Schistosomiasis epidemiology and control: how did we get here and where should we go?

Although a disease of great antiquity, scientific studies of schistosomiasis began only 150 years ago. The complete life-cycle was not described until just before the First World War, making it possible at last to plan proper community control programmes. Inadequate tools prevented their effective implementation until well after the Second World War when new tools became available, thanks to the newly formed World Health Organization. Molluscicides spearheaded control programmes until the late 1970s but were then replaced by the newly developed, safe drugs still used today. Whatever the method used, the initial goal of eradication was, in the light of experience and cost, gradually replaced by less ambitious targets; first to stop transmission and then to reduce morbidity. The most successful programmes combined several methods to minimise reinfection after chemotherapy. Comparisons between different programmes are difficult without using appropriate, standardised diagnostic techniques and the correct epidemiological measurements. Some examples will be presented, mainly from our studies on Schistosoma mansoni in Kenya. Drug resistance on a scale comparable with malaria has not occurred in schistosomiasis but the likely withdrawal of all drugs except praziquantel leaves its control extremely vulnerable to this potential problem. An effective, affordable vaccine for use in endemic countries is unlikely to be ready for at least 5 years, and developing strategies for its use could take a further decade or more, judging from experience with drugs and molluscicides. In the interim, by analogy with malaria, the most cost-effective approach would the use of drugs combined with other methods to stop transmission, including molluscicides. The cost of molluscicides needs to be reduced and fears allayed about their supposedly adverse ecological effects.

Schistosomiasis epidemiology and control: how did we get here and where should we go?

Although a disease of great antiquity, scientific studies of schistosomiasis began only 150 years ago. The complete life-cycle was not described until just before the First World War, making it possible at last to plan proper community control programmes. Inadequate tools prevented their effective implementation until well after the Second World War when new tools became available, thanks to the newly formed World Health Organization. Molluscicides spearheaded control programmes until the late 1970s but were then replaced by the newly developed, safe drugs still used today. Whatever the method used, the initial goal of eradication was, in the light of experience and cost, gradually replaced by less ambitious targets; first to stop transmission and then to reduce morbidity. The most successful programmes combined several methods to minimise reinfection after chemotherapy. Comparisons between different programmes are difficult without using appropriate, standardised diagnostic techniques and the correct epidemiological measurements. Some examples will be presented, mainly from our studies on Schistosoma mansoni in Kenya. Drug resistance on a scale comparable with malaria has not occurred in schistosomiasis but the likely withdrawal of all drugs except praziquantel leaves its control extremely vulnerable to this potential problem. An effective, affordable vaccine for use in endemic countries is unlikely to be ready for at least 5 years, and developing strategies for its use could take a further decade or more, judging from experience with drugs and molluscicides. In the interim, by analogy with malaria, the most cost-effective approach would the use of drugs combined with other methods to stop transmission, including molluscicides. The cost of molluscicides needs to be reduced and fears allayed about their supposedly adverse ecological effects

Schistosoma mansoni: maturation rate and drug susceptibility of different geographic isolates.

The fecundities and drug susceptibilities of Schistosoma mansoni isolates from Senegal, Puerto Rico, and Kenya have been examined in mice. The Senegal parasite, obtained from the field in 1993, was shown to have a longer prepatent period (eggs first recovered in the faeces on Day 46 after infection) than those of two isolates, from Puerto Rico and Kenya, that had been maintained for a long period in the laboratory (faecal eggs recovered on Days 38 and 36 after infection, respectively). A Kenyan isolate, also collected from the field in 1994, was shown to mature more slowly than the laboratory-maintained Kenyan isolate. Tissue egg counts confirmed that early in infection the fecundity of the recently collected isolates from Senegal and Kenya was significantly lower than that of the long-term laboratory-maintained Kenyan isolate. Praziquantel and oxamniquine treatment of 8-week-old infections caused a significant (P < 0.001) reduction in worm burden in all isolates tested. However, the reduction in worm burden after praziquantel treatment of infections of the Senegal isolate (50% reduction) was significantly lower than the > 90% reductions in worm burdens after praziquantel treatment of mice infected with either of the Kenyan isolates (P < 0.001). The study confirms that despite being tolerant to praziquantel, the Senegal isolate is fully susceptible to oxamniquine. The praziquantel tolerance of the Senegal parasite is not solely attributed to the state of maturation of the parasite at the time of drug administration.

St Lucia revisted: the status of schistosomiasis mansoni in 1996, 15 years after the end of the St Lucia project - abstract

Schistosoma mansoni, the only species of schistosome to infect humans in the Western Hemisphere, is currently known to exist in the Caribbean islands of Antigua and St Lucia. The current status of the trematode in these islands has not been investigated for many years. The recent completion of the John Compton Dam, which provides water for the capital, Castries, and expanding developments in the north of St Lucia provided impetus for this study. The current epidemiological study examined hospital and diagnostic laboratory records for sentinel data, carried out a limited cross-sectional prevalence semi-quantitative stool survey in school children and investigated the infection rate in known residual intermediate snail host populations. These data were augmented by ongoing stool and snail surveys. The results indicate that the advances made in the reduction of the human prevalence (40 percent to 5 percent) of S. mansoni during the 16 years of the St Lucia project (1965 - 1981) have been maintained. The residual Schistosoma mansoni population is currently estimated to be more than 3 to 5 thousand people (2.7 - 4.5 percent of the population). Residual populations of Biomphalaria glabrata persists, but are confined to restricted mountain habitats and infected snails have not been reported since 1984. Control measures, that have been implemented by the St Lucia government during the 15 years since the Rockefeller-sponsored project ended, included treatment of infected people and limited environmental and snail control measures. Current plans are to continue surveillance but the development of the dam and the current low prevalence suggest that it may be appropriate at this time for a more aggressive approach and a plan for eradication of the parasite is suggested.(AU)

Short report: diminished susceptibility to praziquantel in a Senegal isolate of Schistosoma mansoni.

There is a recent report of low efficacy of praziquantel (PZQ) treatment of human schistosomiasis in a new Schistosoma mansoni focus in northern Senegal. Biomphalaria pfeifferi snails with patent infections were collected from the area of the focus and transported to the United Kingdom. Groups of mice were infected with cercariae from this Senegalese isolate, or with laboratory-maintained Kenyan or Puerto Rican isolates. In two separate experiments, PZQ was less effective against the parasite from Senegal than against the two other geographic isolates. The reduced susceptibility of S. mansoni to PZQ in infected human populations has important implications for current schistosomiasis control programs.

Current concepts of snail control

Schistosomiasis control was impossible without effective tools. Synthetic molluscicides developed in the 1950s spearheaded community level control. Snail eradication proved impossible but repeated mollusciciding to manage natural snail populations could eliminate transmission. Escalating costs, logistical complexity, its labour-intensive nature and possible environmental effects caused some concern. The arrival of safe, effective, single-dose drugs in the 1970s offered an apparently better alternative but experience revealed the need for repeated treatments to minimise reinfection in programmes relying on drugs alone. Combining treatment with mollusciciding was more successful, but broke down if mollusciciding was withdrawn to save money. The provision of sanitation and safe water to prevent transmission is too expensive in poor rural areas where schistosomiasis is endemic; rendering ineffective public health education linked to primary health care. In the tropics, moreover, children (the key group in maintaining transmission) will always play in water. Large scale destruction of natural snail habitats remains impossibly expensive (although proper design could render many new man-made habitats unsuitable for snails). Neither biological control agents nor plant molluscicides have proved satisfactory alternatives to synthetic molluscicides. Biologists can develop effective strategies for using synthetic molluscicides in different epidemiological situations if only, like drugs, their price can be reduced.

Current concepts of snail control.

Schistosomiasis control was impossible without effective tools. Synthetic molluscicides developed in the 1950s spearheaded community level control. Snail eradication proved impossible but repeated mollusciciding to manage natural snail populations could eliminate transmission. Escalating costs, logistical complexity, its labour-intensive nature and possible environmental effects caused some concern. The arrival of safe, effective, single-dose drugs in the 1970s offered an apparently better alternative but experience revealed the need for repeated treatments to minimise reinfection in programmes relying on drugs alone. Combining treatment with mollusciciding was more successful, but broke down if mollusciciding was withdrawn to save money. The provision of sanitation and safe water to prevent transmission is too expensive in poor rural areas where schistosomiasis is endemic; rendering ineffective public health education linked to primary health care. In the tropics, moreover, children (the key group in maintaining transmission) will always play in water. Large scale destruction of natural snail habitats remains impossibly expensive (although proper design could render many new man-made habitats unsuitable for snails). Neither biological control agents nor plant molluscicides have proved satisfactory alternatives to synthetic molluscicides. Biologists can develop effective strategies for using synthetic molluscicides in different epidemiological situations if only, like drugs, their price can be reduced.

Immuno-epidemiology of Schistosoma mansoni infections in a recently exposed community in Senegal.

Schistosoma mansoni was introduced in the Senegal basin around 1988, due to man-made ecological changes. Since 1991, we investigate a recent but very intense focus, Ndombo, a village near the city of Richard Toll where the outbreak was first described. Four cohorts, each a random sample (+/- 400 subjects each) from this community, were examined and followed up after treatment, starting at 8 month intervals over a 2-year period. Each cohort is examined parasitologically (Kato-Katz), clinically, serologically (circulating antigen and antibody profiles); treated with praziquantel 40 mg/kg; followed up 6-10 weeks, one and two years after treatment; and monitored for water contact patterns and local snail densities. In the first cohort, the prevalence was 91%, with a mean egg count of 663 epg. Prevalences are near 100% in all age groups, but egg counts decline strongly in adults. Antigen detection in serum and urine confirmed that the egg counts genuinely reflect variations of worm burdens, not e.g. of worm fecundity. This is surprising, as in this focus acquired immunity in adults should not have yet developed according to current hypothesis. The antigen detection assays (CAA/CCA) showed high sensitivity and quantitative power, and promising perspectives as a research tool and possibly as a method for non-invasive diagnosis and screening in urine. Epidemiological in subsequent cohorts were highly similar, although seasonal variations were observed possibly due to transmission fluctuations. Anti-AWA and anti-SEA IgE levels increased with age, while IgG4 peaked in the age-group 10 years and correlated well with egg counts.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: A cohort analysis was performed in Ndombo, Senegal, a community of about 4000, in the epicenter of the schistosomiasis outbreak. Four randomly selected cohorts of +or- 400 subjects were surveyed. Each cohort was examined parasitologically, clinically, and serologically (circulating antigen and antibody profiles); treated with praziquantel 40 mg/kg; and followed up at 6-12 weeks and at 1 and 2 years after treatment. The first cohort numbered 422 individuals, of which 91% had positive egg counts, with a mean egg count of 663 eggs per gram feces (epg). Quantitative egg counts in those aged 10-14 were 1409 epg and then declined to 632 epg in the age group 20-29 and to 266 epg in the age group over 40. In cohorts 2 and 3, examined in the spring and autumn, egg counts were substantially lower, particularly in adults, as compared with cohorts 1 and 4, which were both examined in the summer season. 94% of the subjects were positive in the serum circulating anodic antigen (CAA) ELISA, 83% in the serum CAA ELISA, and 95% in the urine circulating cathodic antigen (CCA) ELISA; CAA in urine was less sensitive, and was negative in half of the urine samples. Positivity rates for all assays increased with rising egg counts, and circulating antigen concentrations in both serum and urine correlated well with egg counts. IgE showed a significant increase with age, while IgG4 peaked in the age groups 10-15 and/or 15-19 years. A strong correlation between IgG, IgGl, and IgG4 against both crude antigens with pretreatment egg load was observed. Of the subjects in the first cohort, 61% reported abdominal pain, 33% diarrhea; only 16% showed mild hepatomegaly and only a few children had mild splenomegaly. In the first cohort, 82% of 298 reexamined subjects were still positive for S. mansoni 12 weeks after treatment with praziquantel 40 mg/kg. One year after treatment, cohort 1 showed mean egg counts in children (5-19 years) at 358 epg as compared with 1188 epg pretreatment.

Identification of schistosome-infected snails by detecting schistosomal antigens and DNA sequences.

Cercarial shedding tests do not provide species identification of the schistosomes concerned and cannot detect prepatent schistosomal infections. We have demonstrated that both immunodetection by ELISA of schistosomal antigens in snail hemolymph, and dot hybridization of snail extracts by a DNA probe representing highly repeated sequences, proved suitable for detecting infected snails during prepatency as well as patency. A group-specific monoclonal antibody was found to be suitable for detecting Schistosoma mansoni infection in Biomphalaria sp., but not for positive identification of S. haematobium in Bulinus sp. Comparative evaluation of the diagnostic qualities, and technical aspects and cost of these tests, point to the superiority of the immunodetection approach for large scale detection of snails prepatently infected with S. mansoni. This approach is potentially useful for providing extended information on schistosome-snail epidemiology that may facilitate rapid evaluation of the danger of post-control reinfection, and help make decisions on the time and place of supplementary control measures. In this context the potential usefulness of the immunodetection or DNA probing approach for facilitating catalytic model representation of schistosome-snail epidemiology warrants further evaluation. Specific identification of S. haematobium in Bulinus by either of these approaches may be possible depending on the development of suitable antibodies or DNA probes.

Harmonization of research and control in schistosomiasis.

I have been employed by several different organizations during over 30 years working on schistosomiasis, the majority spent in endemic areas of the Caribbean, South America, Africa and the Western Pacific. Much of the work is best classified as applied research but sometimes it strayed to the extremes of either public health control programmes or pure research. Over this period, there have been several significant research developments that have altered our whole approach to control. Ideally, research and control should complement each other but, in reality, they sometimes have conflicting objectives. Public health workers understandably wish to provide immediate, short-term protection to the communities in their care, but research workers may, within ethical limits, reasonably want to observe untreated communities for extended periods in order to understand the underlying processes of transmission, disease pathogenesis and immunity to help develop more effective control measures. An example of this situation has occurred recently in Senegal where water development projects seem to have favoured the introduction and spread of Schistosoma mansoni in the Senegal River Basin. I have been asked to be the scientific consultant to the newly formed ESPOIR programme, linking European research organizations and the Senegal Ministry of Health, to reconcile the conflicting aims of public health workers, wishing to use whatever funds can be obtained for an immediate chemotherapy to try to eliminate the focus, at present confined to the vicinity of a relatively small, commercially run sugar irrigation scheme; and research workers who see a rare chance to study the development of immune mechanisms in a adults in a community not previously exposed to the infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Human IgE responses to Schistosoma mansoni and resistance to reinfection.

Schistosoma mansoni infected Kenyan patients were treated and the intensities of their reinfections were followed over the next two years. In addition, their pre- and six month post-treatment serum levels of IgG1-4, IgM, and IgE, specific for schistosomula, egg and adult worm, were measured in ELISA. No reinfection took place before six months post-treatment. Reinfection intensities varied with age; the younger children becoming reinfected at significantly higher intensities than older individuals. When antibody and reinfection levels were compared, only the six month post-treatment IgE response against adult worm correlated negatively with intensities of reinfection and, therefore, was predictive of resistance or immunity to reinfection. IgE and IgG specific Western Blots were carried out. The adult worm antigens recognized by IgE were restricted compared with the IgG responses of the same patients, although no individual antigen was uniquely recognized by the IgE isotype. A dominant 22 kDa antigen was recognized by most but not all high IgE responders. Patients with IgE responses against this antigen suffered significantly lower subsequent levels of reinfection, compared with non-responders. A monospecific rabbit antiserum against the 22 kDa adult worm antigen showed that this antigen is specifically located in the tegument of the adult worm and of 'lung' and 'liver' stage schistosomula, but is absent from the early 'skin' schistosomula. It is possible that this antigen is a target for human IgE mediated immune effector mechanisms active against the post skin stage schistosomula and that this is boosted by the death of adult worms.

Harmonization of research and control in schistosomiasis

I have been employed by several different organizations during over 30 years working on schistosomiasis, the majority spent in endemic areas of Caribean, South America, Africa and the Western Pacific. Much of the work is best classified as applied research but sometimes it strayed to the extremes of either public health control programmes or pure research. Over this period, there have been several significant research developments that have altered our whole approach to control. Ideally, research and control should complement each other but, in reality, they sometimes have conflicting objectives. Public health workers understandably wish to provide immediate, shot-term protection to the communities in their care, but research workers may, within ethical limits, reasonably want to observe untreated communities for extended periods in order to understand the underluing process of transmission, disease pathogenesis and immunity to help develop more effective control measures. An example of this situation has occured recently in Senegal where water development projects seem to have favoured the introduction and spreed of Schistosoma mansoni in the Senegal River Basin. I have been asked to be the scientific consultant to the newly formed ESPOIR programme, linking European research organizations and the Senegal Ministry of Health, to reconcile the conflictiong aims of public health workers, wishing to use whatever funds can be obtained for an immediate chemotherapy to try to eliminate the focus, at present confined to the vicinity of a relatively small, commercially run sugar irrigation scheme; and research workers who see a rare chance to study the development of immune mechanisms in a adults in a community not previously exposed to the infection. This information could prove invaluable in understanding the development of immunity and the pathogenesis of disease, leading eventually to the development of vaccines to revolutionise the future approach to schistosomiasis control. Some of our proposed solutions will be described in wich, without denying such treatment as infected people may ethically require and politically demand, we will attempto allow the research workers to gather the data they need

Identification of schistosome-infected snails by detecting schistosomal antigens and DNA sequences

Cercarial shedding tests do not provide species identification of the shistosomes concerned and cannot detect prepatent schistosomal infections. We have demonstrated that both immunodetection by ELISA of schistosomal antigens in snail hemophlymph, and dot hybridization of snail extracts by DNA probe representing highly repeated sequences, proved suitable for detecting infected snails during prepatnecy as well as patency. A group-specific monoclonal antibody was found to be suitable for detecting Schistosoma mansoni infection in Biomphalaria sp., but not for positive identification of S. haematobium in Blulinus sp. Comparative evaluation of the diagnostic qualities, and technical aspects and cost of these tests, point to the superiority of the immunodetection approach for large scale detection of snails prepatently infected with S. mansoni. This approach is potentially useful for providing extended information on schistosome-snail epidemiology that may facilitate rapid evaluation of the danger of post-control reinfection, and help make decisions on the time and place of supplementary control measures. In this context the potential usefulness of the immunodetection or DNA probing approach for facilitating catalytic model representation of schistosome-snail epidemiology warrants further evaluation. Specific identification of S. haematobium in Bulinus by either of these approaches may be possible depending on the development of suitable antibodies or DNA probes

The control of schistosomiasis: epidemiological aspects of reinfection.

Current strategies for schistosomiasis control rely heavily on drug treatment intended to reduce morbidity and disease to an insignificant level of public health importance. This approach reduces but rarely, if ever, eliminates transmission. Indeed, snail infection rates may be little altered by such chemotherapy. Reinfection is inevitable. The mean human community prevalence usually returns rapidly to precontrol levels but the mean intensity of infection takes much longer, distorting the general relationship between the two. Because of the focality of schistosomiasis transmission, retreatment based on mean population prevalence is often too late to protect people living near active transmission sites. However, if suitable methods can be developed to examine man after treatment, they should simplify the detection of the main transmission sites, allowing the employment of alternative, focal control measures to consolidate the beneficial effects of mass chemotherapy.

Studies on the hatchability of Schistosoma mansoni eggs from a naturally infected human community on St Lucia, West Indies.

A relatively simple, standardized hatching test was devised, tested and used to estimate the Schistosoma mansoni hatching rate for 88 St Lucian subjects selected by age, sex and intensity of infection. The hatching rate was dependent on the intensity of infection and rose proportionately with it. The rate also decreased with increasing age of the subject. Sex alone had no direct effect but there was a suggestion of an interaction between sex and age. These results suggest that several hatching tests are necessary, before and after treatment in schistosomicidal drug trials, to permit valid conclusions to be drawn. The hatching data are used in conjunction with survey results to calculate the contamination potential of different age groups in a population. School children (5-14 years old) are about twice as important as young adults (15-29 years old) who, nevertheless, contribute over a quarter of the total contamination potential. However, whereas school children are fairly accessible for mass chemotherapy control programmes, young adults often are not and, furthermore, involve problems associated with the treatment of women of child-bearing age.

Distribution of the snail Biomphalaria glabrata, intermediate host of Schistosoma mansoni, within a St Lucian field habitat.

A total of 6360 mud samples were obtained, in 62 collections made with an exhaustive sampling device, from banana drains on the West Indian island of St Lucia during fortnightly samplings over a 2(1/2)-year period. Analysis of counts of the snail Biomphalaria glabrata from these samples showed that this species had a contagious distribution. This finding is consistent with other evidence that banana drains form a rigorous habitat for B. glabrata. Its distribution was more contagious than that of Oncomelania quadrasi in certain Philippine habitats and several species of aquatic snail in various African irrigation canals. The exact transformation for normalizing the snail counts for standard statistical techniques was z = x(0.287) but the more convenient cube root transformation is probably adequate. However, if too few snails are collected (15 or fewer per 100 samples) or if the frequency distribution of snail counts is discontinuous, with too many widely separated high frequency counts, neither transformation will be entirely satisfactory.

Distribution of the snail Biomphalaria glabrata, intermediate host of Schistosoma mansoni, within a St. Lucian field habitat

A total of 6360 mud samples were obtained, in 62 collections made with an exhaustive sampling device, from banana drains of the West Indian island of St. Lucia during fortnightly samplings over a 2«-year period. Analysis of counts of the snail Biomphalaria glabrata from these samples showed that this species had a contagious distribution. This finding is consistent with other evidence that banana drains from a rigorous habitat for B. glabrata. Its distribution was more contagious than that of Oncomelania quadrasi in certain Philippine habitats and several species of aquatic snail counts for standard statistical techniques was z=x0.287 but the more convenient cube root transformation is probably adequate. However, if too few snails are collected (15 or fewer per 100 samples) or if the frequency distribution of snail counts is discontinuous, with too many widely separated high frequency counts, neither transformation will be entirely satisfactory.(AU)

Persistence of the molluscicide Bayluscide (clonitralide) emulsifiable concentrate on mud surfaces in the tropics

Clonitralide (the active ingredient of the molluscidide Bayluscide) is commonly regarded as non-persistent. It was importnt to determine if this assuption was correct during the development of a programme on St. Lucia to control the intermediate host of Schistosoma mansoni, the snail Biomphalaria glabrata. In 3 separate experiments, aqueous solutions of an emulsifiable concentrate of clonitralide were sprayed onto pans containing dried mud or mud covered with 2.5 cm of water. All snails present at the time of spraying were killed, whether or not water was present. Mortalities were high in similar, unsprayed pans but subsequent chemical and biological assays demonstrated that clonitralide remained active for over a year in tropical conditions, despite several cycles of wetting and drying. Clonitrlide residues from vegetation sprayed in an operational snail control programme remained toxic for 8 weeks exposed to full sunlight, heavy rainfall, temperatures of 20 to 30 degrees C and relative humidities of 70 percent to 95 percent. The implications of these findings for the control of aquatic and amphibious snails are discussed together with some possible mechanisms to explain the persitence of the molluscicide.(AU)