Novel Approaches in the Control of Schistosomiasis: from Rapid Identification to Chemoprophylaxis

Human schistosomiasis is the second most prevalent parasitic disease in the tropics, and has a huge impact on public health and socio-economic development. It is estimated that 652 million people live at risk of infection and that 193 million people are actually infected. Of the 120 million symptomatic cases, 20 million are suffering from severe disease. At present, 85% of all these cases are concentrated in sub-Saharan Africa and they cause an estimated morbidity burden of 3.5 million disability adjusted live years (DALYs). Since the advent of safe, effective, single dose drugs, the emphasis in schistosomiasis control has been on morbidity control. Since praziquantel is active against all schistosome species and has become relatively inexpensive, it is used as the drug of choice. For effective control of schistosomiasis, it is now of central importance to make the drug available to the communities at highest risk of infection. The distribution of schistosomiasis is extremely focal and since resources for health are seriously limited in most schistosomiasis endemic countries, there is a great need to identify high risk communities, so that resources can be better allocated. Due to the focal nature of the disease, neighbouring villages often show different patterns of schistosomiasis morbidity, resulting in large inter-village variation in perceived disease and actual public health importance. A simple procedure using questionnaires has been developed for rapid screening for Schistosoma haematobium infection and it proved to be reliable, non-intrusive and highly cost-effective in 8 African countries. Based on these experiences, WHO published guidelines for district health managers to be used as a first stage in the process of schistosomiasis control. Cote d’Ivoire is now the first country, that has taken advantage of these guidelines and translated them into direct application. In a first step, the feasibility and diagnostic performance of the questionnaire was rigorously validated in an S. haematobium endemic area in central Cote d’Ivoire. Correctly completed questionnaires were obtained from 124 schools (return rate: 91%), with 12,479 children interviewed. Following, previously trained teachers screened 5,959 children with reagent sticks. The questionnaire showed a good diagnostic performance with sensitivity and specificity values between 79% and 96% to detect correctly those schools where the pupils were at high risk of infection. These findings were in agreement with previous studies from other African countries, and the questionnaire approach was recommended for use at the national level. At present, the questionnaires are already being applied in 5 out of 16 districts. The active involvement of University students in distributing and collecting questionnaires in this survey, is a promising innovative approach. Based on the excellent performance of questionnaires for rapid screening of S. haematobium and linked to the ongoing process in Cote d’Ivoire, there was a demand asking for support with implementing this technique also in the Niger State of north-western Nigeria. Questionnaires were returned from 58 schools (return rate: 97%). A total of 3,033 children were interviewed and 2,479 children were screened with reagent sticks by previously trained teachers. Questionnaires also proved to be reliable in this setting, and identified schools at high risk of S. haematobium with sensitivity and specificity values ranging between 64% and 96%. The identification of high risk communities is an important component in the management and implementation of cost-effective schistosomiasis control programmes. For S. mansoni infection, reliable rapid methods have not yet been developed. Therefore possible ways of extending the questionnaire method for S. mansoni were assessed in Cote d’Ivoire. In a first study, perceived signs and symptoms for intestinal morbidity were assessed in focus group discussions with schoolchildren in an area highly endemic for S. mansoni. The most frequently perceived signs and symptoms were then used in a preliminary questionnaire in three schools. Comparison of the results with levels of S. mansoni infection revealed that reported blood in stool was the most reliable symptom to predict an infection (adjusted odds ratio: 2.87; 95% confidence interval (CI): 1.56-5.31). Based on these findings, a questionnaire was developed and distributed to 134 schools. Correctly filled-in questionnaires were returned from 121 schools (90%), with 12,227 children interviewed. 5,047 children were screened by a biomedical team with two consecutive Kato- Katz thick smears. For an individual diagnosis, the two symptoms “blood in stool” and “bloody diarrhoea” were significantly correlated with an S. mansoni infection: adjusted odds ratio 1.59 (95% CI: 1.38-1.83) and 1.34 (95% CI: 1.14-1.58), respectively. For community diagnosis, these two symptoms showed a high sensitivity (88%) and a moderate specificity (58%). Subsequently, it was assessed whether the diagnostic performance of the questionnaire could be improved by asking questions about water contact patterns. Although a positive response to a particular water contact pattern correlated significantly with an infection with S. mansoni, the diagnostic performance was again only moderate. In view of these findings, it was concluded that there is still a considerable amount of research needed before questionnaires can be adopted as a tool to screen for S. mansoni at the community level. Morbidity control in schistosomiasis requires effective initial treatment and the prevention of re-infection. In view of recent concern that praziquantel-tolerance/resistance might develop, there is a great need for research and development of novel substances with antischistosomal properties. Artemether has been identified in China as a promising product for early treatment and prophylaxis. It showed prophylactic effects in animals experimentally infected with S. japonicum, and was a successful prophylactic agent in humans exposed to S. japonicum. Further laboratory experiments showed a prophylactic effect also against S. mansoni. We conducted the first randomised double-blind placebo-controlled trial of oral artemether to prevent S. mansoni infections. 354 schoolchildren were enrolled. Stool samples were examined over four consecutive days, followed by two mass treatments with praziquantel four weeks apart. All S. mansoni negative children were randomly assigned to receive 6 repeated doses of a placebo (n=151) or artemether (n=138) at a dose of 6 mg/kg, spaced by 3 weeks. At the end of the study, the incidence and mean intensity of S. mansoni infection were assessed by examining four consecutive stool samples from the children. The group that received artemether had a significantly lower incidence of S. mansoni infection (31/128 vs. 68/140, relative risk: 0.50, 95% CI: 0.35-0.71, p<0.001). Furthermore, the geometric mean egg output among positive children in the artemether group (19 eggs/g stool) was significantly lower than in placebo recipients (32 eggs/g, p=0.017). Oral artemether was found to be safe and no adverse events occurred. Since artemether is already widely and effectively used against malaria, the use of artemether against schistosomiasis should not be recommended for widespread application in areas where malaria is endemic because of the potential risk of developing drug resistance in the malaria parasite. However, the use of artemether might contribute to a more effective schistosomiasis control in particular epidemiological settings. The findings of the present investigations clearly contributed to means of rapid identification of high risk areas of urinary and intestinal schistosomiasis in general and to the development and management of a national schistosomiasis control programme in Cote d’Ivoire in particular. We are optimistic that in the years to come considerable progress will be seen with the use of artemether (and hopefully also other drugs yet to be discovered) and that these products will take a promising place in a comprehensive strategy for schistosomiasis control.