flank- sis of liver fibrosis due to schistosomiasis japonica. ing region of the TNF-α gene from positions –66 to Ultrasonographic diagnosis determined that there –1107 was amplified by PCR. With hybridization, were 44 persons with grade 0 fibrosis, 81 with grade seven possible combinations of polymorphic sites I fibrosis, 99 with grade II fibrosis, and six with grade in the TNF-α promoter (TNFP) were determined in III fibrosis. The presence of hepatitis B virus (HBV) the present study population, giving alleles desig- was not assessed in these patients, but the preva- nated as TNFP-A, -B, -C, -D, -M1, -M4, and -M7. lence of HBV is about 15% in Jiangxi Province. Most PCR products from each tentative genotype were of the men in the village smoke tobacco and drink cloned and sequenced to confirm the alleles. alcoholic beverages, but the women generally do not. The patients had all been treated with praziqu- Table 1 shows the seven alleles detected in the antel after each positive faecal examination through- present study. The TNFP-A, -B, -C, and -D alleles are out their lives, but it was not possible to estimate the identical to those reported elsewhere, which were precise total worm burden of each patient during identified in a Japanese population. The table shows the clinical course of the disease. Therefore, we ten- the allele frequencies in the TNFP region in patients tatively defined an appropriately exposed person as with different grades of fibrosis in the Chinese popu- someone with a record of repeated treatments for lation. There was no significant association between schistosomiasis japonica over a ten-year period. TNFP alleles and the disease. HLA class I and II allele typing IL-4 and IL-13 genes on chromosome 5q The DNA typing of the HLA-DRB1 gene was per- We analysed the polymorphisms of the Th2 cytokine formed with the PCR sequence-specific oligonu- genes in the same subjects. In these subjects, there cleotide probes (SSOP) method used at the XIth was a significant association between homozy- HLA workshop. HLA-B DNA typing was per- gosity for the IL-13P polymorphism and the liver formed as previously described. In total, 29 alle- fibrosis group. Because the IL-13 gene is local- les for HLA-DRB1, three for HLA-DRB3, two for ized on the long arm of chromosome 5, the IL-13P HLA-DRB5, 13 for HLA-DQA1, 11 for HLA-DQB1, allele must be inherited independently of the HLA four for HLA-DPA1, 18 for HLA-DPB1, and 24 for class II allele that occurs on the short arm of chro- HLA-B were detected in this population. No sig- mosome 6. Therefore, the next question is whether nificant difference in the frequency of the HLA-B there is any interaction between these two genetic types was observed in the two groups defined by markers, HLA and IL-13. As shown in table 1, both the severity of their fibrosis. On the contrary, the HLA-DRB5*0101- and IL-13P*A/A-positive subjects frequencies of several HLA class II alleles were sig- had much higher odds ratios (OR = 24.5) than sub- nificantly increased or decreased in the fibrotic jects positive for only one of these polymorphisms group. When we compared the frequencies of alleles (OR = 5.1 for HLA, OR = 3.7 for IL-13P*A/A), indi- between grade 0 and grades I, II, and III, we found cating these two genetic markers synergistically that HLA-DRB1*1101 (P < 0.001), DQA1*0501 (P < enhance the development of fibrosis after infection. 0.02), and DQB1*0301 (P < 0.03), which are closely The pathogenic IL-13-producing CD4+ T cells are linked, were significantly elevated in the grade 0 preferentially stimulated by the antigen-presenting group, and that HLA-DRB5*0101 was significantly cells expressing HLA-DRB5*0101. elevated in grade I, II, and III fibrotic patients (P < 0.03). This suggests that the HLA-DRB1*1101– DQB1*0301–DQA1*0501 haplotype (P < 0.02) decreases susceptibility to grades I, II, and III fibro-

106 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 Table 1. Synergistic effect of DRB5*0101 (DRB1*1501) and IL-13P-A/A genotype in developing fibrosis

HLA-D RB5* IL-13P Normal Fibrosis OR 95% CI (grade 0) n=36 (grade I, II, III) (%) n=156 (%) 0101 A/A 0 (0.0) 21 (13.4) 24.5 1.41–424.0 0101 – 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 resistance

HLA-DR B1* IL-13P Normal Fibrosis OR 95% CI n=36 (%) n=156 (%) 1101 B 8 (22.2) 9 (5.7) 9.0 2.78–29.1 1101 – 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)

Acknowledgements As shown in fig. 1, vaccination with radiation attenuated cercariae protected the pigs against challenge Chen Honggen, Yin Dong, Gu Xiaonan, and Zhang infection with 200 cercariae. When we vaccinated Shaoji of Jiangxi Province Institute of Parasitic pigs with recombinant paramyosin plus cholera Diseases; Mihoko Kikuchi of Nagasaki University; toxin by nasal administration, we observed a very and Jianxiang Liu and Hong-Chang Yuan of serious adverse event of pneumonitis after the chal- Shanghai Medical University contributed to the lenge infection. Because IL-4 levels in the serum study. were significantly elevated in this group, hypersen- sitivity reaction was suspected to be provoked by MINIATURE PIG IS A UNIQUE MODEL the infection after nasal immunization with cholera FOR HUMAN SCHISTOSOMIASIS toxin plus paramyosin. Moreover, paramyosin vaccination was only effective at reducing the female In looking for the ideal animal model for Schistosoma worm burden. japonicum infection, miniature pigs were percutane- ously infected with 200 S. japonicum cercariae, and parasitological, pathological and serological aspects of the infection were monitored. Egg excretion into faeces began at 5 weeks post-infection (PI), and pronounced excretion of the eggs continued from 8 weeks to 17–20 weeks PI. The average numbers of Figure 1. Radiation attenuated cercariae vaccine eggs per gram of faeces (epg) of the two pigs during the period 8–20 weeks were 288 and 277 respectively. E1%#%%) After 20 weeks PI, the epg gradually decreased and disappeared until 28 wks PI. One pig was sacrificed +%% and examined at 27 weeks PI and the other at 47 8dcigda weeks PI. The number of adult worms recovered )%% from the former pig was 35 and from the latter was 15. Based on this preliminary observation, vaccine experiments were performed using two different '%% >bbjc^oZY systems: 1) radiation attenuated cercariae vaccine, and 2) nasal vaccination using recombinant paramy-

CjbWZgd[Z\\heZg\gVbd[[VZXZh % osin and cholera toxin. We observed partial protec- * + , - . tion after vaccination. LZZ`hedhi"^c[ZXi^dc

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 107 Miniature pig: Acknowledgements • Fifty per cent recovery after the challenge infec- Kanji Watanabe of the Institute of Tropical tion indicated that miniature pigs are a permis- Medicine at Nagasaki University, Takeshi Nara sive host. of Juntendo University, and Takeshi Arakawa of • Attenuated cercariae vaccine reduced the number Ryukyu University contributed to this study. of eggs. • Mucosal immunization decreased the number of female worms. • Cholera toxin plus paramyosin provoked severe acute pneumonitis after challenge infection.

108 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 WORKING PAPER 15. has proved to be the inefficiency of the gene finding Genomics and proteomics: programs (this is not unique to schistosomes). Three were used (Phat, SNAP and glimmerHMM) to pick towards new targets in out genes from the DNA sequence, and they rarely schistosome research agree precisely on what represents the predicted coding region. Nevertheless, with careful interroga- R. Alan Wilson tion, it is possible to discover many novel features of Department of Biology, University of York, PO Box 373, schistosome gene structure. York YO10 5YW, UK Following release of version 1 of the draft genome, work has continued at WTSI, under the supervision The first years of the 21st century have seen quite of Dr Matt Berriman, to improve the assembly by the remarkable advances in our knowledge of the schis- generation and sequencing of a fosmid library con- tosome genome and the application of new technol- structed from randomly sheared DNA. As a result ogies such as microarrays and proteomics to exploit the genome has now been assembled into 13 000 the accumulating information. In this working paper supercontigs with an N50 of 824 kb, i.e. 50% of the I shall review the many possibilities now open to nucleotides are in scaffolds > 800 kb. This is about researchers. Potential pitfalls and limitations are the size of the average protozoan chromosome; in also considered, together with the technical obsta- contrast, the individual schistosome chromosomes cles that must be overcome before the maximum are around 30–40 Mb each, which gives some idea benefits for schistosomiasis control can accrue. of the magnitude of the assembly task. Work has also continued at TIGR, under the supervision of Dr The bulk of material covered relates to Schistosoma Najib el-Sayed, to retrain the gene finding programs mansoni for two reasons. Firstly, it is the most trac- with a larger number of full length coding sequences table species experimentally, so research on it gener- (CDS). Version 3 of the assembly is currently being ally sets the pace. Secondly, it is the species on which screened at TIGR with the improved gene finders to I have undertaken most of my investigations over obtain a new set of predicted genes which will form the last 35 years. The narrow focus is not intended to the substrate for gene annotation, both automatic belittle the efforts made with S. japonicum where the and manual (two annotators are currently employed difficulty in maintaining the snail intermediate host, full time at WTSI). It is anticipated that version 3 will and the small amount of cercarial material obtain- be released to the community shortly, with publica- able, create special problems. The same is true for tion of the genome paper scheduled for mid 2006. the experimentally even more difficult S. haemato- In the short term it is unlikely that the genome will bium, where effort needs to be concentrated because be assembled into eight chromosome-sized chunks, it infects the largest number of individuals in sub- with genes assigned to each. One obstacle is the pau- Saharan Africa, causing the greatest morbidity and city of gene mapping to individual chromosomes, in annual mortality among the three principal human which the pioneering work has been undertaken as schistosomes.1 a collaboration by Drs LoVerde and Hirai.2,3

A sequencing project for S. japonicum is also under THE SCHISTOSOME GENOME way based at the Chinese National Human Genome Shotgun sequencing of the S. mansoni genome was Centre in Shanghai. A draft assembly of the Chinese undertaken 2002–2004 as a joint effort between The reads has been attempted at WTSI but the current Institute of Genomic Research (TIGR), Rockville, status of the project is unclear (Berriman, personal USA, and the Wellcome Trust Sanger Institute communication). (WTSI), Cambridge, UK; it generated more than three million reads to provide approximately 8x Prospects coverage of the 280 MB genome. A major intrinsic Helminth genomes are an integral part of the next obstacle to genome assembly has been, and remains, five-year plan at WTSI, commencing mid 2006. the presence of large amounts of repeat sequence Efforts to improve the quality of the S. mansoni (comprising up to 40% of the genome, mostly in a genome sequence will continue. S. haematobium is number of retrotransposon families [see below]). A also listed and the priority it receives will depend genome database, SchistoDB.org, was created and on the enthusiasm and lobbying of the schistosome version 1 of the draft assembly was released to the research community. Possession of three schisto- research community in February 2005, with auto- some genome sequences will confer significant ben- matic annotation of the genes. Another limitation

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 109 efits, especially in the sphere of gene finding (cf. the array with access for all.) Both cDNAs10,11 and oligo- sequencing of five species of yeast4). nucleotides12 have been printed onto glass slides and used to investigate a number of biological questions. To date, these have centred on gender-associated THE TRANSCRIPTOME and stage-specific expression, but the possibilities The characterization of expressed schistosome genes are endless. The first small-scale S. mansoni cDNA really got under way in 1995 with the publication of array10 was used to identify 12 female and 4 male- the first expressed sequence tag (EST) project5 that associated gene transcripts, and these observations added more than 400 new sequences to the database. were subsequently expanded using a much larger In the next eight years, about 15 000 EST sequences oligonucleotide array that revealed 197 transcripts were put into the public domain. The situation then with a gender biased pattern of gene expression in changed dramatically with the generation, anal- the adult schistosome.12 A small S. japonicum cDNA ysis and simultaneous publication of two large microarray also highlighted around 20 female and 8 EST datasets for S. mansoni6 and S. japonicum.7 The male-associated transcripts in two different isolates former study, by a Brazilian consortium, used the of the parasite. Finally an array based on mRNA ORESTES technique8 to sample mRNA from six life exclusively from the lung schistosomulum, contain- cycle stages (egg, miracidium, sporocyst germ ball, ing >6000 features representing >3000 genes, was cercaria, lung schistosomulum and adult). Analysis used to screen mRNA from six other life cycle stages of the 120 000 ESTs revealed a genome containing at to pinpoint genes highly expressed in, or specific to, least 14 000 genes, with an estimated 7000 expressed the lung stage.11 A total of 563 genes proved to be in each life cycle stage, around 1000 of which were differentially regulated across the life cycle stages thought likely to be stage-specific. The transcrip- used, around 50 of which were highly expressed at tome dataset was estimated to sample 92% of S. man- the lung stage. soni expressed genes.6 The latter study by a Chinese group sampled mRNA from adult worms and eggs.7 A limitation in current microarray A total of >43 000 ESTs were assembled into >13 000 construction clusters which the authors believed comprised most of the protein-coding genes (~15 000) in the parasite The current microarrays have been largely con- (this conclusion leaves little scope for stage-specific structed using cDNAs either taken from the pub- expression). lic databases or purpose generated. Until we get a definitive list of CDS from the genome sequencing These datasets have proved invaluable for gene project, a serious obstacle lies in the way of extend- finding but also revealed the large number of tran- ing the arrays to provide greater genome coverage. scribed retrotransposons,9 none yet demonstrated The fact that the Brazilian S. mansoni transcriptome to be actively moving around the genome. The data project generated ESTs using the ORESTES tech- have also opened up the possibilities for in silico nique that relies on random priming, means that analyses of biochemical and cellular mechanisms, their strandedness is unknown. They can be com- for example in development, cell adhesion and piled into clusters, but the strandedness of these signalling.6,7 The research community is now well clusters will only be known if they contain one or placed to characterize pathways for which we have more ESTs from conventionally generated cDNAs. some knowledge, and to begin the more difficult We estimate that, of the >30,000 clusters and singlets task of investigating systems novel to schistosomes. in the S. mansoni database, >20 000 are composed At least 65% of schistosome EST clusters have no exclusively of ORESTES sequences. The problem homology with the genes of other organisms and for array construction could be solved by print- many of these will surely encode proteins that con- ing ‘sense’ and ‘antisense’ copies from each cluster tribute to the unique features of the genus. with unknown strandedness on the slide, but this would increase its size by around 70% (from 30 000 Possession of a well characterized transcript data- to 50 000 features) and its cost proportionally. base will permit the construction of a genome-wide microarray with which to investigate patterns of The triploblastic acoelomate trap gene expression throughout the life cycle and within Investigations that ask questions simply about gen- individual tissues. A number of studies have already der- or stage-specific expression do not encounter been published with arrays that inevitably achieve the triploblastic acoelomate problem. Schistosomes only partial coverage. (To the author’s knowledge have a solid body plan with differentiated cells at least five separate S. mansoni and two S. japonicum and tissues representing the major organ systems arrays have been constructed, cf. the filarial research of higher animals, such as nerve, muscle, gut, community, which has settled on one Brugia malayi nephridia and gonads. (It is only necessary to look

110 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 at electron micrographs of miracidia to see how ily achieved by 2D electrophoresis (2DE), using many cell types can be packed into a small space.) immobilized pH gradients for the first dimension.20 Furthermore the cells are firmly adherent to each Although 2DE has its detractors, it has one singular other, and methods do not exist for their separa- advantage over other separation techniques in that tion. This becomes a problem when the investigator the relative amounts of constituents within a given wants to determine where in the parasite genes of preparation can be quantified, using image analy- interest are being expressed. For example, if surface- sis and densitometry software. A second approach expressed genes that might serve as vaccine candi- involves trypsinisation of the protein mixture fol- dates are sought, then it is important to determine lowed by separation of the peptides by liquid chro- that they are expressed in tegument cell bodies or matography (LC). Alternatively, proteins may be gut epithelia and not in some cell type buried deep separated by 1D electrophoresis, trypsinised, and within the organism. Equally, when attempting to the peptides separated by LC. LC approaches are designate the components of a signalling pathway, ideal for insoluble proteins such as membrane con- the investigator needs to know that all candidates stituents, but there is presently no easy way to obtain are expressed in the same cell type. information on the relative amounts of different proteins in such a mixture. Prospects The final step in proteomics is to subject the sam- • A genome wide microarray for each schistosome ple to mass spectrometry (MS). MALDI ToF MS will species should become feasible when the full list produce a peptide mass fingerprint from the tryp- of CDS is available. Ideally, following the filaria- tic digest of a single gel spot. Selected peptides can sis model, this would be constructed by a con- then be fragmented by collision with a gas to yield sortium, with access for all researchers, at cost. fragmentation spectra. Database searching with There is an abundance of biological questions e.g. Mascot software against theoretical digests of that can be tackled by transcriptome analysis and S. mansoni cDNA sequences or predicted CDS from thus plenty of scope for many research groups. the genome assembly, translated in all six reading • Establishing the cell/tissue in which genes are frames, enables the link between the parent protein expressed needs to be addressed if array results and its CDS to be made. However, a putative func- are to be made meaningful at a level beyond sim- tion can only be assigned if an annotation is availa- ple stage-specificity. ble (remember that 65% of S. mansoni EST clusters • The capacity for reverse genetics in schistosomes have no homology to other organisms). is in its infancy. Transient transfection of reporter genes has been achieved13,14,15 but no system is Proteomics has some advantages over microarray available for stable transfection into the germ analysis, particularly because the expressed proteins line. There is not even a schistosome cell line16 endow a cell or parasite stage with its specific func- that would permit homologous gene disruption tions, whereas detection of mRNA does not always or over expression. equate to the presence of protein. In addition, the • Disruption of gene function has been achieved acoelomate body plan is not an insuperable obsta- with small interfering RNAs (RNAi) but the cle to analysis of protein expression at the cell or tis- effects are presently limited to only a few life sue level since a life cycle stage can be fractionated cycle stages and are short term.17,18,19 More effi- using conventional cell biological techniques such cient ways of introducing the RNA constructs as gradient centrifugation. On the other hand, sen- into the parasite need to be developed. sitivity is an issue and, unless desired protein sub- sets can be enriched, scarce constituents will not be All the above demand high priority for research identified. efforts in the immediate future if the full benefits of microarray analysis are to accrue. A number of schistosome proteomic studies have already been published and the influence of the PROTEOMICS approach is set to grow since it can provide answers to questions of composition that were posed in some The proteome can be defined as the total protein cases decades ago. The first report compared the sol- complement of an organism, tissue, cell or organelle. uble proteome of S. mansoni across four life cycle The suite of techniques that has been developed pro- stages21 revealing that the abundant cytosolic com- vides a way to link any protein to its encoding DNA ponents such as 14-3-3, actin, enolase, and aldo- (provided the sequence is in the database). The first lase were common to the four stages investigated. step is to separate a complex mixture into its con- Furthermore, the list included several of the first stituent proteins. For soluble proteins this is read- generation vaccine candidates such as triose phos-

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 111 phate isomerase, glyceraldehyde-3-phosphate dehy- some glycan structures but no papers have been drogenase, glutathione-S-transferase and fatty acid published to date. binding protein. Subsequent studies have focused on the composition of the adult tegument separated Prospects from worm bodies by freeze-thaw treatment22 and As with proteomics, glycobiology is undergoing further enriched by density gradient centrifuga- a rapid expansion in techniques and possibilities. tion and differential extraction.23 The results of these The current limitations in synthesizing the deduced investigations have enabled the protein constituents structures for experimental purposes are being of the tegument and its surface membrane complex solved and the first glycan arrays have been con- to be explored. Furthermore, the proteins of both structed.28 It should thus soon be theoretically possi- parasite and host origin, most exposed on the exter- ble to ‘print’ the full range of glycan structures from nal surface, have been investigated by surface bioti- schistosomes and use them, for example, to probe nylation.24 Lastly, the cercarial secretions used in the acquired immune responses of human and lab- host skin penetration have been characterized25 and oratory hosts to schistosome infection or vaccina- several proteases and putative immunomodulators tion. In parenthesis, it should be noted that glycan identified.26 epitopes are often the predominant stimulators of antibody production.29 Another application of Prospects such arrays would be in the identification of inter- Proteomics has developed to the point where there acting partners within the parasite or among host are two very obvious applications that can rapidly macromolecules. generate new knowledge: • Composition of the parasite–host interface. This THE IMMUNOME will require a combination of tissue fractionation and the collection of secretions. Inevitably, to get In theory, the combination of proteomics and serol- sufficient material for analysis, much of the work ogy should provide a powerful tool to identify will need to be performed with in vitro cultured antibody targets among schistosome proteins and stages where integrity is essential to avoid gener- glycans. At a superficial level this is the case, with ation of spurious composition data. This avenue the combination of 2DE separation of soluble pro- will undoubtedly identify novel vaccine candi- teins, their blotting onto membranes and probing dates and immunomodulators. with antibody permitting the most reactive proteins • Pull down assays with bait proteins to recover to be identified by MS. However, in the author’s interacting partners in e.g. signalling pathways, investigations, the reactive proteins turn out to be cell adhesion. Given the amount of material the same abundant cytosolic proteins that were involved, the approach will probably be lim- cloned from expression library screens using antis- ited to adult worm preparations. However, it era a decade or more ago. In the one published may prove invaluable for pinpointing novel drug study using the blotting approach,30 the same gly- targets. colytic enzymes, chaperones and muscle proteins were again the dominant antigens. Conversely, antibody detection of proteins on Western blots appears THE SCHISTOSOME GLYCOME to be one or two orders of magnitude more sensitive Similar techniques to MS analysis can also be than gel stains such as Sypro Ruby so that strong applied to the glycan chains attached to schistosome reactions are often present that have no visible coun- proteins and lipids. The parasite fractions of inter- terpart on the gel suitable for MS analysis. est are first treated enzymatically or chemically to release the glycans. A glycan mass fingerprint can Prospects then be generated by MS and, due to the relatively Technical issues need to be addressed before char- small number of sugar structures involved, empir- acterization of the immunome becomes a useful ical compositions obtained.27 Linkage analysis can tool for e.g. pinpointing vaccine candidates. One then be performed to identify the precise mon- possibility to increase the sensitivity of proteom- osaccharides involved and their glycosidic bond ics in general is pre-depletion of protein fractions links, allowing the complete glycan structures to be with a cocktail of antibodies against the abundant deduced. To the author’s knowledge at least two cytosolic proteins so that larger quantities of scarce groups, at the University of Leiden, The Netherlands proteins can be loaded onto gels for 2D separation. (Dr C Hokke), and Imperial College, London (Prof. In this context, obtaining sufficient parasite mate- A Dell), are actively involved in analysing schisto- rial from stages other than adult worms or cercariae will be a challenge. Finally, the problem of mem-

112 Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 brane proteins needs to be addressed. These could 11) Dillon GP et al. Microarray analysis identifies well represent important vaccine targets but they genes preferentially expressed in the lung schis- are not amenable to 2DE and blotting and they are tosomulum of Schistosoma mansoni. International also much scarcer than cytosolic components. It is Journal for Parasitology, 2006, 36(1):1–8. possible that a combination of detergent extraction 12) Fitzpatrick JM et al. An oligonucleotide microarray of membranes and immuno-precipitation would be for transcriptome analysis of Schistosoma mansoni adequate for the purpose, provided that conforma- and its application/use to investigate gender-asso- tional epitopes were not destroyed. ciated gene expression. Molecular and Biochemical Parasitology, 2005, 141:1–13. CONCLUSIONS 13) Davis RE et al. Transient expression of DNA and RNA in parasitic helminths by using particle bom- Collectively, the several avenues outlined above bardment. Proceedings of the National Academy provide the possibility for unprecedented gains in of Sciences of the United States of America, 1999, our knowledge of schistosomes and their interac- 96:8687–8692. tions with the mammalian host. The future is bright, 14) Wippersteg V et al. HSP70-controlled GFP expres- but both ingenuity and resources are needed if rapid sion in transiently transformed schistosomes. progress is to be made. Molecular and Biochemical Parasitology, 2002, 120:141–150. 15) Wippersteg V et al. Biolistic transformation of References Schistosoma mansoni with 5’ flanking regions of two peptidase genes promotes tissue-specif- 1) van der Werf MJ et al. Quantification of clinical ic expression. International Journal for Parasitology, morbidity associated with schistosome infection in 2005, 35:583–589. sub-Saharan Africa. Acta Tropica, 2003, 86:125–139. 16) Bayne CJ et al. In vitro cultivation of cells from lar- 2) LoVerde PT et al. Schistosoma mansoni genome val Schistosoma mansoni. Journal of Parasitology, project: an update. Parasitology International, 2004, 1004, 80:29–35. 53:183–192. 17) Skelly PJ, Da’dara A, Harn DA. Suppression of 3) Hirai H, Hirai Y. FISH mapping for helminth cathepsin B expression in Schistosoma manso- genome. Methods in Molecular Biology, 2004, ni by RNA interference. International Journal for 270:379–394. Parasitology, 2003, 33:363–369. 4) Kellis M et al. Sequencing and comparison of yeast 18) Boyle JP et al. Using RNA interference to manip- species to identify genes and regulatory elements. ulate endogenous gene expression in Schistosoma Nature, 2003, 423:241–254. mansoni sporocysts. Molecular and Biochemical 5) Franco GR et al. Identification of new Schistosoma Parasitology, 2003, 128:205–215. mansoni genes by the EST strategy using a direc- 19) Correnti JM, Pearce EJ. Transgene expression in tional cDNA library. Gene, 1995, 152:141–147. Schistosoma mansoni: introduction of RNA into 6) Verjovski-Almeida S et al. Transcriptome analy- schistosomula by electroporation. Molecular and sis of the acoelomate human parasite Schistosoma Biochemical Parasitology, 2004, 137:75–79. mansoni. Nature Genetics, 2003, 35:148–157. 20) Ashton PD, Curwen RS, Wilson RA. Linking pro- 7) Hu W et al. Evolutionary and biomedical implica- teome and genome: how to identify parasite pro- tions of a Schistosoma japonicum complementary teins. Trends in Parasitology, 2001, 17:198–202. DNA resource. Nature Genetics, 2003, 35:139–147. 21) Curwen, RS et al. The Schistosoma mansoni solu- 8) Neto ED et al. Minilibraries constructed from ble proteome: a comparison across four life-cycle cDNA generated by arbitrarily primed RT-PCR: an stages. Molecular and Biochemical Parasitology, 2004, alternative to normalized libraries for the genera- 138:57–66. tion of ESTs from nanogram quantities of mRNA. 22) van Balkom BW et al. Mass spectrometric analysis Gene, 1997, 186:135–142. of the Schistosoma mansoni tegumental sub-pro- 9) DeMarco R et al. Saci-1, -2, and -3 and Perere, four teome. Journal of Proteome Research, 2005, 4:958–966. novel retrotransposons with high transcription- 23) Braschi S et al. The tegument surface membranes al activities from the human parasite Schistosoma of the human blood parasite Schistosoma mansoni: mansoni. Journal of Virology, 2004, 78:2967–2978. a proteomic analysis after differential extraction. 10) Hoffmann KF, Johnston DA, Dunne DW. Proteomics, 2006, 6(5):1471–1482. Identification of Schistosoma mansoni gender- 24) Braschi S, Wilson RA. Proteins exposed at the associated gene transcripts by cDNA microarray adult schistosome surface revealed by bioti- profiling. Genome Biology, 2002, 3:Research 0041. nylation. Molecular and Cellular Proteomics, 2006, 5(2):347–356.

Report of the Scientific Working Group on Schistosomiasis, 2005 • TDR/SWG/07 113 25) Knudsen GM et al. Proteomic analysis of Schistosoma mansoni cercarial secretions. Molecular and Cellular Proteomics, 2005, 4(12):1862– 1875. 26) Curwen RS et al. Identification of novel proteases and immunomodulators in the secretions of schistosome cercariae that facilitate host entry. Molecular and Cellular Proteomics, 2006, 5:835–844. 27) Kawar ZS et al. Novel poly-GalNAcbeta1-4GlcNAc (LacdiNAc) and fucosylated poly-LacdiNAc N-glycans from mammalian cells expressing beta1,4-N-acetylgalactosaminyltransferase and alpha1,3-fucosyltransferase. Journal of Biological Chemistry, 2005, 280:12810–12819. 28) Drickhamer K, Taylor ME. Glycan arrays for functional glycomics. Genome Biology, 2002, 3(12): reviews1034. 29) Eberl M et al. Antibodies to glycans dominate the host response to schistosome larvae and eggs: is their role protective or subversive? Journal of Infectious Diseases, 2001, 183:1238–1247. 30) Mutapi F et al. Praziquantel treatment of individuals exposed to Schistosoma haematobium enhances serological recognition of defined parasite antigens. Journal of Infectious Diseases, 2005, 192:1108–1118.

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

TDR/SWG/05 Scientific Working Group

Report on Schistosomiasis Report Report on

14–16 November 2005 Geneva, Switzerland The Special Programme for Research and Training in Tropical Diseases (TDR) is a global programme of scientific collaboration established in 1975. Its focus is research into neglected diseases of the poor, with the goal of improving existing approaches and developing new waysto prevent, diagnose, treat and control these diseases. TDR is sponsored by the following organizations: Special Programme for Research & Training www.who.int/tdr in Tropical Diseases (TDR) sponsored by UNICEF/UNDP/World Bank/WHO World Bank TDR/SWG/07 Original: English