Background
Human schistosomiasis is a neglected tropical disease which affects more than 230 million people worldwide [
1] and accounts for an estimated 1.9 million disability-adjusted life years annually [
2]. The disease is mostly prevalent in sub-Sharan Africa (SSA), where up to 90% of the world’s total cases live, leading to an estimate of 280,000 deaths each year [
3]. Human schistosomiasis is caused by five species of flatworm parasites belonging to the
Schistosoma genus. The two most notable species,
Schistosoma haematobium and
Schistosoma mansoni are predominant in SSA and cause urogenital and intestinal schistosomiasis, respectively [
4]. People get infected during occupational, domestic or recreational activities in contact with freshwater containing infested snail intermediate hosts [
5].
Schistosoma infections can be treated by the praziquantel (PZQ), a drug routinely used at the standard oral dose of 40 mg/kg body weight [
6]. In the past 10 years, PZQ has been repeatedly administered in sub-Saharan Africa through National Schistosomiasis Control Programs (NSCP), to children aged between 5 and 14, to prevent them from developing severe, late-stage chronic forms of the disease [
7,
8]. Between 2010 and 2019, the total number of people treated has increased considerably from 33 to 105.4 million and the number of tablets for the 2020 campaigns was estimated at 226 million [
9]. Although globally efficient, this ongoing and repeated mass drug administration (MDA) acts as an important drug pressure which could lead to the development of schistosome strains which are resistant to the PZQ [
10]. Several studies have monitored the efficacy of PZQ in field populations in endemic countries. The majority of these studies indicated a considerable reduction of morbidity and transmission of schistosomiasis, with a high cure rates and satisfactory eggs reduction rates [
11,
12], while some reported treatment failure based on low CR and ERR [
13]. None of them has confirmed the existence of schistosome resistance to the PZQ, but there is always a need to continuously monitor PZQ efficacy in various epidemiological situations.
In Senegal, prior to the Diama dam being constructed in 1986 to prevent the intrusion of seawater into the Senegal river, intestinal schistosomiasis had never been reported in the Senegal river delta [
14], and only a low prevalence of
S. haematobium (average 10.4%) had been found in villages situated in the higher land away from the river, where the transmission sites were rain pools [
15]. The same epidemiological situation was described by Vercruysse et al
. in 1985 [
16], in several villages near the Lampsar river in the lower valley and in the Podor area in the middle valley, where the prevalence of haematuria varied between 0 and 33%. Once the Diama dam was operational, extensive water development took place in the Senegal river basin, resulting in a large increase in the amount of freshwater available for irrigation [
17]. Two years later, Talla et al
. reported for the first time the presence of
S. mansoni in the town of Richard Toll [
14]. More generally, such major changes to the Senegal river basin scale led to the expansion of the population of snails which are schistosomes’ intermediate hosts, which led subsequently to a major outbreak of intestinal schistosomiasis [
14,
18‐
20] and an increase in the prevalence of urinary schistosomiasis [
21]. Over the same period, the Manantali dam was completed upstream in Mali, to control the flow of the Senegal river and to generate electricity. It contributed significantly to the observed increase in the infection intensity of urinary schistosomiasis in the middle valley, where prevalence reached 55% within 7 years [
22] and up to between 95.5 and 100% between 2006 and 2007 [
23,
24]. Since 2009, regular MDA programmes by the Senegalese NSCP have been conducted in several endemic villages along the Senegal river basin [
25], but the disease still constitutes a public health problem in certain localities where a high prevalence of urogenital schistosomiasis has been observed, including in the town of Richard Toll (87%) and around the Lac de Guiers (88%) area [
26]. The efficacy of PZQ against
S. haematobium and
S. mansoni and the patterns of re-infection in this region have been evaluated by previous studies [
23,
27‐
30]. Historically, PZQ resulted in generally low cure rates (18–42.5%) and a moderate reduction of infection intensity, especially for
S. mansoni [
28‐
30]. In more recent studies, a high reduction of infection intensity (between 97–98%) was achieved, with high cure rates (81–95%) after a single dose of PZQ (40 mg/kg) for
S. mansoni and a 100% cure rate after a second dose at a 6 week interval for
S. haematobium [
23,
27]. This variability in response to schistosome parasites to the drug sparked controversy over possible resistance to PZQ, especially for
S. mansoni in Senegal [
13]. The high egg loads before treatment, as well as the rapid re-infection rate, were evoked to explain the poor response of the parasites to PZQ [
4,
20,
23]. However, the possibility of emerging PZQ-resistant schistosome strains remains a global concern [
31‐
33] and the efficacy of treatment in the field needs to be continuously monitored in areas undertaking MDA. In the Senegal river basin, schistosomiasis transmission occurs in three major epidemiological systems, depending on the type of water access: the Senegal river and its tributaries, the Lac de Guiers, and irrigation canals. The dynamics of schistosomiasis transmission can vary from one type to another, mainly due to differences in the snail intermediate hosts’ dynamics [
34,
35], the extent and accessibility of the transmission sites [
36], the nature of the water contact behaviour [
37], and the unequal exposure of the population [
38]. The aim of this study was primarily to evaluate the prevalence of
S. haematobium among these systems and, secondarily, to monitor the efficacy of a single dose of PZQ and the pattern of re-infection in five villages located in these three epidemiological systems in the Senegal river basin.
Discussion
The first objective of this study was to determine the current prevalence of
S. haematobium and the intensity of infection, which are indicators of morbidity in five villages divided into three different epidemiological systems close to the Senegal river. At baseline, the percentage of urinary schistosomiasis and infection intensity in the villages studied were in line with an overall trend of a reduction in prevalence in the studied area. Indeed, 14 years ago, before regular MDA programmes were conducted, very high prevalence, between 89 and 95%, was reported in school-aged children from the Lac de Guiers and the River Doue areas, based on data collected in 2006 and 2007 [
24]. After 5 or 6 years of repeated MDA programmes, prevalence dropped in several villages established in the Senegal river basin. Indeed, while in 2016, a
S. haematobium prevalence of 88% was reported in children and adults from six villages including the village of Mbane [
26], in 2017, a 66.7% overall prevalence was reported in six villages located along the Senegal river and its tributaries and ten other located on the shores of Lac de Guiers, excluding the village of Mbane [
38]. In this study, the prevalence of
S. haematobium in children from the village of Mbane using the Lac de Guiers and children living in Ndiawara and Dioundou using the river were relatively low (between 38 and 46%) compared to previous high prevalence rates [
24]. We expected to find a high prevalence, since the urine examination conducted to calculate the baseline prevalence took place after the highest transmission period of
S. haematobium (around May–July) in the Lac de Guiers area and along the Senegal river [
35]. However, it appears that the decline in prevalence in the Senegal river basin began a few years ago, before our study, as indicate by previous studies [
26,
38]. The low prevalence obtained in our study suggests that changes in the epidemiological situation of urinary schistosomiasis and intestinal schistosomiasis are under way in several villages in the Senegal river basin, due to the MDA programmes conducted by the Senegalese NSCP, which began in 2009 and targets school-aged children with therapeutic coverage of around 90% [
25]. A recent study in sub-Saharan Africa comparing the situation before regular MDA programmes (2000–2010) and after MDA programmes (2011–2019) demonstrated that countries which undertook multiple rounds of preventive chemotherapy with high coverage over a 3-year period showed a considerable decline in the prevalence of schistosomiasis [
44]. Unlike the situation in the villages bordering the Lac de Guiers and the river, our results showed that in the populations we studied, the burden of
S. haematobium is highest in children living in villages bordering the irrigation canal. Indeed, in the villages of Guia and Khodit, the prevalence and intensity of infection remains very high, with prevalence of over 90%. This dramatic situation is similar to that which was reported before regular MDA programmes in 2007–2008 by Webster et al. [
23], with a very high prevalence (95%) of
S. haematobium. Early studies in the Senegal river basin reported that people who practice irrigated agriculture are more infected than others [
45]. The very high prevalence of schistosomiasis and the intensity of infection in children living in the villages using the irrigation canals indicate that there are still significant transmission hotspots in the Senegal river basin, despite repeated MDA programmes. This means that these communities are consistently exposed to
S. haematobium due to the proximity of the primary canal to people’s homes, as well as greater use of the canal by the population as part of their daily recreational or household activities, via the multiple points of contact with the water which exist along the canal. Several studies have established that the proximity of the households and or schools to natural water sources such as lakes, rivers and ponds is directly linked to the prevalence and intensity of the disease in sub-Saharan Africa [
46,
47]. Targeting schistosomiasis at the village level, or by considering the nature and ecology of the transmission sites is an important way of orienting and adapting the strategy of intervention in order to achieve the NSCP objective, which is the long-term reduction of prevalence and morbidity of schistosomiasis.
Our findings suggest that conducting MDA programmes once every 2 years in school-aged children according to the WHO recommendation, in the villages of Mbane, Dioundou and Ndiawara, whose inhabitants use the lake and the river, is necessary [
48]. However, in the villages of Guia and Khodit, whose populations frequent the irrigation canal, we suggest adapting the treatment strategy by administering a double treatment every 6 months in school-aged children and at-risk adults.
The second objective of this study was to assess the efficacy of PZQ treatment and the pattern of re-infection. Four weeks after treatment, the prevalence and intensity of
S. haematobium drastically dropped in all villages. Very high CRs (> 96%) and ERRs (> 98%) were obtained in children from the sites near the Lac de Guiers and the river sites, where baseline prevalence and intensity were low. Even in the villages using the irrigation canal, where baseline prevalence and intensity of infection were very high, heavy intensity infections were almost completely eliminated, with an ERR of 96.9% and a satisfactory CR of 88.7%. This meets the aim of reducing morbidity and thus, confirms the efficacy of a single dose of 40 mg/kg PZQ for the treatment of urinary schistosomiasis. A previous study reported a CR > 80% 6 weeks after treatment in four villages in the Podor area, with marked declines in levels of infection [
22]. Webster et al
. reported similar high ERR rates (97.8%) in children from the village of Guia 6 weeks after the administration of two rounds of 40 mg/kg at 3-week intervals, while a low CR (47.1%) was obtained [
23]. Our satisfactory CR may be associated with the fact that even children for whom a single miracidia was detected in the urine sample after treatment were considered to be uncured. Indeed, if a single egg in the parasitological sample is considered to be a failure of cure, without egg hatching for confirmation, this can lead to low CR but high ERR [
49,
50]. However, several non-exclusive factors including, for instance, the transmission dynamic of
S. haematobium, the baseline prevalence and infection intensity, the age of the targeted population, the PZQ dose, the timing of PZQ efficacy diagnosis, and the rapidity of re-infection could explain the differences in the CR and EER observed between studies within and between countries [
12,
23,
49,
51,
52]. In the case of our study, as there was insufficient time for re-infection between treatment and assessment time to result in egg production [
17,
23], the 13/16 failed cases observed after treatment in the villages near the irrigation canal were probably the result of the maturation of pre-existing juvenile parasites, since PZQ has no effect on them [
53]. Alternatively, this result could also reflect a higher resistance among some parasite genotypes to the treatment. In general, it is difficult to obtain 100% CR and ERR following treatment with PZQ, even in areas with low prevalence and infection intensity. Some parasites that are not completely killed can continue excreting viable eggs even after three doses of PZQ [
40]. To explain this, parameters such as infection intensity, low drug absorption, high levels of catabolism, rapid re-infection, and the lack of acquired immunity have often been advocated [
23,
54]. It is thus very difficult to tease apart the possible resistance to treatment from treatment failure in the field. Drug-induced resistance can only be confirmed by linking changes in resistance allele frequencies to phenotypic indicators of drug tolerance or reduced susceptibility [
55]. It is very important to monitor PZQ resistance given the drug pressure in endemic areas in sub-Saharan Africa, in particular in the Senegal river basin [
10,
49]. In this regard, hybridisation between Schistosoma species have been repeatedly documented in this geographical area [
26,
56‐
58] and are thought to potentially promote the emergence of hybrid-resistant strains of schistosomes [
59‐
62]. Thus, the genomic comparison of parasite communities before and after several rounds of treatment using the next generation sequencing approach is indispensable and will enable the detection of possible resistance markers of Schistosome to PZQ by scanning whole genomes [
55,
63].
One major obstacle in the fight against schistosomiasis in SSA is the fact that a patient who has just been cured of infection can be almost instantaneously reinfected after contact with infested water. In our study, re-infection occurred 7 months after treatment, and reflected the variation in the baseline prevalence in the different epidemiological systems, with the highest rate (42.4%) in the villages near the irrigation canal and the lowest rates in those close to the Lac de Guiers (18.4%) and the river (14.8%). Nevertheless, the infection levels were still markedly reduced compared to pre-treatment in all villages. Similar results were reported by Shaw et al
. in the middle valley, in the villages of Diatar and Guia, where MDA was administered, while in Donaye and Niandane where MDA was not administered, prevalence levels had returned to pre-treatment levels after 6 months [
30]. Webster et al. [
23] also reported, in a cohort of children in 2009 and 2010, that 6 months after treatment, the prevalence after re-infection approached the baseline in the village of Guia whose population frequented the irrigation canal. Schistosomiasis transmission and re-infection are known to feature focal differentiation in endemic areas, as transmission is regulated by the distribution and dynamics of the snail intermediate hosts in freshwater, which depends on the environmental and ecological conditions. Therefore, the transmission of schistosomiasis could vary from one area to another and even within the same endemic villages from 1 year to the next [
52,
64]. In the river and the Lac de Guiers,
S. haematobium transmission is perennial, as water is present all year long, while the canals may dry depending on agricultural activities in the farms [
35]. The highest rate of re-infection observed in children from Guia and Khodit who used the canal could be due to a high exposure of the population due to their proximity and frequency of contact with the canal water as well as its accessibility. However, these locations also present all the environmental conditions that are favourable for the snail host populations and/or for the parasites to be transmitted, thus constituting important transmission hotspots. In our study, re-infection was checked at the end of the high transmission season in March–April, 7 months after treatment. At this time point, any
S. haematobium parasites that had reinfected the children should be adults and should have started to excrete eggs in the urine. However, by comparing our results to those previously reported in the Senegal river basin, it would appear that there is a new pattern of re-infection, which is not rapid, with low to moderate rates, contrary to the previous year, where re-infection was rapid and could sometimes reach baseline prevalence [
22,
23]. Overall, our results show that regular annual MDA programmes have had an impact on reducing the prevalence and intensity of infection, and have limited the re-infection rates of
S. haematobium in the Senegal river basin. So while waiting for the development and roll-out of a future anti-schistosome vaccine, which will contribute greatly to the ultimate elimination of the disease [
65], a multisectoral approach will be required. This will include epidemiological surveillance, effective risk mapping, correctly timing control measures on the snail intermediate hosts, adapting the treatment regimen at the village level, improving access to clean water, sanitation and hygiene, and public health education to induce behavioural change and prevent infection and re-infection [
36,
66,
67].
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