Evaluation of the therapeutic efficacy of praziquantel against schistosomes in seven countries with ongoing large-scale deworming programs.

The World Health Organization (WHO) recommends periodic assessment of the therapeutic efficacy of praziquantel (PZQ) to detect reduced efficacy that may arise from drug resistance in schistosomes. In this multi-country study (2014), we assessed the therapeutic efficacy of a single oral dose of PZQ (40 mg/kg) against Schistosoma mansoni (Brazil, Cameroon, Ethiopia, Mali, Madagascar and Tanzania), S. haematobium (Cameroon, Ethiopia, Mali, Tanzania and Zanzibar) and S. japonicum (the Philippines) infections in school-aged children, across a total of 12 different trials. Each trial was performed according to the standardized methodology for evaluating PZQ efficacy as described by the WHO. Overall, therapeutic efficacy, measured as the reduction in arithmetic mean of schistosome egg counts following drug administration (egg reduction rate; ERR), was high for all three schistosome species (S. mansoni: 93.4% (95%CI: 88.8-96.8); S. haematobium: 97.7% (95%CI: 96.5-98.7) and S. japonicum: 90.0% (95%CI: 68.4-99.3). At the trial level, therapeutic efficacy was satisfactory (point estimate ERR ≥90%) for all three Schistosoma species with the exception of S. mansoni in Cameroon where the ERR was 88.5% (95%CI: 79.0-95.1). Furthermore, we observed that in some trials individual drug response could vary significantly (wide 95%CI) and that few non-responsive individuals could significantly impact ERR point estimates. In conclusion, these results do not suggest any established reduced efficacy of the standard PZQ treatment to any of the three schistosome species within these countries. Nevertheless, the substantial degree of variation in individual responses to treatment in some countries underpins the need for future monitoring. The reported ERR values serve as reference values to compare with outcomes of future PZQ efficacy studies to ensure early detection of reduced efficacies that could occur as drug pressure continues increase. Finally, this study highlights that 95%CI should be considered in WHO guidelines to classify the therapeutic efficacy of PZQ.

A large light-mass component of cosmic rays at 10(17)-10(17.5) electronvolts from radio observations.

Cosmic rays are the highest-energy particles found in nature. Measurements of the mass composition of cosmic rays with energies of 10(17)-10(18) electronvolts are essential to understanding whether they have galactic or extragalactic sources. It has also been proposed that the astrophysical neutrino signal comes from accelerators capable of producing cosmic rays of these energies. Cosmic rays initiate air showers--cascades of secondary particles in the atmosphere-and their masses can be inferred from measurements of the atmospheric depth of the shower maximum (Xmax; the depth of the air shower when it contains the most particles) or of the composition of shower particles reaching the ground. Current measurements have either high uncertainty, or a low duty cycle and a high energy threshold. Radio detection of cosmic rays is a rapidly developing technique for determining Xmax (refs 10, 11) with a duty cycle of, in principle, nearly 100 per cent. The radiation is generated by the separation of relativistic electrons and positrons in the geomagnetic field and a negative charge excess in the shower front. Here we report radio measurements of Xmax with a mean uncertainty of 16 grams per square centimetre for air showers initiated by cosmic rays with energies of 10(17)-10(17.5) electronvolts. This high resolution in Xmax enables us to determine the mass spectrum of the cosmic rays: we find a mixed composition, with a light-mass fraction (protons and helium nuclei) of about 80 per cent. Unless, contrary to current expectations, the extragalactic component of cosmic rays contributes substantially to the total flux below 10(17.5) electronvolts, our measurements indicate the existence of an additional galactic component, to account for the light composition that we measured in the 10(17)-10(17.5) electronvolt range.

Preventive chemotherapy in human helminthiasis: theoretical and operational aspects.

Preventive chemotherapy (PC), the large-scale distribution of anthelminthic drugs to population groups at risk, is the core intervention recommended by the WHO for reducing morbidity and transmission of the four main helminth infections, namely lymphatic filariasis, onchocerciasis, schistosomiasis and soil-transmitted helminthiasis. The strategy is widely implemented worldwide but its general theoretical foundations have not been described so far in a comprehensive and cohesive manner. Starting from the information available on the biological and epidemiological characteristics of helminth infections, as well as from the experience generated by disease control and elimination interventions across the world, we extrapolate the fundamentals and synthesise the principles that regulate PC and justify its implementation as a sound and essential public health intervention. The outline of the theoretical aspects of PC contributes to a thorough understanding of the different facets of this strategy and helps comprehend opportunities and limits of control and elimination interventions directed against helminth infections.

Moderate and high endemicity of schistosomiasis is a predictor of the endemicity of soil-transmitted helminthiasis: a systematic review.

The authors conducted a systematic literature review with the following aims: to investigate how frequently soil-transmitted helminthiasis (STH) infections are endemic where schistosomiasis is present; and to assess the correlation between the risk level of schistosomiasis and that of STH. Among 155 sites on which data were collected and analyzed, schistosomiasis was present in 130, all of which were also co-endemic for STH, whereas 25 sites were endemic only for STH. Ninety percent (117 out of 130) of the areas eligible for preventive chemotherapy (PC) against schistosomiasis are also eligible for PC against STH. This fact provides managers of control programmes with the operationally important indication that use of available information on endemicity of schistosomiasis is a valid tool to predict the presence of STH in the same geographical area and to estimate the need of PC for STH. The implementation of this tool is expected to save financial and human resources and help accelerate the scale-up of PC throughout the world.

Estimation of the cost of large-scale school deworming programmes with benzimidazoles.

This study estimates the cost of distributing benzimidazole tablets in the context of school deworming programmes: we analysed studies reporting the cost of school deworming from seven countries in four WHO regions. The estimated cost for drug procurement to cover one million children (including customs clearance and international transport) is approximately US$20000. The estimated financial costs (including the cost of training of personnel, drug transport, social mobilization and monitoring) is, on average, equivalent to US$33000 per million school-age children with minimal variation in different countries and continents. The estimated economic costs of distribution (including the time spent by teachers, and health personnel at central, provincial and district level) to cover one million children approximately corresponds to US$19000. This study shows the minimal cost of school deworming activities, but also shows the significant contribution (corresponding to a quarter of the entire cost of the programme) provided by health and education systems in endemic countries even in the case of drug donations and donor support of distribution costs.

Praziquantel: its use in control of schistosomiasis in sub-Saharan Africa and current research needs.

Treatment with praziquantel (PZQ) has become virtually the sole basis of schistosomiasis control in sub-Saharan Africa and elsewhere, and the drug is reviewed here in the context of the increasing rate that it is being used for this purpose. Attention is drawn to our relative lack of knowledge about the mechanisms of action of PZQ at the molecular level, the need for more work to be done on schistosome isolates that have been collected recently from endemic areas rather than those maintained in laboratory conditions for long periods, and our reliance for experimental work mainly on Schistosoma mansoni, little work having been done on S. haematobium. There is no evidence that resistance to PZQ has been induced in African schistosomes as a result of its large-scale use on that continent to date, but there is also no assurance that PZQ and/or schistosomes are in any way unique and that resistant organisms will not be selected as a result of widespread drug usage. The failure of PZQ to produce complete cures in populations given a routine treatment should therefore solicit considerable concern. With few alternatives to PZQ currently available and/or on the horizon, methods to monitor drug-susceptibility in African schistosomes need to be devised and used to help ensure that this drug remains effective for as long a time as possible.

Schistosomiasis control in China: the impact of a 10-year World Bank Loan Project (1992-2001).

China has been carrying out large-scale schistosomiasis control since the mid-1950s, but in the early 1990s, schistosomiasis was still endemic in eight provinces. A World Bank Loan Project enabled further significant progress to be made during the period 1992-2001. The control strategy was focused on the large-scale use of chemotherapy -- primarily to reinforce morbidity control -- while at the same time acting on transmission with the ultimate goal of interrupting it. Chemotherapy was complemented by health education, chemical control of snails and environmental modification where appropriate. A final evaluation in 2002 showed that infection rates in humans and livestock had decreased by 55% and 50%, respectively. The number of acute infections and of individuals with advanced disease had also significantly decreased. Although snail infection rates continued to fluctuate at a low level, the densities of infected snails had decreased by more than 75% in all endemic areas. The original objectives of the China World Bank Loan Project for schistosomiasis control had all been met. One province, Zhejiang, had already fulfilled the criteria for elimination of schistosomiasis by 1995. The project was therefore a success and has provided China with a sound basis for further control.

The WHO dose pole for the administration of praziquantel is also accurate in non-African populations.

In 2001, WHO developed a pole for the administration of praziquantel without the use of weighing scales, with encouraging results in African populations. In the present study, the pole was tested on height/weight data from 9354 individuals from 11 non-African countries. In more than 98% of the individuals (95% CI 97.8-98.4) the pole estimated an acceptable dosage (30-60 mg/kg), a performance statistically similar to that observed in African populations. Reproducing the present pole in the form of a strip of paper and including it in each container of praziquantel would greatly facilitate the administration of the drug in large-scale interventions.

Progress in the prevention and control of schistosomiasis and soil-transmitted helminthiasis.

In the last two decades important progress has been made in the understanding the epidemiology and the disease burden of schistosomiasis and soil-transmitted nematodes infection. In addition, practical tools for disease control have been developed and a strategy for the prevention and control of morbidy of schistosomaisis and soil-transmitted nematodes infection has been endorsed by the World Health Organization. This paper presents the recent progress in the prevention and control of these infections: the estimates of chronic and subtle morbidity in high risk groups and the evidence that these chronic and severe sequelae of infections can be reversed by appropriate treatment; the use of anthelminthic drugs during pregnancy and lactation; the relevance to control morbidity due to these infections also in pre-school children; the efficacy of anthelminthic drugs and the possible threat of drug resistance; price, quality and accessibility of treatment by delivering drugs through the school system and ways of reaching also non-enrolled school-age children. Finally, the strategy, targets and recommendations of the World Health Organization for the control of schistosomiasis and soil-transmitted nematodes infection are described.

Water-related disease patterns before and after the construction of the Diama dam in northern Senegal.

The ecological changes caused by projects for the development of water resources are known to affect the epidemiology of water-related diseases. The effects of the construction of the Diama dam (completed in 1986) in the Senegal River on the epidemiology of malaria, urinary and intestinal schistosomiasis, diarrhoea and dysentery were investigated in four districts in northern Senegal. To make allowance for any general trend in reported morbidity (caused by changes in demography or the healthcare system), the numbers of cases of these illnesses reported by the basic healthcare facilities before and after the completion of the dam were compared with those of respiratory disease. Prior to the construction of the dam, malaria was the most encountered water-related disease in the medical records of all districts, followed by diarrhoea, dysentery and urinary schistosomiasis. This order remained the same after the completion of the dam. Despite the optimism of health-assessment reports prepared prior to the construction of the Diama dam, the unexpected appearance and spread of intestinal schistosomiasis as well as an increase in the incidence of urinary schistosomiasis have aggravated public health in the Senegal River basin. It remains to be judged whether the economic benefits of the dam will counterbalance its adverse effects.

Field test of the 'dose pole' for praziquantel in Zanzibar.

A graduated pole for height measurement, estimating the number of praziquantel tablets needed for treatment, was field-tested on 1289 children in Zanzibar. A bathroom-type scale performed better than the dose pole in delivering the optimal dose (40-60 mg/kg) and the 2 methods performed similarly in delivering a dose considered appropriate (30-60 mg/kg).

The global epidemiological situation of schistosomiasis and new approaches to control and research.

While the distribution of schistosomiasis has changed over the last 50 years and there have been successful control programmes, the number of people estimated to be infected or at risk of infection has not been reduced. Today, 85% of the number of infected people are estimated to be on the African continent where few control efforts are made. In terms of disease burden, there is therefore a growing discrepancy between sub-Saharan Africa and the rest of the world. WHO has now developed a dual strategy for the control of schistosomiasis: a strategy for morbidity control adapted to the public health context in high burden areas, and a strategy to consolidate control in areas where a low endemic level has been reached and elimination may be feasible. Related to this new vision, some research needs are pointed out.

Development and validation of a 'tablet pole' for the administration of praziquantel in sub-Saharan Africa.

A pole estimating, for each individual, the number of praziquantel tablets needed for treatment according to height was tested in 20 data sets (n = 25,688). In more than 98% of the cases the indicated dose was within the range that has proven efficacious and safe (30 and 60 mg/kg).

Are poor responses to praziquantel for the treatment of Schistosoma mansoni infections in Senegal due to resistance? An overview of the evidence.

This paper summarizes and concludes in-depth field investigations on suspected resistance of Schistosoma mansoni to praziquantel in northern Senegal. Praziquantel at 40 mg/kg usually cures 70-90% of S. mansoni infections. In an initial trial in an epidemic S. mansoni focus in northern Senegal, only 18% of the cases became parasitologically negative 12 weeks after treatment, although the reduction in mean egg counts was within normal ranges (86%). Among other hypotheses to explain the observed low cure rate in this focus, the possibility of drug resistance or tolerance had to be considered. Subsequent field trials with a shorter follow-up period (6-8 weeks) yielded cure rates of 31-36%. Increasing the dose to 2 x 30 mg/kg did not significantly improve cure rates, whereas treatment with oxamniquine at 20 mg/kg resulted in a normal cure rate of 79%. The efficacy of praziquantel in this focus could be related to age and pre-treatment intensity but not to other host factors, including immune profiles and water contact patterns. Treatment with praziquantel of individuals from the area residing temporarily in an urban region with no transmission, and re-treatment after 3 weeks of non-cured individuals within the area resulted in normal cure rates (78-88%). The application of an epidemiological model taking into account the relation between egg counts and actual worm numbers indicated that the low cure rates in this Senegalese focus could be explained by assuming a 90% worm reduction after treatment with praziquantel; in average endemic situations, such a drug efficacy would result in normal cure rates. Laboratory studies by others on the presence or absence of praziquantel resistance in Senegalese schistosome strains have so far been inconclusive. We conclude that there is no convincing evidence for praziquantel-resistant S. mansoni in Senegal, and that the low cure rates can be attributed to high initial worm loads and intense transmission in this area.