Protein tyrosine kinases as new potential targets against human schistosomiasis

In spite of the numerous efforts made to control their transmission, parasite schistosomes still represent a serious public health concern and a major economic problem in many developing countries. Praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis and the only one that is available for mass chemotherapy. However, its widespread use and its inefficacy on juvenile parasites raise fears that schistosomes will develop drug resistance, and make the development of alternative drugs highly desirable. Protein tyrosine kinases (PTKs) are key molecules that control cell differentiation and proliferation and they already represent important targets for molecular cancer therapy. The recent characterization in Schistosoma mansoni of several cytosolic and receptor PTKs, with properties similar but also divergent from their vertebrate counterparts, opens new perspectives for the development of novel strategies in chemotherapy of schistosomiasis, which could be based on the use of parasite-specific tyrosine phosphorylation inhibitors.     

Towards control of schistosomiasis in sub-Saharan Africa

Approximately 80% of the 200 million people infected with schistosomiasis inhabit sub-Saharan Africa, and the annual mortality is estimated to be 280,000. Praziquantel is the drug of choice in the treatment of schistosomiasis and pregnant women may now be treated. It was agreed at the World Health Assembly in 2001 that at least 75% of school-aged children in high burden areas should be treated for schistosomiasis and soil-transmitted helminth infections by 2010 to reduce morbidity. A grant from the Bill and Melinda Gates Foundation to the Schistosomiasis Control Initiative, Imperial College of Science, Technology and Medicine, London has enabled control programmes to be initiated in Uganda, Tanzania, Zambia, Burkina Faso, Niger and Mali. Additional programmes have recently commenced in Zanzibar with a grant from the Health Foundation to The Natural History Museum, London and in Cameroon. Combination treatment for schistosomiasis, gastrointestinal helminths and filariasis reduces costs of control programmes. The EC Concerted Action Group on 'Praziquantel: its central role in the chemotherapy of schistosome infection' met in Yaoundé Cameroon in 2004 to discuss recent developments in laboratory and field studies. The use of standard operating procedures will enable data on drug action on schistosomes produced in different laboratories to be compared. With the ever increasing use of praziquantel there is a possibility of the development of resistance by schistosomes to the drug, hence the necessity to explore the activities of other compounds. Artemether, unlike praziquantel, is effective against immature schistosomes. The effectiveness of mirazid, an extract of myrrh, is controversial as data from different laboratories are equivocal. It is suggested that an independent body such as the World Health Organization should determine whether mirazid should be used in the treatment of schistosomiasis.     

Urinary schistosomiasis on Pemba Island: low-cost diagnosis for control in a primary health care setting

In the 1970s and early 1980s indirect diagnosis of urinary schistosomiasis, using urinalysis reagent strips for proteinuria and haematuria, was proposed as a possible alternative to the more accurate but very time-consuming parasitological methods. The recent experience o f the Schistosomiasis Control Programme for Pemba Island, which used a combination of (1) observations o f grossly bloody urine specimens, (2) results from reagent strips for measuring haematuria, and (3) treatment with praziquantel, is the first large-scale example o f a simple, inexpensive and promising alternative for controlling the morbidity caused by this parasite.     

Onchocerciasis control programme-The human perspective

The West African Onchocerciasis Control Programme (OCP), launched in 1974, seeks to interrupt transmission o f Onchocerca volvulus (Fig. I) over a vast area now encompassing 11 countries. The main strategy has been vector control using larvicides (particularly temephos) against blockfly larvae in fast-flowing rivers and streams. More recently, the programme has also begun to implement large-scale chemotherapy using ivermectin. The OCP has an operational budget approaching US$25 million a year. The control activities have led to a dramatic decrease in the incidence of new cases, while overall prevalence of infection has been reduced from about 25-30% to below 5%, accomponied by a similar drop in the numbers o f people presenting severe ocular involvement or blindness. Entomological, clinical and epidemiological results of the programme have been discussed in detail -particularly in the various reports produced by programme personnel and associated researchers (eg. Ref. I). Here, we asked James Senghor and Ebrohim Samba to discuss what the programme has meant to the people involved.     

A Robust Method for Estimating Optimal Treatment Regimes

Summary A treatment regime is a rule that assigns a treatment, among a set of possible treatments, to a patient as a function of his/her observed characteristics, hence “personalizing” treatment to the patient. The goal is to identify the optimal treatment regime that, if followed by the entire population of patients, would lead to the best outcome on average. Given data from a clinical trial or observational study, for a single treatment decision, the optimal regime can be found by assuming a regression model for the expected outcome conditional on treatment and covariates, where, for a given set of covariates, the optimal treatment is the one that yields the most favorable expected outcome. However, treatment assignment via such a regime is suspect if the regression model is incorrectly specified. Recognizing that, even if misspecified, such a regression model defines a class of regimes, we instead consider finding the optimal regime within such a class by finding the regime that optimizes an estimator of overall population mean outcome. To take into account possible confounding in an observational study and to increase precision, we use a doubly robust augmented inverse probability weighted estimator for this purpose. Simulations and application to data from a breast cancer clinical trial demonstrate the performance of the method.     

Bayesian Risk Mapping and Model-Based Estimation of Schistosoma haematobium–Schistosoma mansoni Co-distribution in C?te d′Ivoire

Background

Schistosoma haematobium and Schistosoma mansoni are blood flukes that cause urogenital and intestinal schistosomiasis, respectively. In Côte d′Ivoire, both species are endemic and control efforts are being scaled up. Accurate knowledge of the geographical distribution, including delineation of high-risk areas, is a central feature for spatial targeting of interventions. Thus far, model-based predictive risk mapping of schistosomiasis has relied on historical data of separate parasite species.

Methodology

We analyzed data pertaining to Schistosoma infection among school-aged children obtained from a national, cross-sectional survey conducted between November 2011 and February 2012. More than 5,000 children in 92 schools across Côte d′Ivoire participated. Bayesian geostatistical multinomial models were developed to assess infection risk, including S. haematobium–S. mansoni co-infection. The predicted risk of schistosomiasis was utilized to estimate the number of children that need preventive chemotherapy with praziquantel according to World Health Organization guidelines.

Principal Findings

We estimated that 8.9% of school-aged children in Côte d′Ivoire are affected by schistosomiasis; 5.3% with S. haematobium and 3.8% with S. mansoni. Approximately 2 million annualized praziquantel treatments would be required for preventive chemotherapy at health districts level. The distinct spatial patterns of S. haematobium and S. mansoni imply that co-infection is of little importance across the country.

Conclusions/Significance

We provide a comprehensive analysis of the spatial distribution of schistosomiasis risk among school-aged children in Côte d′Ivoire and a strong empirical basis for a rational targeting of control interventions.     

Historical view of schistosomiasis japonica in Japan: implementation and evaluation of disease-control strategies in Yamanashi Prefecture

We summarized historical aspects of disease control activities targeting schistosomiasis japonica in Kofu basin, Yamanashi Prefecture, Japan. Kofu Basin was one of the biggest endemic foci of schistosomiasis japonica in Japan, and the last place where transmission of Schistosoma japonicum was confirmed in Japan. Because of the most severe endemic situations in Yamanashi, intensive control measures had been implemented by the central as well as the local government. The last human case in Japan was in 1977, which is just before praziquantel being available. Therefore, the main efforts were focused on snail control. Mass examination and mass chemotherapy were implemented, however, the compliance was not so good because of the severe side effects due to the available therapeutics, Stibnal. Along with socioeconomic development after World War II, big changes in land use, life style, and farming led drastic reduction in the disease prevalence in Kofu Basin in the 1960s. A large amount of budget was also used for disease control. Cementing water canals covered more than 95% of paddy fields in Kofu Basin, and this resulted in ecological changes. After elimination of schistosomiasis, environmental repair is the urgent subject in Kofu Basin. Our experiences in Yamanashi contain both good influences and also a lot of reflection. It is important to evaluate each activity in our history before we give intensive cooperation with countries where endemic foci is still present.     

Are Ca2+ channels targets of praziquantel action?

Praziquantel is the current drug of choice for the control of schistosomiasis. It is highly effective against all species of schistosomes and shows minimal adverse effects. Though introduced for the treatment of schistosomiasis more than 20 years ago, the mode of action of praziquantel remains to be elucidated. This review will focus on advances in defining the molecular target of praziquantel action, with particular emphasis on recent work indicating an important role for voltage-gated calcium channels.     

Determining Treatment Needs at Different Spatial Scales Using Geostatistical Model-Based Risk Estimates of Schistosomiasis

Background

After many years of neglect, schistosomiasis control is going to scale. The strategy of choice is preventive chemotherapy, that is the repeated large-scale administration of praziquantel (a safe and highly efficacious drug) to at-risk populations. The frequency of praziquantel administration is based on endemicity, which usually is defined by prevalence data summarized at an arbitrarily chosen administrative level.

Methodology

For an ensemble of 29 West and East African countries, we determined the annualized praziquantel treatment needs for the school-aged population, adhering to World Health Organization guidelines. Different administrative levels of prevalence aggregation were considered; country, province, district, and pixel level. Previously published results on spatially explicit schistosomiasis risk in the selected countries were employed to classify each area into distinct endemicity classes that govern the frequency of praziquantel administration.

Principal Findings

Estimates of infection prevalence adjusted for the school-aged population in 2010 revealed that most countries are classified as moderately endemic for schistosomiasis (prevalence 10–50%), while four countries (i.e., Ghana, Liberia, Mozambique, and Sierra Leone) are highly endemic (>50%). Overall, 72.7 million annualized praziquantel treatments (50% confidence interval (CI): 68.8–100.7 million) are required for the school-aged population if country-level schistosomiasis prevalence estimates are considered, and 81.5 million treatments (50% CI: 67.3–107.5 million) if estimation is based on a more refined spatial scale at the provincial level.

Conclusions/Significance

Praziquantel treatment needs may be over- or underestimated depending on the level of spatial aggregation. The distribution of schistosomiasis in Ethiopia, Liberia, Mauritania, Uganda, and Zambia is rather uniform, and hence country-level risk estimates are sufficient to calculate treatment needs. On the other hand, countries like Burkina Faso, Mali, Mozambique, Sudan, and Tanzania show large spatial heterogeneity in schistosomiasis risk, which should be taken into account for calculating treatment requirements.     

Schistosomiasis in African infants and preschool children: to treat or not to treat?

The occurrence of schistosomiasis in African infants and preschool children has been largely overlooked, with preventive chemotherapy usually focused on school-aged children instead. Two recent surveys by Bosompem et al. and Odogwu et al. have shown that schistosomiasis in younger children is much more common than previously thought. This article highlights the importance of the disease in this age group and discusses the future prospects for schistosomiasis control.     

The potential of artemether for the control of schistosomiasis

Schistosomiasis continues to rank – following malaria – at the second position of the world's parasitic diseases in terms of the extent of endemic areas and the number of infected people. There is yet no vaccine available and the current mainstay of control is chemotherapy with praziquantel used as the drug of choice. In view of concern about the development of tolerance and/or resistance to praziquantel, there is a need for research and development of novel drugs for the prevention and cure of schistosomiasis. Interestingly, derivatives of artemisinin, which are already effectively used in the treatment of malaria, also exhibit antischistosomal properties. Significant advances have been made with artemether, the methyl ether derivative of artemisinin. We review the discovery of the antischistosomal activity of artemether by Chinese scientists two decades ago; the detailed laboratory studies of the susceptibility of, and effect on, the different developmental stages of Schistosoma japonicum, Schistosoma mansoni and Schistosoma haematobium to artemether; the possible mechanism of action and the potential long-term toxicity. Finally, we look at the effect of combined treatment with artemether and praziquantel; and clinical findings thus far obtained from randomised controlled trials with oral artemether for the prevention of patent infections and morbidity. The review intends to create a forum for strategic discussion of how these laboratory and clinical findings could be translated into public health actions. We conclude that artemether – as part of integrated current control measures and adapted to specific socio-ecological and epidemiological settings – has considerable potential to significantly reduce the current burden of schistosomiasis in many parts of the world.     

Prevalence of soil-transmitted helminth infections,schistosomiasis, and lymphatic filariasis before and after preventive chemotherapy initiation in the Philippines: A systematic review and meta-analysis

ObjectiveTo estimate the impact of preventive chemotherapy on the prevalence and intensity of soil-transmitted helminth (STH) infections, schistosomiasis, and lymphatic filariasis in the Philippines, using systematic review and meta-analysis.MethodsWe included reports reporting prevalence of STH infections, schistosomiasis, or lymphatic filariasis in the Philippines published until 31 March 2021. Peer-reviewed studies were identified in electronic databases. Grey literature reports by the University of the Philippines and the Department of Health were also included. Pooled infection prevalence, before and after the initiation of preventive chemotherapy, stratified by age group, was calculated using the inverse variance heterogeneity model.FindingsA total of 109 reports were included in the review and meta-analysis. Overall prevalence of moderate-heavy intensity Ascaris lumbricoides (6.6%) and Trichuris trichiura (2.7%) infection after initiation of preventive chemotherapy were significantly lower than the prevalence prior to initiation (23.6% for A. lumbricoides and 12.2% for T. trichiura). Prevalence reductions were also found in school and preschool-age children for A. lumbricoides and T. trichiura. Studies conducted after preventive chemotherapy initiation had significantly lower overall prevalence of moderate-heavy intensity schistosomiasis (3.1% vs 0.2%) and of schistosomiasis in school-age children (30.5% vs 1%). Pooled prevalence of lymphatic filariasis prior to preventive chemotherapy initiation was 3.2% across 12 provinces, while currently only two provinces still have prevalence of more than 1%. There were no published studies reporting prevalence of lymphatic filariasis after initiation of preventive chemotherapy. Heterogeneity was high with I² mostly above 90%.ConclusionThe burden of STH infections and schistosomiasis in children were significantly lower in studies conducted following the initiation of preventive chemotherapy. Eliminating morbidity and interrupting transmission, however, may require expanded control initiatives including community-wide treatment, and improved water, sanitation, and hygiene. Lymphatic filariasis burden has decreased since the implementation of preventive chemotherapy, with all but two provinces having reached the elimination of lymphatic filariasis as a public health problem.     

Parasitic worms: knowledge, attitudes, and practices in Western Côte d'Ivoire with implications for integrated control

Background

In the developing world where parasitic worm infections are pervasive, preventive chemotherapy is the key strategy for morbidity control. However, local knowledge, attitudes, and practices (KAP) of parasitic worms are poorly understood, although such information is required for prevention and sustainable control.

Methods

We carried out KAP surveys in two rural communities of Côte d''Ivoire that were subjected to school-based and community-based research and control activities. We used qualitative and quantitative methods. The former included observations, in-depth interviews with key informants, and focus group discussions with school children and adults. Quantitative methods consisted of a structured questionnaire administered to household heads.

Principal Findings

Access to clean water was lacking in both communities and only a quarter of the households had functioning latrines. There was a better understanding of soil-transmitted helminthiasis than intestinal schistosomiasis, but community-based rather than school-based interventions appeared to improve knowledge of schistosomiasis. In the villages with community-based interventions, three-quarters of household interviewees knew about intestinal schistosomiasis compared to 14% in the village where school-based interventions were implemented (P<0.001). Whereas two-thirds of respondents from the community-based intervention village indicated that the research and control project was the main source of information, only a quarter of the respondents cited the project as the main source.

Conclusions/Significance

Preventive chemotherapy targeting school-aged children has limitations, as older population segments are neglected, and hence lack knowledge about how to prevent and control parasitic worm infections. Improved access to clean water and sanitation is necessary, along with health education to make a durable impact against helminth infections.     

Biological methods for the control of freshwater snails

As a result of the advent of new drugs and diagnostic techniques, the emphasis in the control of schistosomiasis has changed from snail control to chemotherapy for infected individuals. However, chemotherapy does not prevent reinfection and there remains a need to reduce snail densities in human water supplies. In the past, treatment with molluscicides has proved ineffective, expensive and has had environmental drawbacks. Here, Henry Madsen describes research into alternative methods of snail control. As yet, little is known of the predators and parasites of schistosome intermediate hosts, but such agents could be suitable as biocontrol agents. To date, the most promising results have been obtained from experimental introductions of competitive snail species, but this strategy still has its drawbacks under many environmental conditions and the development of a universal method of biological control for the intermediate hosts of schistosomes is still a long way off.     

Schistosomiasis: Evaluation of the indirect fluorescent antibody,complement fixation,and slide flocculation tests in screening for schistosomiasis

Foreign Service personnel undergo pertinent parasitologic examinations upon return from foreign duty posts. Under this program, 2800 sera have been evaluated for schistosomiasis in this laboratory. The majority of individuals tested were considered to have limited exposure to schistosomiasis, although a few indigenous people from endemic areas also were screened. Nonindigenous populations usually gave stronger serological reactions than did indigenous populations. A comparison was made between those having protozoan and helminthic infections and those that were negative parasitologically. A number of subjects with tissue-phase helminths were evaluated and consistently gave strong reactions in the indirect fluorescent antibody (IFA) tests. On the other hand, there was no characteristic pattern observed in individuals with low serum titers. The IFA test proved to be highly sensitive and sufficiently specific for screening, provided that low background reactions were disregarded (i.e., when +/? and 1+ reactions were ignored at low serum dilutions). Thus, the IFA test was the method of choice for screening. Recourse to the complement fixation (CF) and slide flocculation (SF) tests, however, was necessary for definitive diagnosis. In view of the differences in the antigens and the serodiagnostic technics used in this survey, absolute correlation of test results could not be expected. Nevertheless, the three procedures (IFA, CF, and SF) showed excellent correlation in proven cases of schistosomiasis.     

Bayesian spatial analysis of a national urinary schistosomiasis questionnaire to assist geographic targeting of schistosomiasis control in Tanzania, East Africa

Spatial modelling was applied to self-reported schistosomiasis data from over 2.5 million school students from 12,399 schools in all regions of mainland Tanzania. The aims were to derive statistically robust prevalence estimates in small geographical units (wards), to identify spatial clusters of high and low prevalence and to quantify uncertainty surrounding prevalence estimates. The objective was to permit informed decision-making for targeting of resources by the Tanzanian national schistosomiasis control programme. Bayesian logistic regression models were constructed to investigate the risk of schistosomiasis in each ward, based on the prevalence of self-reported schistosomiasis and blood in urine. Models contained covariates representing climatic and demographic effects and random effects for spatial clustering. Degree of urbanisation, median elevation of the ward and median normalised difference vegetation index (NDVI) were significantly and negatively associated with schistosomiasis prevalence. Most regions contained wards that had >95% certainty of schistosomiasis prevalence being >10%, the selected threshold for bi-annual mass chemotherapy of school-age children. Wards with >95% certainty of schistosomiasis prevalence being >30%, the selected threshold for annual mass chemotherapy of school-age children, were clustered in north-western, south-western and south-eastern regions. Large sample sizes in most wards meant raw prevalence estimates were robust. However, when uncertainties were investigated, intervention status was equivocal in 6.7-13.0% of wards depending on the criterion used. The resulting maps are being used to plan the distribution of praziquantel to participating districts; they will be applied to prioritising control in those wards where prevalence was unequivocally above thresholds for intervention and might direct decision-makers to obtain more information in wards where intervention status was uncertain.     

Zoonotic schistosomiasis in non-human primates: past, present and future activities at the human-wildlife interface in Africa

Schistosomiasis is one of the world's most widely distributed and prevalent parasitic diseases. Less widely recognized is that some species of Schistosoma, including several that commonly affect humans, also cause disease in other mammalian species; in particular, infections in non-human primates are known. With interest increasing in emerging zoonotic diseases, the status of schistosomiasis as a zoonotic infection is in need of re-appraisal, especially in light of advances in application of molecular screening and epidemiological tools where newly reported infections raise general animal welfare and conservation concerns. Focusing on Africa, this review provides a summary of the occurrence of schistosomiasis in non-human primates and discusses new ways in which surveillance for schistosomiasis should be integrated into more effective conservation management and disease control strategies. Emphasis is on the more common forms of human schistosomiasis, their clinical manifestations and epidemiological significance in terms of infection reservoir potential.     

Lemming winter habitat choice: a snow-fencing experiment

The insulative value of early and deep winter snow is thought to enhance winter reproduction and survival by arctic lemmings (Lemmus and Dicrostonyx spp). This leads to the general hypothesis that landscapes with persistently low lemming population densities, or low amplitude population fluctuations, have a low proportion of the land base with deep snow. We experimentally tested a component of this hypothesis, that snow depth influences habitat choice, at three Canadian Arctic sites: Bylot Island, Nunavut; Herschel Island, Yukon; Komakuk Beach, Yukon. We used snow fencing to enhance snow depth on 9-ha tundra habitats, and measured the intensity of winter use of these and control areas by counting rodent winter nests in spring. At all three sites, the density of winter nests increased in treated areas compared to control areas after the treatment, and remained higher on treated areas during the treatment. The treatment was relaxed at one site, and winter nest density returned to pre-treatment levels. The rodents’ proportional use of treated areas compared to adjacent control areas increased and remained higher during the treatment. At two of three sites, lemmings and voles showed significant attraction to the areas of deepest snow accumulation closest to the fences. The strength of the treatment effect appeared to depend on how quickly the ground level temperature regime became stable in autumn, coincident with snow depths near the hiemal threshold. Our results provide strong support for the hypothesis that snow depth is a primary determinant of winter habitat choice by tundra lemmings and voles.     

The 1992-1999 World Bank Schistosomiasis Research Initiative in China: outcome and perspectives.

Ongoing efforts over the last 50 years, aiming at the elimination of schistosomiasis in the People's Republic of China, have been spectaculary successful in reducing the prevalence and intensity of the infection. The endemic areas have been reduced to core regions with particular problems such as the middle and lower reaches of the Changjiang River (Yangtze), the land adjacent to the lakes of central China and certain mountainous areas in Sichuan and Yunnan. An effort to eradicate schistosomiasis as a public health problem in these areas, by means of mass chemotherapy in regions of high prevalence and selective chemotherapy in others, provided good results initially but a lasting effect proved unattainable with chemotherapy alone. A small part of the funds available for this effort were used for research and training. Overseen by a Joint Research Management Committee (JRMC), research training was intensified resulting in improved applications and a better quality of the scientific level of the research finally carried out. Several new control tools were produced which may improve future control approaches, which might achieve a more than temporary relief. In evaluating the contributions made, it was found that the great environmental variations between the eight provinces where control activities were implemented was the main reason why general use of chemotherapy only could not be entirely successful. The inclusion of a research component proved beneficial both for the short- and long-term control and the JRMC proved useful in exposing that sustained progress cannot be achieved without back-up by other approaches, e.g. snail control. Suggested future activities include strengthening of intersectoral and industrial collaboration but finding financial support for continuing the JRMC initiative in some form. It is crucial to consolidate progress made.