A. Ly

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 × 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.

Increase of malaria attacks among children presenting concomitant infection by Schistosoma mansoni in Senegal.

Helminthic infections concomitant with malaria are common in inter-tropical areas. A recent study showed that mice co-infected with Schistosoma mansoni and Plasmodium chabaudi develop higher P. chabaudi parasitaemia and had a higher mortality rate. This important observation deserved to be further investigated among human populations.Malaria attacks were recorded in 512 children aged 6–15 years living in Richard Toll (Northern Senegal) among whom 336 were infected by S. mansoni, and 175 were not. The incidence rate of malaria attacks was significantly higher among S. mansoni-infected individuals, particularly those carrying the highest worm loads, as compared to uninfected subjects (26.6% versus 16,4 %). In contrast, the rate of malaria attacks was lower, without reaching significance, in medium grade S. mansoni infections. Thus, infection by S. mansoni affects susceptibility to malaria, but this can vary according to the intensity of parasite load. The immunological mechanisms underlying this dual effect need to be further explored.

Efficacy of praziquantel against Schistosoma mansoni in northern Senegal

Two treatments with praziquantel (PZQ) 40 mg/kg, 40 d apart, were given to individuals in a recently established (< 6 years) Schistosoma mansoni focus in the Senegal River Basin (SRB). Efficacy of treatment was evaluated 4 weeks after each treatment. Among 130 individuals who provided stool samples on days 0, 118 and 153 and were treated on days 85 and 125, 113 (87%) were infected with S. mansoni before treatment. The overall geometric mean faecal egg count of the infected individuals was 478 eggs/g. Four weeks after the first treatment (day 118), the overall cure rate was only 42.5% and the overall reduction in intensity of infection was 70.7%. However, 4 weeks after the second treatment (day 153), the overall cure rate rose to 76.1% and the overall reduction in intensity was 88.1%. The greatest increase in cure rate between the 2 treatments was in those individuals who were initially the most heavily infected (> 1000 eggs/g). There was no apparent difference in cure rate between younger (< 20 years) and older individuals (> 20 years). No evidence for the existence of a PZQ tolerant strain of S. mansoni was found. Two treatments of PZQ 40 mg/kg, 40 d apart, were sufficient to give an adequate cure rate and high reductions in the intensity of infection. As there was insufficient time for reinfection between treatment and follow-up to result in egg production, the low cure rate observed after one treatment was probably the result of a combination of high infection intensity and the maturation of pre-existing prepatents S. mansoni infections.

Gender-dependent specific immune response during chronic human Schistosomiasis haematobia

The cellular and humoral acquired immune responses to Schistosoma haematobium 28 kD gluthathione S‐Transferase (Sh28GST) antigen were evaluated in a Senegalese population chronically infected with S. haematobium parasite. We show a gender‐dependent immune response in adult individuals presenting similar intensities of infection. Indeed, the specific IgA response and production of TGF‐β and IL‐10 were found significantly higher in females compared to males. In addition, we showed that this profile was combined with a weak production of Th1‐related cytokines (TNFα and IFNγ) and was associated with an absence of proliferation to the antigen. A significantly higher Nuclear Matrix Protein 41/7 secretion, an apoptosis marker, was specifically observed in mononuclear blood cell cultures of females suggesting that a specific cell death process was engaged in a gender‐dependent manner. This specific profile could be associated with the so‐called T helper type‐3 (Th3) immune response specifically promoting the production of IgA and would be developed upon the down‐regulation of the specific Type‐1 response by a probable cell death mechanism. This gender‐dependent immune regulation, which may be under the influence of nonimmunological factors like sexual hormones, may be related to the chronicity of the infection.

Malaria co-infection in children influences antibody response to schistosome antigens and inflammatory markers associated with morbidity

The epidemiological coexistence of schistosomiasis and malaria is frequently observed in developing countries. Co-infection with malaria in children could influence the development of acquired immunity associated with the resistance or the pathology of schistosomiasis. In the present study, performed during May to June 1996 in Senegal, the humoral immune response to Schistosoma haematobium 28 kDa glutathione S-transferase (Sh28GST) vaccinal antigen and to soluble egg antigens (SEA) has been evaluated in individuals infected by S. haematobium. Specific immunoglobulin G3 (IgG3) and IgE responses were significantly higher in co-infected children with Plasmodium falciparum compared with children infected with S. haematobium only. In addition, circulating levels of interferon-gamma (IFN-gamma), interleukin-10 (IL-10), and soluble tumor necrosis factor receptor II (sTNF-RII), 3 parameters associated with schistosomiasis morbidity, were significantly increased in co-infected children. Taken together, this study indicated that malaria co-infection can both influence the acquired specific immune response to schistosome antigens and unbalance the regulation of inflammatory factors closely involved in schistosomiasis pathology.

The epidemiology of a recent focus of mixed Schistosoma haematobium and Schistosoma mansoni infections around the "Lac de Guiers" in the Senegal River Basin Senegal.

Summary A village with mixed Schistosoma mansoni and S. haematobium infections (probably in a early endemic phase) was identified around the Lac de Guiers in the Senegal River Basin. In documenting the epidemiology of both schistosomes, we focused on prevalence and intensity of infection, transmission patterns and the impact of treatment. S. mansoni prevalences (near 100%) and egg counts (overall geometric mean eggs per gram of faeces (epg) of 589 were high in all age groups, with 35% of individuals excreting > 1000 epg, and showing a slow decline in egg output only after the age of 30 years. The overall prevalence (28%) and egg counts (2% > 50 eggs/10 ml) of S. haematobium were low, with mean counts of 6.3 eggs/10 ml. Maximal mean S. mansoni egg counts were found in 5–9 year‐old boys and in 15–19 year‐old girls; S. haematobium maximal counts in 1–4 year‐old boys and in girls aged 5–9. Extremely high Biomphalaria pfeifferi infection ratios were recorded over the whole year. Following a single treatment, re‐infection was rapid with prevalences and mean egg counts of both Schistosoma species reaching pretreatment levels within 7 months.

The effects of irrigated agriculture on the transmission of urinary schistosomiasis in the Middle and Upper Valleys of the Senegal River basin

The importance of the increase in irrigated land on the perimeters of the Middle and Upper Valleys of the Senegal River basin, on the prevalence and intensity of urinary schistosomiasis, was investigated. Surveys were conducted, in May—June 1997, to determine the prevalence and intensity of Schistosoma haematobium infection among 1445 children aged 7–14 years: 1011 in 10 villages near Matam, and 434 in four villages near Bakel. Macrohaematuria was present in seven of the study villages (four near Matam and three near Bakel), whereas microhaematuria was present in all the villages, with prevalences of 10%–73%. A second survey, conducted, in June 1999, on 755 children from nine of the study villages near Matam, demonstrated significant increases in the prevalences of both micro- and macro-haematuria in three of the villages, all of which were adjacent to the Senegal River and practising irrigated agriculture. None of the other study villages re-surveyed was irrigating any of its agricultural land. A longitudinal survey was also carried out, between May 1997 and November 1998, on about 10% of the population (2272 subjects) of Nguidjilone, north of Matam; selective treatment with praziquantel (40 mg/kg) was given in May 1997, and mass treatment in May 1998. The data analysed were those relating to the 125 individuals who provided samples at each survey. Very severe infections (>1000 eggs/10ml urine) were seen in five subjects in May 1997. One year later (i.e. 1 year after the selective treatment), the prevalence of urinary schistosomiasis had increased in every age-group. Although prevalence had decreased slightly by November 1998 (6 months after the mass treatment), the intensity of the infections seen had increased in every age-group. At the end of the dry season (May—June 1997), Bulinus truncatus infected with schistosome cercariae were recovered from the Senegal River. However, immediately after the next rainy season (November 1997), no snails were found at any collection site on the river.

Morbidity induced by Schistosoma haematobium infections, as assessed by ultrasound before and after treatment with praziquantel, in a recently expanded focus (Senegal River basin).

Seven years after the completion of two dams in the Senegal River basin, 203 individuals from four villages around Podor in the middle valley, where Schistosoma haematobium infections were present, were examined in June 1995. In December 1995 a single dose of praziquantel (40 mg/kg) was given to each of these subjects, who were re-examined in April 1996. Clinical and parasitological signs of infection were investigated at both examinations, and ultrasonography was performed to check for lesions of the urinary tract induced by S. haematobium. As uninfected controls, 200 people from four villages where S. haematobium was absent were similarly examined, in November 1995. Prior to treatment, bladder irregularities were observed in 43% of the subjects from Podor but only 6% of the uninfected controls. The severity of the bladder lesions visible by ultrasonography was significantly associated with intensity of infection, despite the generally low levels of infection in the subjects mean = 13.1 eggs/10 ml urine). Four months after treatment, however, the frequency of bladder irregularities among the subjects (11%) was similar to that in the uninfected controls and intensities of infection and other clinical signs of disease had also significantly declined. The prevalence of haematuria, for example, fell from 35% pre-treatment to 10% post-treatment. The results indicate that the onset of S. haematobium morbidity can be relatively rapid even in areas with seasonal and low levels of transmission, and demonstrate that treatment to reduce morbidity in such areas is important and could be relatively simple and very effective.

The effect of different treatment regimens on the epidemiology of seasonally transmitted Schistosoma haematobium infections in four villages in the Senegal River Basin, Senegal

This paper describes the present epidemiological situation of Schistosoma haematobium in 4 villages in the middle valley of the Senegal River Basin, in terms of level and intensity of infection, seasonality of transmission, and intermediate hosts, and the effect of different treatment schedules with praziquantel on the overall infection levels and re-infection rates. The longitudinal study involving 7 surveys was carried out between June 1995 and March 1997 in Diatar, Guia, Donaye and Niandane. The prevalence and intensity of infection remained low throughout the survey (< 55% and < 12 eggs/10 mL urine), and there were no systematic differences in the prevalence or intensity of infection between men and women. Before treatment, infections were highly aggregated in individuals and were concentrated in children (aged < 15 years) with 85% of the potential contamination; no individual aged > 24 years produced > 50 eggs/10 mL urine. Using WHO guidelines mass treatment was given to all Diatar and Guia villagers in December 1995, whereas in Donaye and Niandane only individuals positive for eggs were treated. Six weeks post-treatment cure rates in all villages were > 80%, with marked declines in levels of infection (< 20% and < 4.5 eggs/10 mL). By March 1997 infection levels in Donaye and Niandane had returned to pre-treatment levels, whereas in the 2 mass-treated villages (Diatar and Guia) infection levels were still markedly reduced compared to pre-treatment levels. Rates of conversion were very low between all surveys; however, there was an apparent high level of reversion (> 20%), due to the alternation of individuals apparently positive and negative between surveys. Water and infected snails were present from June to March. Therefore, owing to the high aggregation of infections in children, the low overall infection levels and the transmission period, it is suggested that in this area the best treatment schedule would be selective treatment of school-aged children in March/April, probably on an annual basis.

Observations on the compatibility between Bulinus spp. and Schistosoma haematobium in the Senegal River basin

Snail-infection experiments were carried out with a number of different species and populations of Bulinus and isolates of Schistosoma haematobium. The parasites came from six localities in the Senegal River basin (SRB), in the Lower Valley (Mbodiene), Middle Valley (Podor, Diatar and Nguidjilone), and Upper Valley (Aroundou and Galladé). Isolates of S. haematobium from the Middle and Upper Valleys all showed some compatibility with laboratory-bred B. truncatus from Mali, but none of these isolates was compatible with laboratory-bred B. truncatus originating from Senegal. Schistosoma haematobium from Diatar (Middle Valley) was compatible with B. senegalensis, whereas S. haematobium from Mbodiene (Lower Valley), which is naturally transmitted by B. globosus, was incompatible with B. senegalensis and B. truncatus. These data demonstrate that different isolates of S. haematobium from different regions of the SRB exhibit distinct intermediate-host specificities, which in turn will have an effect on the epidemiology of the disease, including the periods of transmission. It is apparent that, in addition to B. senegalensis and B. globosus, B. truncatus, the most widespread bulinid snail in the SRB, may be playing a role in the epidemiology of urinary schistosomiasis. This conclusion has obvious implications for the future spread of urinary schistosomiasis in the SRB. Chemical and physical measurements from assorted habitats along the SRB, including pH, temperature, salinity, conductivity, and resistivity, are also reported.