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Efficacy of praziquantel and reinfection patterns in single and mixed infection foci for intestinal and urogenital schistosomiasis in Cameroon
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Efficacy of praziquantel and reinfection patterns in single and mixed infection foci for intestinal and urogenital schistosomiasis in Cameroon Louis-Albert Tchuem Tchuenté a,b,∗ , Sabine C. Momo a , J. Russell Stothard c , David Rollinson d a
Centre for Schistosomiasis and Parasitology, P.O. Box 7244 Yaoundé, Cameroon Laboratory of Parasitology and Ecology, Faculty of Sciences, University of Yaoundé I, P.O. Box 812 Yaoundé, Cameroon c Parasitology Department, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK d Wolfson Wellcome Biomedical Laboratories, The Natural History Museum, London SW7 5BD, UK b
a r t i c l e
i n f o
Article history: Received 18 January 2013 Received in revised form 11 June 2013 Accepted 12 June 2013 Available online xxx Keywords: Schistosomiasis Schistosoma haematobium Schistosoma mansoni Praziquantel Efficacy Mixed infection Re-infection pattern Transmission Snail Cameroon
a b s t r a c t The regular administration of the anthelminthic drug praziquantel (PZQ) to school-aged children (and other high-risk groups) is the cornerstone of schistosomiasis control. Whilst the performance of PZQ against single schistosome species infections is well-known, performance against mixed species infections is less so, as are patterns of re-infection following treatment. To address this, a study using a double treatment with PZQ, administered at 40 mg/kg spaced by 3 weeks, took place in two mixed intestinalurogenital schistosomiasis foci in northern Cameroon (Bessoum and Ouro-Doukoudje) and in one single intestinal schistosomiasis infection focus (Makenene). A total of just under 1000 children were examined and the Schistosoma-infected children were re-examined at several parasitological follow-ups over a 1-year period posttreatment. Overall cure rates against Schistosoma spp. in the three settings were good, 83.3% (95% confidence interval (CI) = 77.9–87.7%) in Bessoum, 89.0% (95% CI = 79.1–94.6%) in Ouro Doukoudje, and 95.3% (95% CI = 89.5–98.0%) in Makenene. Interestingly, no case of mixed schistosome infection was found after treatment. Cure rates for S. mansoni varied from 99.5% to 100%, while that for S. haematobium were considerably lower, varying from 82.7% to 88.0%. Across transmission settings, patterns of re-infection for each schistosome species were different such that generalizations across foci were difficult. For example, at the 6-month follow-up, re-infection rates were higher for S. haematobium than for S. mansoni with re-infection rates for S. haematobium varying from 9.5% to 66.7%, while for S. mansoni, lower rates were observed, ranging between nil and 24.5%. At the 12-month follow-up, re-infection rates varied from 9.1% to 66.7% for S. haematobium and from nil to 27.6% for S. mansoni. Alongside these parasitological studies, concurrent malacological surveys took place to monitor the presence of intermediate host snails of schistosomiasis. In the two northern settings, three species of Bulinus (intermediate host snail of S. haematobium) were collected; i.e. Bulinus truncatus, B. globosus and B. senegalensis, however, Biomphalaria pfeifferi (intermediate host snail of S. mansoni) was much rarer despite repeated and intensive searching and was suggestive of limited local transmission potential of S. mansoni during this time. While this study highlights that performance of PZQ was satisfactory in this region, with somewhat greater impact upon intestinal than urogenital schistosomiasis, the dynamics of local transmission are shown, however, to be complex. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Schistosomiasis remains of significant public health importance worldwide, with an estimated 207 million people infected; over 90% of all schistosomiasis cases are found in sub-Saharan
∗ Corresponding author at: Centre for Schistosomiasis and Parasitology, P.O. Box 7244, Yaoundé, Cameroon. Tel.: +237 7770 7436; fax: +237 2221 5077. E-mail address: [email protected] (L.-A. Tchuem Tchuenté).
Africa (Steinmann et al., 2006; Utzinger et al., 2009). Worldwide the disease is caused by six species of blood flukes: Schistosoma haematobium, Schistosoma mansoni, Schistosoma japonicum, Schistosoma intercalatum, Schistosoma guineensis and Schistosoma mekongi. In sub-Saharan Africa, the two predominant species are S. haematobium (causing urogenital schistosomiasis) and S. mansoni (causing intestinal schistosomiasis). The disease mainly affects the poorest of the poor and is a considerable local health burden in communities where access to clean water, improved sanitation and water-hygiene are elusive (WHO, 2002).
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Please cite this article in press as: Tchuem Tchuenté, L.-A., et al., Efficacy of praziquantel and reinfection patterns in single and mixed infection foci for intestinal and urogenital schistosomiasis in Cameroon. Acta Trop. (2013), http://dx.doi.org/10.1016/j.actatropica.2013.06.007
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There have been many attempts to control schistosomiasis in sub-Saharan Africa within the past 10 years, and significant progress has been made in sustaining continued interventions against schistosomiasis with the promotion of better access to de-worming medications. With the increased resources from international donors and the development of preventive chemotherapy strategy, large-scale administration of praziquantel (PZQ) has been fostered and amplified to national levels in several countries (WHO, 2006, 2011). Generic PZQ is currently the drug of choice for the treatment of schistosomiasis and is the only commercially available antischistosomal medicine. It is highly efficacious against all six schistosome species that parasitize humans. However, PZQ treatment may not be fully curative (Geary et al., 2010). Several clinical trials have assessed PZQ efficacy against different Schistosoma species causing disease in humans (Utzinger et al., 2000; Tchuem Tchuenté et al., 2001a, 2004; Raso et al., 2004; Midzi et al., 2008; Barakat and Morshedy, 2011; Olliaro et al., 2011; Lovis et al., 2012). The efficacy of PZQ is most often measured in terms of percentage reduction in the number of patients who cease egg excretion (commonly used term: cure rate), and the reduction in the mean number (whether arithmetic or geometric) of eggs excreted in those who still continue to excrete eggs (i.e. those with active infections remaining) (commonly used term: egg reduction rate). Despite few reports of treatment failures (Stelma et al., 1995; Wang et al., 2012), the majority of studies showed a good efficacy of PZQ, with particularly high egg reduction rates, especially when levels of local transmission are considered low-to-moderate due to seasonality of environmental transmission when opportunities for re-infection are generally much lower. In terms of monitoring control at national levels, regular observations on the general efficacy of treatment are considered good public health practice. Several studies have been conducted on PZQ efficacy against S. mansoni and S. haematobium in single infection situations. However, little is known about the efficacy of this drug in mixed infections of these two schistosome species in humans. In Africa, the high burden of the disease is due to S. haematobium and S. mansoni. These two species are widely distributed and evidence has accumulated on their population dynamics epidemiology and increasing co-endemicity (Garba et al., 2010, 2013; Webster et al., 2013). Although PZQ is effective at clearing worms, re-infection will occur after treatment. The rate and intensity of re-infection post-PZQ chemotherapy varies between schistosome species, and also differs according to transmission dynamics and endemicity level. Interestingly, the effectiveness of PZQ is sometimes lower for S. mansoni than for S. haematobium (King et al., 2011). The increase of large-scale interventions and repeated treatment with PZQ in endemic countries will impact on the transmission and epidemiology of schistosomiasis. Studies also showed the influence of transmission season on treatment efficacy. In areas with a seasonal transmission pattern, the effect of PZQ can be enhanced if treatment takes place during low transmission season (Augusto et al., 2009). To shed new light on these aspects of treatment with PZQ in mixed schistosome species infections, under the auspices of the CONTRAST project (a multidisciplinary alliance to optimize schistosomiasis control and transmission surveillance in subSaharan Africa), a multi-country study was conducted to assess the dynamics of transmission, the efficacy of PZQ treatment and the re-infection patterns in single and mixed infection foci of S. haematobium and S. mansoni. The study was conducted following a standard protocol, including parasitological baseline survey, double treatment 3 weeks apart, and follow-up surveys at several time intervals up to 12 months after treatment. The two-treatment regimen at a 3-week interval has been demonstrated as the most appropriate protocol for the assessment of PZQ efficacy against schistosomes (Renganathan and Cioli, 1998; Tchuem Tchuenté
et al., 2001a, 2004). As PZQ is not effective against immature schistosomes, these parasites can mature and produce eggs a few weeks after treatment (Botros et al., 2005). A double treatment within a short interval will eliminate pre-existing immature parasites and the few residual schistosomes surviving a single drug administration, even with a 99% efficacy (Renganathan and Cioli, 1998). The research conducted in Niger and Senegal are published elsewhere in this special issue of Acta Tropica (Garba et al., 2013; Webster et al., 2013). In this paper, we present the results of the study conducted in Cameroon. The study provides an important insight into the understanding of PZQ efficacy and the dynamics of human reinfections after treatment in mixed infection settings of S. mansoni and S. haematobium. 2. Material and methods 2.1. Study sites Based on previous parasitological data (Tchuem Tchuenté et al., 2001b; Cunin et al., 2003), three epidemiological settings were selected for the study: (i) two settings in the Lagdo area, North region of Cameroon where prevalence of S. mansoni–S. haematobium co-infections exceeded 50%, i.e. the villages of Bessoum and Ouro Doukoudje; and (ii) one setting in the Centre region where single S. mansoni transmission occurred, i.e. the town of Makenene. Bessoum (geographical coordinates 9.13269◦ N latitude, 13.71405◦ E longitude) and Ouro Doukoudje (9.10014◦ N, 13.71956◦ E) are located at approximately 20 km and 15 km from the Lagdo hydroelectric dam, respectively, hence some 80 km from Garoua, the capital city of the North region of Cameroon. The climate is tropical-Sudanese, marked by two unequal seasons: a long dry season, from November to May, and a short rainy season, from June to October. Makenene (4.89929◦ N, 10.78432◦ E) is located in the wet equatorial zone, at approximately 200 km from Yaoundé, the capital city of Cameroon (Fig. 1). 2.2. Ethical consideration The study was approved by the National Ethics Committee of Cameroon (reference no. 072/CNE/DNM08) and was a public health intervention conducted by the Ministry of Health and the Ministry of Education. Stool and urine samples were collected from children in schools with the approval of the administrative authorities, school inspectors, directors and teachers. The objectives of the study were explained to the schoolchildren and to their parents or guardians from whom written informed consent was obtained. Children willing to participate were registered. Each child was assigned a unique identification number and results were entered in a database and kept confidential. All children who participated in the study were treated with PZQ at a dose of 40 mg/kg. Other children were treated during the mass drug administration campaign implemented by the National Programme for the Control of Schistosomiasis and Intestinal Helminthiasis (NPCSIH). 2.3. Study design and data collection The study was conducted in Bessoum and Ouro Doukoudje between October 2007 and October 2008, and in Makenene from October 2009 to September 2010. At baseline parasitological surveys, in each of the three settings, stool and urine samples were collected from schoolchildren over two consecutive days. Details on number of children sampled per setting are provided in Fig. 2. The samples were collected between 11:00 and 14:00 h, in 60 ml plastic screw-cap vials, transferred to the local laboratory and processed the same day. In the laboratory, two Kato-Katz thick smears per stool sample, using 41.7 mg templates, were prepared
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Bessoum Ouro Doukoudje
N
Makenene
3
and examined under a microscope for S. mansoni by experienced laboratory technicians. Urine samples were subjected to a filtration method for detection of S. haematobium eggs. Each urine sample was agitated to ensure adequate dispersal of eggs, 10 ml of urine were filtered through Nucleopore® filter, and filters were examined under a microscope for the presence of schistosome eggs. Schistosome infections were recorded; the number of eggs was counted and intensity of infection was calculated and expressed as eggs per gram of faeces (EPG) for S. mansoni or eggs per 10 ml of urine (eggs/10 ml) for S. haematobium. Then all children were treated with PZQ 40 mg/kg. Children were re-treated at 3 weeks after the initial treatment, without additional specimen examination. Six weeks after the initial treatment, parasitological surveys were repeated in order to assess PZQ efficacy. Similarly, stool and urine samples were collected from children over two consecutive days, and duplicate Kato-Katz thick smears and one urine filtration were performed per stool and urine samples, respectively. In order to investigate the re-infection patterns posttreatment in the different settings, parasitological surveys with the collection of two consecutive day stool and urine samples and duplicate KatoKatz and urine filtration were conducted on the children cohorts at 6 and 12 months after the initial treatment. At the end of the study, all positive children received further treatment. 2.4. Malacological surveys
0 30 60
120
180
240 Kilometers
Fig. 1. Map showing the location of the three study villages in Cameroon where the study on efficacy of praziquantel in S. mansoni single (Makenene) and S. mansoni–S. haematobium mixed infections (Bessoum and Ouro Doukoudje) foci were conducted between 2007 and 2010.
Malacological surveys were conducted in main water sites in the study villages/towns. In the Lagdo area, selected sites in irrigation canals, rivers and streams were prospected. In Makenene, snail collection was made in various sites of the Mock River, known to be important water-contact points. Snail sampling was carried out at baseline, 6 weeks, 6 months, 9 months and 12 months followup surveys. Snails were collected with scoops and transported to the Centre for Schistosomiasis and Parasitology (CSP) laboratory in Yaoundé for identification and cercariae shedding tests. In the
Bessoum
Ouro Doukoudje
Makenene
TOTAL
M = 171 F = 95 Total = 266
M = 100 F = 50 Total = 150
M = 267 F = 294 Total = 561
M = 538 F = 439 Total = 977
Children infected
Sh+ = 255 Sm+ = 231 Sh+Sm+ = 224 Total + =262
Sh+ = 113 Sm+ = 90 Sh+Sm+ = 66 Total + =137
Sh+ = 0 Sm+ = 275 Sh+Sm+ = 0 Total + =275
Sh+ = 368 Sm+ = 596 Sh+Sm+ = 290 Total + =674
Children treated
n = 266
n = 150
n = 561
n = 977
Week 6
Follow-up
n = 256
n = 68
n = 127
n = 451
Month 6
Follow-up
n = 250
n = 76
n = 121
n = 447
Month 12
Follow-up
n = 250
n = 75
n = 107
n = 432
Week 0
Children registered and examined
Fig. 2. Number of children involved in the different phases of the praziquantel efficacy study in Cameroon. Flow chart showing the number of children included at the baseline survey (week 0) and at follow-up surveys at 6 weeks, 6 months and 12 months after treatment with praziquantel. The numbers of children infected with S. mansoni (Sm) and/or S. haematobium (Sh) at the baseline are also indicated.
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laboratory, the snails were exposed individually to artificial light between 11:00 and 14:00 h to stimulate the shedding of cercariae. This was repeated up to 6 weeks after collection or until snails died.
species infections in Ouro Doukoudje; and 49.0% for S. mansoni in Makenene. The overall Schistosoma prevalences (infection by any of the two schistosome species) were 98.5% in Bessoum and 91.3% in Ouro Doukoudje (Table 1). In all three settings, there was no significant difference of schistosome infections between boys and girls. With reference to age, children were divided into two groups: (i) <10 years and (ii) ≥10 years. The comparison of these two age groups showed a significant difference for S. haematobium infections in Bessoum (34.6% for children <10 years vs. 61.3% for children ≥10 years, P = 0.009), whereas the difference was not significant for other infections and settings (P > 0.25). For the follow-up surveys, only those children who were positive at baseline were selected and included in the cohorts. At the end of the 1-year follow-up, stratified by setting, only children who participated to all phases of the study and provided all required stool and urine samples were selected for further analysis; i.e. 222 children from Bessoum, 64 from Ouro Doukoudje and 107 from Makenene; giving a total of 393 children.
2.5. Statistical analysis The data were analyzed by the epidemiological unit of CSP using appropriate statistical tests and methods. Data were entered in a Microsoft Excel spreadsheet, checked and validated. The data were subsequently exported into SPSS (IBM, version 19) for statistical analysis. Only children who participated in all parasitological surveys, with complete data records, were included in the final analysis (per-protocol analysis). Analyses were performed for the three study settings separately to determine PZQ efficacy and re-infection rates/patterns posttreatment resulting from different S. mansoni–S. haematobium co-infection and single infection levels. To obtain a standardized measure of infection, the geometric mean infection intensities of S. mansoni and S. haematobium, expressed as EPG or eggs/10 ml, were estimated for the three study cohorts. Egg counts of the two consecutive days were averaged (arithmetic mean) at the individual child level. The parasitological cure rates were calculated as the proportion of children excreting eggs at the first survey before treatment and who were not excreting eggs in their stool and/or urine 6 weeks after the initial treatment. Ninety-five percent confidence intervals (CIs) were calculated for proportions. Geometric mean (GM) values of all individuals were used to assess mean egg counts of each group. The GM was calculated as the antilogarithm of the mean of all log transformed egg counts + 1. The intensity reduction rate was calculated as [1 − (GM egg counts after treatment/GM egg counts before treatment)] × 100. To test for changes in cure rate with time, Pearson’s 2 tests on proportions were carried out. In all cases, a P-value < 0.05 was taken to indicate statistical significance.
3.2. Cure rates Three weeks after the second treatment (i.e. 6 weeks after the initial treatment), the overall Schistosoma spp. cure rates in the three settings were 83.3% (95% CI = 77.9–87.7%) in Bessoum, 89.0% (95% CI = 79.1–94.6%) in Ouro Doukoudje, and 95.3% (95% CI = 89.5–98%) in Makenene. No case of mixed infections was found after the treatment. Detailed analysis of Bessoum and Ouro Doukoudje showed that cure rates for S. mansoni varied from 99.5% to 100%. Cure rates for S. haematobium were lower, varying from 82.7% to 88.0% (Table 2). 3.3. Intensity reduction rates Six weeks after the first treatment (3 weeks after the second treatment), the GM intensity of infection had decreased by more than 98% for both schistosome species in all three settings (Table 2). The egg counts remained very low in all settings at 6 and 12 months posttreatment. There were no significant differences in infection intensities between the three settings.
3. Results 3.1. Baseline prevalence and cohort selection The current study was planned to include at least 100 schistosome-infected children in the cohort for each of the three settings. To ensure this all children enrolled in the single school existing in each of the villages of Bessoum and Ouro Doukoudje were invited to participate in the study. At the baseline survey, i.e. week 0, stool and urine samples were collected from a total of 266 children in Bessoum, 150 in Ouro Doukoudje and 561 in Makenene, giving an overall total of 977 pupils (538 boys and 439 girls) for the three settings. The overall male:female ratio was 1.2:1. The baseline infection prevalences were 95.9% for S. haematobium, 86.8% for S. mansoni and 84.2% for mixed species infections in Bessoum; 75.3% for S. haematobium, 60.0% for S. mansoni and 44% for mixed
3.4. Re-infection patterns The patterns of re-infection for each schistosome species in the different settings are summarized in Table 3. The re-infection rates were higher for S. haematobium than for S. mansoni. At 6 months posttreatment, reinfection rates for S. haematobium varied from 40.0% to 66.7% in Bessoum, and from 9.5% to 20.0% in Ouro Doukoudje. For S. mansoni, no re-infection was observed in Ouro Doukoudje, and it was only 2.0% in Bessoum, and 24.5% in Makenene. At 12 months posttreatment, re-infection rates varied from
Table 1 Baseline infection prevalence of schistosomiasis in Bessoum, Ouro Doukoudje and Makenene, Cameroon.
*
Overall S. haematobium
Single S. haematobium
Overall S. mansoni
Single S. mansoni
No. positive
%
No. positive
%
Sample
No. of samples
No. positive
%
No. positive
%
No. positive
%
Bessoum
Urine Stool
266 266
255 7*
95.9 –
28 –
10.5 –
11* 231
– 86.8
– 8
– 3.0
224
84.2
262
98.5
Ouro Doukoudje
Urine Stool
150 150
113 3*
75.3 –
47 –
31.3 –
4* 90
– 60.0
– 24
– 16.0
66
44.0
137
91.3
Makenene
Urine Stool
561 561
– 49.0
– 275
– 49.0
0
0
275
49.0
0 –
0 –
0 –
– 275
%
Overall Schistosoma spp.
Village
0 –
No. positive
Mixed S. haematobium and S. mansoni
Ectopic elimination of schistosome eggs, i.e. S. haematobium eggs in stool and S. mansoni eggs in urine.
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Village
No. of subjects
GM* for S. haematobium (eggs/10 ml)
GM for S. mansoni (EPG)
Any Schistosoma spp. after 2 treatments
S. mansoni after 2 treatments
S. haematobium after 2 treatments
Before treatment
Cure rate (%)
GM (eggs/ 10 ml)
Intensity reduction rate (%)
Cure rate (%)
GM (EPG)
Intensity reduction rate (%)
Cure rate (%)
Single S. haematobium Single S. mansoni Mixed infections All infection types
25 6 191 222
178.6 – 118.6 109.2
– 73.0 86.7 52.2
88.0 – 82.7 83.8
1.2 – 1.2 1.2
99.4 – 99.0 99.0
– 100 99.5 99.5
– 1.0 1.0 1.0
– 98.6 98.8 98.1
– – – 83.3
Ouro Doukoudje
Single S. haematobium Single S. mansoni Mixed infections All infection types
42 22 0 64
13.3 – – 5.5
– 88.2 – 4.7
85.7 – – 85.7
1.1 – – 1.1
91.7 – – 80.0
– 100 – 100
– 1.0 – 1.0
– 98.9 – 78.7
– – – 89.0
Makenene
Single S. mansoni
1.2
99.5
95.3
107
–
229.7
–
–
–
95.3
GM, geometric egg count per 10 ml of urine for S. haematobium or per gram of faeces for S. mansoni (EPG).
Table 3 Posttreatment re-infection rates and intensity reduction rates in schoolchildren in mixed and single infections with S. haematobium and S. mansoni at 6 and 12 months in Bessoum, Ouro Doukoudje and Makenene, Cameroon. Village
Infection type before treatment
6 months after treatment
S. haematobium
12 months after treatment
S. haematobium or S. mansoni
S. haematobium
Intensity reduction rate (%)
Re-infection rate (%)
Re-infection rate (%)
Intensity reduction rate (%)
Re-infection rate (%)
Intensity reduction rate (%)
Re-infection rate (%)
S. mansoni
Re-infection rate (%)
Intensity reduction rate (%)
Re-infection rate (%)
S. mansoni
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Bessoum
S. haematobium or S. mansoni
Bessoum
Single S. haematobium Single S. mansoni Mixed infections All infection types
63.6 66.7 40.5 43.3
97.6 – 98.0 97.9
– 0 2.1 2.0
– 98.6 98.8 98.0
– – – 45.4
40.0 66.7 32.7 33.6
97.7 – 97.4 97.4
16.0 0 18.7 18.1
– 98.6 98.0 96.7
– – – 30.6
Ouro Doukoudje
Single S. haematobium Single S. mansoni Mixed infections All infection types
20.0 9.5 – 20.0
89.6 – –
0 0 – 0
98.6 98.9 – 78.5
– – – 17.5
16.2 9.1 – 16.2
90.9 – – 78.9
16.7 4.5 – 4.5
– 98.8 – 68.7
– – – 19.2
Makenene
Single S. mansoni
–
–
24.5
98.6
24.5
–
–
27.6
99.0
27.6
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Infection type before treatment
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Table 2 Cure rates, geometric mean egg counts and intensity reduction rates in schoolchildren in mixed and single infections with S. haematobium and S. mansoni after 2 treatments with praziquantel at 3-week interval in Bessoum, Ouro Doukoudje and Makenene, Cameroon. Parasitological examinations were conducted 3 weeks after the second treatment.
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Total
Total
Fig. 3. Posttreatment evolution of schistosome infection prevalence in the village of Bessoum, Cameroon at 6 weeks, 6 months and 12 months. (A) S. mansoni (Sm) and (B) S. haematobium (Sh) prevalence in the different groups of children infected at baseline with either single or both schistosome species.
32.7% to 66.7% for S. haematobium in Bessoum, and from 9.1% to 16.2% in Ouro Doukoudje. Re-infection rates for S. mansoni were 4.5–16.7% in Ouro Doukoudje, 0–18.7% in Bessoum, and 27.6% in Makenene. The dynamics of infection prevalence in the three settings are illustrated in Figs. 3–5. Overall, re-infections were higher for S. haematobium than for S. mansoni. Moreover, more rapid reinfection with S. haematobium was observed in Bessoum compared to Ouro Doukoudje.
3.5. Results from the malacological surveys A total of seven species of snails were collected in the localities of Bessoum and Ouro Doukoudje, i.e. B. truncatus, B. globosus, B. senegalensis, Biomphalaria pfeifferi, Afrogyrus coretus, Melanoides tuberculata and Physa acuta. B. globosus was the most abundant species, whereas Biomphalaria pfeifferi was very rare; indeed it was found only on one occasion. In Makenene, five species of snails were collected: Biomphalaria pfeifferi, A. coretus, M. tuberculata, P. acuta and B. forskalii. Here, Biomphalaria pfeifferi was the most abundant species.
The cercariae shedding tests revealed natural infections only in B. globosus (18.4%) in the Lagdo area, and only in Biomphalaria pfeifferi (68.2%) collected in Makenene. 4. Discussion The results of the present study show that a double treatment with PZQ (two doses of 40 mg/kg spaced by 3 weeks) is highly efficacious with cure rates varying between 82% and 100% and egg reduction rates above 98% in all settings. Previous studies demonstrated significant increases of cure rates and intensity reduction rates after a second dose of PZQ in settings where low efficacy was observed after a single treatment with PZQ (Picquet et al., 1998; Barakat and Morshedy, 2011). Low PZQ cure rates were mainly attributed to less sensitivity of the immature schistosome worms to PZQ, that survive the treatment, continue their development and then start oviposition. It has been demonstrated and confirmed that a double treatment regimen at 3-week interval was the most appropriate protocol for the assessment of PZQ efficacy against schistosomes (Renganathan and Cioli, 1998; Tchuem Tchuenté et al., 2001a, 2004). However, few investigations using this protocol have been conducted thus far which, if undertaken within
Please cite this article in press as: Tchuem Tchuenté, L.-A., et al., Efficacy of praziquantel and reinfection patterns in single and mixed infection foci for intestinal and urogenital schistosomiasis in Cameroon. Acta Trop. (2013), http://dx.doi.org/10.1016/j.actatropica.2013.06.007
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Fig. 4. Posttreatment evolution of schistosome infection prevalence in the village of Ouro Doukoudje, Cameroon at 6 weeks, 6 months and 12 months. (A) S. mansoni (Sm) and (B) S. haematobium (Sh) prevalence in the different groups of children infected at baseline with either single or both schistosome species.
national control programmes, of course, increases the demand for additional stocks of PZQ. Interestingly, using slightly longer intervals between the two treatments, e.g. 4–5 weeks, previous studies already reported high cure rates against S. mansoni (Utzinger et al., 2000) and S. haematobium (N’Goran et al., 2003). Although our study showed a high efficacy of PZQ against both S. mansoni and S. haematobium, cure rates were higher for S. mansoni in comparison to S. haematobium, suggesting a higher efficacy of PZQ against S. mansoni. The cure rates for S. haematobium were within the range of PZQ cure rates (83–89%) reported in previous studies (Tchuem Tchuenté et al., 2004). Higher cure rates for S. haematobium were also reported in younger children, 1–5 years old (Mutapi et al., 2011) and children attending primary school (5–17 years) in Zimbabwe (Midzi et al., 2008). Interestingly, different results were obtained in different S. haematobium settings in Niger, with variation of cure rates 6-week posttreatment from moderate (49.2–58.9%) in single transmission foci to high (96.0–98.4%) in mixed infection foci (Garba et al., 2013). In contrast to our results, in Niger the efficacy of PZQ was much higher against S. haematobium than S. mansoni, with the cure rates against the later species ranging from 51.7% to 60.2%. The low cure and egg reduction rates observed against S. mansoni in the two mixed infection foci
in Niger raised concern about a potential development of worm tolerance to PZQ in these areas where repeated mass treatments with PZQ have been conducted over the past years (Garba et al., 2013). Follow-up investigations on this issue are recommended in
Fig. 5. Posttreatment evolution of infection prevalence of S. mansoni in Makenene, Cameroon at 6 weeks, 6 months and 12 months.
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these areas. Similar low cure rates were obtained by Sacko and colleagues in a study conducted in two villages in Mali. In these villages cure rates of 46.0% and 56.8% were obtained 3 months after a double treatment given 2 weeks apart (Sacko et al., 2009). It is known that the efficacy of PZQ treatment could be influenced by several factors, including the transmission season. Augusto and colleagues observed significant difference in cure rates between cohorts of S. haematobium-infected schoolchildren treated in the high transmission season (69.7%) compared to those treated in the low transmission season (98.2%) in southern Mozambique. Treatment administered 2 months after the end of the high transmission season provided the highest observed cure rates. Hence, the authors concluded that in areas with a seasonal transmission pattern, the effect of PZQ could be enhanced if treatment takes place during the low transmission season (Augusto et al., 2009). In the villages of Bessoum and Makenene, the egg reduction rates posttreatment were very high (>98%) for both S. mansoni and S. haematobium, either in single or mixed infections; contrary to Ouro Doukoudje where egg reduction rates varied from 78.7% to 98.9%. The low egg reduction rate in the later focus was probably due to low level of infection intensities before treatment. Indeed, the pretreatment GM egg counts ranged between 109.2 and 178.6 eggs/10 ml for S. haematobium and between 73.0 and 229.7 EPG for S. mansoni in Bessoum and Makenene, whereas they were only 5.5–13.3 eggs/10 ml and 4.7–88.2 EPG in Ouro Doukoudje. Our results on re-infection patterns posttreatment showed different dynamics of re-infection prevalence in the different study settings, with significant difference between the two schistosome species. Interestingly, the re-infection rates were higher for S. haematobium at any of the follow-up time points posttreatment and in all study settings. In the areas of Bessoum and Ouro Doukoudje, the re-infections of children with S. mansoni were very low, and up to only 2% after one year post-treatment. One of the factors that might explain this low re-infection rate is the local malacological fauna encountered in these settings. Indeed, the snail intermediate hosts of S. haematobium (three different Bulinus species) were abundant, while the snail intermediate host for S. mansoni (i.e. Biomphalaria pfeifferi) was very rare and was found only at one occasion in one survey site in Bessoum, suggestive that opportunities for environmental transmission were low during this period. The re-infection patterns of schistosomiasis after anthelminthic chemotherapy vary between schistosome species and are governed by multiple factors such as local ecology and epidemiology, human exposure to water, intensity of transmission within a given community, geographical, environmental and socioeconomic factors (Kahama et al., 1999; Ernould et al., 2004; Cundill et al., 2011). In the present study, the re-infection with S. haematobium in the two northern Cameroon settings was higher than that with S. mansoni, similarly to observations in settings along the Niger River (Garba et al., 2013); and contrary to the general trend reporting more rapid re-infection with S. mansoni than S. haematobium (Daffalla and Fenwick, 1982; Ernould et al., 2004). Detailed analysis taking into account the pretreatment features/characteristics revealed significant differences of re-infection patterns between pretreatment intensity classes, with higher re-infection rates among children with heavy intensity of S. mansoni (≥400 EPG) before treatment (P < 0.05). No significant difference was observed between pretreatment intensity classes for S. haematobium. Also, no significant difference was observed between sex and age groups for both schistosome species. In conclusion, the present study revealed that PZQ is efficacious in the management of dual species schistosome infections. In the northern Cameroon setting, the drug was particularly effective against S. mansoni, lower efficacy was observed against S. haematobium. Re-infection patterns were significantly higher for S. haematobium, which may be explained in part by higher levels
of local transmission as evidenced by snail surveys and observed cercarial shedding. Our study showed that transmission dynamics and re-infection patterns posttreatment are complex and generalizations could not be made between foci in light of local changes in the malacological fauna. Acknowledgements We would like to thank the technicians, school headmasters, teachers and all people in the health districts of Lagdo and Makenene who contributed in any way for their assistance and help with the collection of information and data necessary for this study. We are grateful to Laurentine Sumo for her contribution in field surveys, and to Cesaire Kuete Fouodo and Jules Brice Tchatchueng Mbougua for their contribution in statistical analysis of data. References Augusto, G., Magnussen, P., Kristensen, T.K., Appleton, C.C., Vennervald, B.J., 2009. 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Efficacy of praziquantel and reinfection patterns in single and mixed infection foci for intestinal and urogenital schistosomiasis in Cameroon Louis-Albert Tchuem Tchuenté a,b,∗ , Sabine C. Momo a , J. Russell Stothard c , David Rollinson d a
Centre for Schistosomiasis and Parasitology, P.O. Box 7244 Yaoundé, Cameroon Laboratory of Parasitology and Ecology, Faculty of Sciences, University of Yaoundé I, P.O. Box 812 Yaoundé, Cameroon c Parasitology Department, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK d Wolfson Wellcome Biomedical Laboratories, The Natural History Museum, London SW7 5BD, UK b
a r t i c l e
i n f o
Article history: Received 18 January 2013 Received in revised form 11 June 2013 Accepted 12 June 2013 Available online xxx Keywords: Schistosomiasis Schistosoma haematobium Schistosoma mansoni Praziquantel Efficacy Mixed infection Re-infection pattern Transmission Snail Cameroon
a b s t r a c t The regular administration of the anthelminthic drug praziquantel (PZQ) to school-aged children (and other high-risk groups) is the cornerstone of schistosomiasis control. Whilst the performance of PZQ against single schistosome species infections is well-known, performance against mixed species infections is less so, as are patterns of re-infection following treatment. To address this, a study using a double treatment with PZQ, administered at 40 mg/kg spaced by 3 weeks, took place in two mixed intestinalurogenital schistosomiasis foci in northern Cameroon (Bessoum and Ouro-Doukoudje) and in one single intestinal schistosomiasis infection focus (Makenene). A total of just under 1000 children were examined and the Schistosoma-infected children were re-examined at several parasitological follow-ups over a 1-year period posttreatment. Overall cure rates against Schistosoma spp. in the three settings were good, 83.3% (95% confidence interval (CI) = 77.9–87.7%) in Bessoum, 89.0% (95% CI = 79.1–94.6%) in Ouro Doukoudje, and 95.3% (95% CI = 89.5–98.0%) in Makenene. Interestingly, no case of mixed schistosome infection was found after treatment. Cure rates for S. mansoni varied from 99.5% to 100%, while that for S. haematobium were considerably lower, varying from 82.7% to 88.0%. Across transmission settings, patterns of re-infection for each schistosome species were different such that generalizations across foci were difficult. For example, at the 6-month follow-up, re-infection rates were higher for S. haematobium than for S. mansoni with re-infection rates for S. haematobium varying from 9.5% to 66.7%, while for S. mansoni, lower rates were observed, ranging between nil and 24.5%. At the 12-month follow-up, re-infection rates varied from 9.1% to 66.7% for S. haematobium and from nil to 27.6% for S. mansoni. Alongside these parasitological studies, concurrent malacological surveys took place to monitor the presence of intermediate host snails of schistosomiasis. In the two northern settings, three species of Bulinus (intermediate host snail of S. haematobium) were collected; i.e. Bulinus truncatus, B. globosus and B. senegalensis, however, Biomphalaria pfeifferi (intermediate host snail of S. mansoni) was much rarer despite repeated and intensive searching and was suggestive of limited local transmission potential of S. mansoni during this time. While this study highlights that performance of PZQ was satisfactory in this region, with somewhat greater impact upon intestinal than urogenital schistosomiasis, the dynamics of local transmission are shown, however, to be complex. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Schistosomiasis remains of significant public health importance worldwide, with an estimated 207 million people infected; over 90% of all schistosomiasis cases are found in sub-Saharan
∗ Corresponding author at: Centre for Schistosomiasis and Parasitology, P.O. Box 7244, Yaoundé, Cameroon. Tel.: +237 7770 7436; fax: +237 2221 5077. E-mail address: [email protected] (L.-A. Tchuem Tchuenté).
Africa (Steinmann et al., 2006; Utzinger et al., 2009). Worldwide the disease is caused by six species of blood flukes: Schistosoma haematobium, Schistosoma mansoni, Schistosoma japonicum, Schistosoma intercalatum, Schistosoma guineensis and Schistosoma mekongi. In sub-Saharan Africa, the two predominant species are S. haematobium (causing urogenital schistosomiasis) and S. mansoni (causing intestinal schistosomiasis). The disease mainly affects the poorest of the poor and is a considerable local health burden in communities where access to clean water, improved sanitation and water-hygiene are elusive (WHO, 2002).
0001-706X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.actatropica.2013.06.007
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There have been many attempts to control schistosomiasis in sub-Saharan Africa within the past 10 years, and significant progress has been made in sustaining continued interventions against schistosomiasis with the promotion of better access to de-worming medications. With the increased resources from international donors and the development of preventive chemotherapy strategy, large-scale administration of praziquantel (PZQ) has been fostered and amplified to national levels in several countries (WHO, 2006, 2011). Generic PZQ is currently the drug of choice for the treatment of schistosomiasis and is the only commercially available antischistosomal medicine. It is highly efficacious against all six schistosome species that parasitize humans. However, PZQ treatment may not be fully curative (Geary et al., 2010). Several clinical trials have assessed PZQ efficacy against different Schistosoma species causing disease in humans (Utzinger et al., 2000; Tchuem Tchuenté et al., 2001a, 2004; Raso et al., 2004; Midzi et al., 2008; Barakat and Morshedy, 2011; Olliaro et al., 2011; Lovis et al., 2012). The efficacy of PZQ is most often measured in terms of percentage reduction in the number of patients who cease egg excretion (commonly used term: cure rate), and the reduction in the mean number (whether arithmetic or geometric) of eggs excreted in those who still continue to excrete eggs (i.e. those with active infections remaining) (commonly used term: egg reduction rate). Despite few reports of treatment failures (Stelma et al., 1995; Wang et al., 2012), the majority of studies showed a good efficacy of PZQ, with particularly high egg reduction rates, especially when levels of local transmission are considered low-to-moderate due to seasonality of environmental transmission when opportunities for re-infection are generally much lower. In terms of monitoring control at national levels, regular observations on the general efficacy of treatment are considered good public health practice. Several studies have been conducted on PZQ efficacy against S. mansoni and S. haematobium in single infection situations. However, little is known about the efficacy of this drug in mixed infections of these two schistosome species in humans. In Africa, the high burden of the disease is due to S. haematobium and S. mansoni. These two species are widely distributed and evidence has accumulated on their population dynamics epidemiology and increasing co-endemicity (Garba et al., 2010, 2013; Webster et al., 2013). Although PZQ is effective at clearing worms, re-infection will occur after treatment. The rate and intensity of re-infection post-PZQ chemotherapy varies between schistosome species, and also differs according to transmission dynamics and endemicity level. Interestingly, the effectiveness of PZQ is sometimes lower for S. mansoni than for S. haematobium (King et al., 2011). The increase of large-scale interventions and repeated treatment with PZQ in endemic countries will impact on the transmission and epidemiology of schistosomiasis. Studies also showed the influence of transmission season on treatment efficacy. In areas with a seasonal transmission pattern, the effect of PZQ can be enhanced if treatment takes place during low transmission season (Augusto et al., 2009). To shed new light on these aspects of treatment with PZQ in mixed schistosome species infections, under the auspices of the CONTRAST project (a multidisciplinary alliance to optimize schistosomiasis control and transmission surveillance in subSaharan Africa), a multi-country study was conducted to assess the dynamics of transmission, the efficacy of PZQ treatment and the re-infection patterns in single and mixed infection foci of S. haematobium and S. mansoni. The study was conducted following a standard protocol, including parasitological baseline survey, double treatment 3 weeks apart, and follow-up surveys at several time intervals up to 12 months after treatment. The two-treatment regimen at a 3-week interval has been demonstrated as the most appropriate protocol for the assessment of PZQ efficacy against schistosomes (Renganathan and Cioli, 1998; Tchuem Tchuenté
et al., 2001a, 2004). As PZQ is not effective against immature schistosomes, these parasites can mature and produce eggs a few weeks after treatment (Botros et al., 2005). A double treatment within a short interval will eliminate pre-existing immature parasites and the few residual schistosomes surviving a single drug administration, even with a 99% efficacy (Renganathan and Cioli, 1998). The research conducted in Niger and Senegal are published elsewhere in this special issue of Acta Tropica (Garba et al., 2013; Webster et al., 2013). In this paper, we present the results of the study conducted in Cameroon. The study provides an important insight into the understanding of PZQ efficacy and the dynamics of human reinfections after treatment in mixed infection settings of S. mansoni and S. haematobium. 2. Material and methods 2.1. Study sites Based on previous parasitological data (Tchuem Tchuenté et al., 2001b; Cunin et al., 2003), three epidemiological settings were selected for the study: (i) two settings in the Lagdo area, North region of Cameroon where prevalence of S. mansoni–S. haematobium co-infections exceeded 50%, i.e. the villages of Bessoum and Ouro Doukoudje; and (ii) one setting in the Centre region where single S. mansoni transmission occurred, i.e. the town of Makenene. Bessoum (geographical coordinates 9.13269◦ N latitude, 13.71405◦ E longitude) and Ouro Doukoudje (9.10014◦ N, 13.71956◦ E) are located at approximately 20 km and 15 km from the Lagdo hydroelectric dam, respectively, hence some 80 km from Garoua, the capital city of the North region of Cameroon. The climate is tropical-Sudanese, marked by two unequal seasons: a long dry season, from November to May, and a short rainy season, from June to October. Makenene (4.89929◦ N, 10.78432◦ E) is located in the wet equatorial zone, at approximately 200 km from Yaoundé, the capital city of Cameroon (Fig. 1). 2.2. Ethical consideration The study was approved by the National Ethics Committee of Cameroon (reference no. 072/CNE/DNM08) and was a public health intervention conducted by the Ministry of Health and the Ministry of Education. Stool and urine samples were collected from children in schools with the approval of the administrative authorities, school inspectors, directors and teachers. The objectives of the study were explained to the schoolchildren and to their parents or guardians from whom written informed consent was obtained. Children willing to participate were registered. Each child was assigned a unique identification number and results were entered in a database and kept confidential. All children who participated in the study were treated with PZQ at a dose of 40 mg/kg. Other children were treated during the mass drug administration campaign implemented by the National Programme for the Control of Schistosomiasis and Intestinal Helminthiasis (NPCSIH). 2.3. Study design and data collection The study was conducted in Bessoum and Ouro Doukoudje between October 2007 and October 2008, and in Makenene from October 2009 to September 2010. At baseline parasitological surveys, in each of the three settings, stool and urine samples were collected from schoolchildren over two consecutive days. Details on number of children sampled per setting are provided in Fig. 2. The samples were collected between 11:00 and 14:00 h, in 60 ml plastic screw-cap vials, transferred to the local laboratory and processed the same day. In the laboratory, two Kato-Katz thick smears per stool sample, using 41.7 mg templates, were prepared
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Bessoum Ouro Doukoudje
N
Makenene
3
and examined under a microscope for S. mansoni by experienced laboratory technicians. Urine samples were subjected to a filtration method for detection of S. haematobium eggs. Each urine sample was agitated to ensure adequate dispersal of eggs, 10 ml of urine were filtered through Nucleopore® filter, and filters were examined under a microscope for the presence of schistosome eggs. Schistosome infections were recorded; the number of eggs was counted and intensity of infection was calculated and expressed as eggs per gram of faeces (EPG) for S. mansoni or eggs per 10 ml of urine (eggs/10 ml) for S. haematobium. Then all children were treated with PZQ 40 mg/kg. Children were re-treated at 3 weeks after the initial treatment, without additional specimen examination. Six weeks after the initial treatment, parasitological surveys were repeated in order to assess PZQ efficacy. Similarly, stool and urine samples were collected from children over two consecutive days, and duplicate Kato-Katz thick smears and one urine filtration were performed per stool and urine samples, respectively. In order to investigate the re-infection patterns posttreatment in the different settings, parasitological surveys with the collection of two consecutive day stool and urine samples and duplicate KatoKatz and urine filtration were conducted on the children cohorts at 6 and 12 months after the initial treatment. At the end of the study, all positive children received further treatment. 2.4. Malacological surveys
0 30 60
120
180
240 Kilometers
Fig. 1. Map showing the location of the three study villages in Cameroon where the study on efficacy of praziquantel in S. mansoni single (Makenene) and S. mansoni–S. haematobium mixed infections (Bessoum and Ouro Doukoudje) foci were conducted between 2007 and 2010.
Malacological surveys were conducted in main water sites in the study villages/towns. In the Lagdo area, selected sites in irrigation canals, rivers and streams were prospected. In Makenene, snail collection was made in various sites of the Mock River, known to be important water-contact points. Snail sampling was carried out at baseline, 6 weeks, 6 months, 9 months and 12 months followup surveys. Snails were collected with scoops and transported to the Centre for Schistosomiasis and Parasitology (CSP) laboratory in Yaoundé for identification and cercariae shedding tests. In the
Bessoum
Ouro Doukoudje
Makenene
TOTAL
M = 171 F = 95 Total = 266
M = 100 F = 50 Total = 150
M = 267 F = 294 Total = 561
M = 538 F = 439 Total = 977
Children infected
Sh+ = 255 Sm+ = 231 Sh+Sm+ = 224 Total + =262
Sh+ = 113 Sm+ = 90 Sh+Sm+ = 66 Total + =137
Sh+ = 0 Sm+ = 275 Sh+Sm+ = 0 Total + =275
Sh+ = 368 Sm+ = 596 Sh+Sm+ = 290 Total + =674
Children treated
n = 266
n = 150
n = 561
n = 977
Week 6
Follow-up
n = 256
n = 68
n = 127
n = 451
Month 6
Follow-up
n = 250
n = 76
n = 121
n = 447
Month 12
Follow-up
n = 250
n = 75
n = 107
n = 432
Week 0
Children registered and examined
Fig. 2. Number of children involved in the different phases of the praziquantel efficacy study in Cameroon. Flow chart showing the number of children included at the baseline survey (week 0) and at follow-up surveys at 6 weeks, 6 months and 12 months after treatment with praziquantel. The numbers of children infected with S. mansoni (Sm) and/or S. haematobium (Sh) at the baseline are also indicated.
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laboratory, the snails were exposed individually to artificial light between 11:00 and 14:00 h to stimulate the shedding of cercariae. This was repeated up to 6 weeks after collection or until snails died.
species infections in Ouro Doukoudje; and 49.0% for S. mansoni in Makenene. The overall Schistosoma prevalences (infection by any of the two schistosome species) were 98.5% in Bessoum and 91.3% in Ouro Doukoudje (Table 1). In all three settings, there was no significant difference of schistosome infections between boys and girls. With reference to age, children were divided into two groups: (i) <10 years and (ii) ≥10 years. The comparison of these two age groups showed a significant difference for S. haematobium infections in Bessoum (34.6% for children <10 years vs. 61.3% for children ≥10 years, P = 0.009), whereas the difference was not significant for other infections and settings (P > 0.25). For the follow-up surveys, only those children who were positive at baseline were selected and included in the cohorts. At the end of the 1-year follow-up, stratified by setting, only children who participated to all phases of the study and provided all required stool and urine samples were selected for further analysis; i.e. 222 children from Bessoum, 64 from Ouro Doukoudje and 107 from Makenene; giving a total of 393 children.
2.5. Statistical analysis The data were analyzed by the epidemiological unit of CSP using appropriate statistical tests and methods. Data were entered in a Microsoft Excel spreadsheet, checked and validated. The data were subsequently exported into SPSS (IBM, version 19) for statistical analysis. Only children who participated in all parasitological surveys, with complete data records, were included in the final analysis (per-protocol analysis). Analyses were performed for the three study settings separately to determine PZQ efficacy and re-infection rates/patterns posttreatment resulting from different S. mansoni–S. haematobium co-infection and single infection levels. To obtain a standardized measure of infection, the geometric mean infection intensities of S. mansoni and S. haematobium, expressed as EPG or eggs/10 ml, were estimated for the three study cohorts. Egg counts of the two consecutive days were averaged (arithmetic mean) at the individual child level. The parasitological cure rates were calculated as the proportion of children excreting eggs at the first survey before treatment and who were not excreting eggs in their stool and/or urine 6 weeks after the initial treatment. Ninety-five percent confidence intervals (CIs) were calculated for proportions. Geometric mean (GM) values of all individuals were used to assess mean egg counts of each group. The GM was calculated as the antilogarithm of the mean of all log transformed egg counts + 1. The intensity reduction rate was calculated as [1 − (GM egg counts after treatment/GM egg counts before treatment)] × 100. To test for changes in cure rate with time, Pearson’s 2 tests on proportions were carried out. In all cases, a P-value < 0.05 was taken to indicate statistical significance.
3.2. Cure rates Three weeks after the second treatment (i.e. 6 weeks after the initial treatment), the overall Schistosoma spp. cure rates in the three settings were 83.3% (95% CI = 77.9–87.7%) in Bessoum, 89.0% (95% CI = 79.1–94.6%) in Ouro Doukoudje, and 95.3% (95% CI = 89.5–98%) in Makenene. No case of mixed infections was found after the treatment. Detailed analysis of Bessoum and Ouro Doukoudje showed that cure rates for S. mansoni varied from 99.5% to 100%. Cure rates for S. haematobium were lower, varying from 82.7% to 88.0% (Table 2). 3.3. Intensity reduction rates Six weeks after the first treatment (3 weeks after the second treatment), the GM intensity of infection had decreased by more than 98% for both schistosome species in all three settings (Table 2). The egg counts remained very low in all settings at 6 and 12 months posttreatment. There were no significant differences in infection intensities between the three settings.
3. Results 3.1. Baseline prevalence and cohort selection The current study was planned to include at least 100 schistosome-infected children in the cohort for each of the three settings. To ensure this all children enrolled in the single school existing in each of the villages of Bessoum and Ouro Doukoudje were invited to participate in the study. At the baseline survey, i.e. week 0, stool and urine samples were collected from a total of 266 children in Bessoum, 150 in Ouro Doukoudje and 561 in Makenene, giving an overall total of 977 pupils (538 boys and 439 girls) for the three settings. The overall male:female ratio was 1.2:1. The baseline infection prevalences were 95.9% for S. haematobium, 86.8% for S. mansoni and 84.2% for mixed species infections in Bessoum; 75.3% for S. haematobium, 60.0% for S. mansoni and 44% for mixed
3.4. Re-infection patterns The patterns of re-infection for each schistosome species in the different settings are summarized in Table 3. The re-infection rates were higher for S. haematobium than for S. mansoni. At 6 months posttreatment, reinfection rates for S. haematobium varied from 40.0% to 66.7% in Bessoum, and from 9.5% to 20.0% in Ouro Doukoudje. For S. mansoni, no re-infection was observed in Ouro Doukoudje, and it was only 2.0% in Bessoum, and 24.5% in Makenene. At 12 months posttreatment, re-infection rates varied from
Table 1 Baseline infection prevalence of schistosomiasis in Bessoum, Ouro Doukoudje and Makenene, Cameroon.
*
Overall S. haematobium
Single S. haematobium
Overall S. mansoni
Single S. mansoni
No. positive
%
No. positive
%
Sample
No. of samples
No. positive
%
No. positive
%
No. positive
%
Bessoum
Urine Stool
266 266
255 7*
95.9 –
28 –
10.5 –
11* 231
– 86.8
– 8
– 3.0
224
84.2
262
98.5
Ouro Doukoudje
Urine Stool
150 150
113 3*
75.3 –
47 –
31.3 –
4* 90
– 60.0
– 24
– 16.0
66
44.0
137
91.3
Makenene
Urine Stool
561 561
– 49.0
– 275
– 49.0
0
0
275
49.0
0 –
0 –
0 –
– 275
%
Overall Schistosoma spp.
Village
0 –
No. positive
Mixed S. haematobium and S. mansoni
Ectopic elimination of schistosome eggs, i.e. S. haematobium eggs in stool and S. mansoni eggs in urine.
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Village
No. of subjects
GM* for S. haematobium (eggs/10 ml)
GM for S. mansoni (EPG)
Any Schistosoma spp. after 2 treatments
S. mansoni after 2 treatments
S. haematobium after 2 treatments
Before treatment
Cure rate (%)
GM (eggs/ 10 ml)
Intensity reduction rate (%)
Cure rate (%)
GM (EPG)
Intensity reduction rate (%)
Cure rate (%)
Single S. haematobium Single S. mansoni Mixed infections All infection types
25 6 191 222
178.6 – 118.6 109.2
– 73.0 86.7 52.2
88.0 – 82.7 83.8
1.2 – 1.2 1.2
99.4 – 99.0 99.0
– 100 99.5 99.5
– 1.0 1.0 1.0
– 98.6 98.8 98.1
– – – 83.3
Ouro Doukoudje
Single S. haematobium Single S. mansoni Mixed infections All infection types
42 22 0 64
13.3 – – 5.5
– 88.2 – 4.7
85.7 – – 85.7
1.1 – – 1.1
91.7 – – 80.0
– 100 – 100
– 1.0 – 1.0
– 98.9 – 78.7
– – – 89.0
Makenene
Single S. mansoni
1.2
99.5
95.3
107
–
229.7
–
–
–
95.3
GM, geometric egg count per 10 ml of urine for S. haematobium or per gram of faeces for S. mansoni (EPG).
Table 3 Posttreatment re-infection rates and intensity reduction rates in schoolchildren in mixed and single infections with S. haematobium and S. mansoni at 6 and 12 months in Bessoum, Ouro Doukoudje and Makenene, Cameroon. Village
Infection type before treatment
6 months after treatment
S. haematobium
12 months after treatment
S. haematobium or S. mansoni
S. haematobium
Intensity reduction rate (%)
Re-infection rate (%)
Re-infection rate (%)
Intensity reduction rate (%)
Re-infection rate (%)
Intensity reduction rate (%)
Re-infection rate (%)
S. mansoni
Re-infection rate (%)
Intensity reduction rate (%)
Re-infection rate (%)
S. mansoni
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Bessoum
S. haematobium or S. mansoni
Bessoum
Single S. haematobium Single S. mansoni Mixed infections All infection types
63.6 66.7 40.5 43.3
97.6 – 98.0 97.9
– 0 2.1 2.0
– 98.6 98.8 98.0
– – – 45.4
40.0 66.7 32.7 33.6
97.7 – 97.4 97.4
16.0 0 18.7 18.1
– 98.6 98.0 96.7
– – – 30.6
Ouro Doukoudje
Single S. haematobium Single S. mansoni Mixed infections All infection types
20.0 9.5 – 20.0
89.6 – –
0 0 – 0
98.6 98.9 – 78.5
– – – 17.5
16.2 9.1 – 16.2
90.9 – – 78.9
16.7 4.5 – 4.5
– 98.8 – 68.7
– – – 19.2
Makenene
Single S. mansoni
–
–
24.5
98.6
24.5
–
–
27.6
99.0
27.6
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Infection type before treatment
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Table 2 Cure rates, geometric mean egg counts and intensity reduction rates in schoolchildren in mixed and single infections with S. haematobium and S. mansoni after 2 treatments with praziquantel at 3-week interval in Bessoum, Ouro Doukoudje and Makenene, Cameroon. Parasitological examinations were conducted 3 weeks after the second treatment.
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Total
Total
Fig. 3. Posttreatment evolution of schistosome infection prevalence in the village of Bessoum, Cameroon at 6 weeks, 6 months and 12 months. (A) S. mansoni (Sm) and (B) S. haematobium (Sh) prevalence in the different groups of children infected at baseline with either single or both schistosome species.
32.7% to 66.7% for S. haematobium in Bessoum, and from 9.1% to 16.2% in Ouro Doukoudje. Re-infection rates for S. mansoni were 4.5–16.7% in Ouro Doukoudje, 0–18.7% in Bessoum, and 27.6% in Makenene. The dynamics of infection prevalence in the three settings are illustrated in Figs. 3–5. Overall, re-infections were higher for S. haematobium than for S. mansoni. Moreover, more rapid reinfection with S. haematobium was observed in Bessoum compared to Ouro Doukoudje.
3.5. Results from the malacological surveys A total of seven species of snails were collected in the localities of Bessoum and Ouro Doukoudje, i.e. B. truncatus, B. globosus, B. senegalensis, Biomphalaria pfeifferi, Afrogyrus coretus, Melanoides tuberculata and Physa acuta. B. globosus was the most abundant species, whereas Biomphalaria pfeifferi was very rare; indeed it was found only on one occasion. In Makenene, five species of snails were collected: Biomphalaria pfeifferi, A. coretus, M. tuberculata, P. acuta and B. forskalii. Here, Biomphalaria pfeifferi was the most abundant species.
The cercariae shedding tests revealed natural infections only in B. globosus (18.4%) in the Lagdo area, and only in Biomphalaria pfeifferi (68.2%) collected in Makenene. 4. Discussion The results of the present study show that a double treatment with PZQ (two doses of 40 mg/kg spaced by 3 weeks) is highly efficacious with cure rates varying between 82% and 100% and egg reduction rates above 98% in all settings. Previous studies demonstrated significant increases of cure rates and intensity reduction rates after a second dose of PZQ in settings where low efficacy was observed after a single treatment with PZQ (Picquet et al., 1998; Barakat and Morshedy, 2011). Low PZQ cure rates were mainly attributed to less sensitivity of the immature schistosome worms to PZQ, that survive the treatment, continue their development and then start oviposition. It has been demonstrated and confirmed that a double treatment regimen at 3-week interval was the most appropriate protocol for the assessment of PZQ efficacy against schistosomes (Renganathan and Cioli, 1998; Tchuem Tchuenté et al., 2001a, 2004). However, few investigations using this protocol have been conducted thus far which, if undertaken within
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Fig. 4. Posttreatment evolution of schistosome infection prevalence in the village of Ouro Doukoudje, Cameroon at 6 weeks, 6 months and 12 months. (A) S. mansoni (Sm) and (B) S. haematobium (Sh) prevalence in the different groups of children infected at baseline with either single or both schistosome species.
national control programmes, of course, increases the demand for additional stocks of PZQ. Interestingly, using slightly longer intervals between the two treatments, e.g. 4–5 weeks, previous studies already reported high cure rates against S. mansoni (Utzinger et al., 2000) and S. haematobium (N’Goran et al., 2003). Although our study showed a high efficacy of PZQ against both S. mansoni and S. haematobium, cure rates were higher for S. mansoni in comparison to S. haematobium, suggesting a higher efficacy of PZQ against S. mansoni. The cure rates for S. haematobium were within the range of PZQ cure rates (83–89%) reported in previous studies (Tchuem Tchuenté et al., 2004). Higher cure rates for S. haematobium were also reported in younger children, 1–5 years old (Mutapi et al., 2011) and children attending primary school (5–17 years) in Zimbabwe (Midzi et al., 2008). Interestingly, different results were obtained in different S. haematobium settings in Niger, with variation of cure rates 6-week posttreatment from moderate (49.2–58.9%) in single transmission foci to high (96.0–98.4%) in mixed infection foci (Garba et al., 2013). In contrast to our results, in Niger the efficacy of PZQ was much higher against S. haematobium than S. mansoni, with the cure rates against the later species ranging from 51.7% to 60.2%. The low cure and egg reduction rates observed against S. mansoni in the two mixed infection foci
in Niger raised concern about a potential development of worm tolerance to PZQ in these areas where repeated mass treatments with PZQ have been conducted over the past years (Garba et al., 2013). Follow-up investigations on this issue are recommended in
Fig. 5. Posttreatment evolution of infection prevalence of S. mansoni in Makenene, Cameroon at 6 weeks, 6 months and 12 months.
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these areas. Similar low cure rates were obtained by Sacko and colleagues in a study conducted in two villages in Mali. In these villages cure rates of 46.0% and 56.8% were obtained 3 months after a double treatment given 2 weeks apart (Sacko et al., 2009). It is known that the efficacy of PZQ treatment could be influenced by several factors, including the transmission season. Augusto and colleagues observed significant difference in cure rates between cohorts of S. haematobium-infected schoolchildren treated in the high transmission season (69.7%) compared to those treated in the low transmission season (98.2%) in southern Mozambique. Treatment administered 2 months after the end of the high transmission season provided the highest observed cure rates. Hence, the authors concluded that in areas with a seasonal transmission pattern, the effect of PZQ could be enhanced if treatment takes place during the low transmission season (Augusto et al., 2009). In the villages of Bessoum and Makenene, the egg reduction rates posttreatment were very high (>98%) for both S. mansoni and S. haematobium, either in single or mixed infections; contrary to Ouro Doukoudje where egg reduction rates varied from 78.7% to 98.9%. The low egg reduction rate in the later focus was probably due to low level of infection intensities before treatment. Indeed, the pretreatment GM egg counts ranged between 109.2 and 178.6 eggs/10 ml for S. haematobium and between 73.0 and 229.7 EPG for S. mansoni in Bessoum and Makenene, whereas they were only 5.5–13.3 eggs/10 ml and 4.7–88.2 EPG in Ouro Doukoudje. Our results on re-infection patterns posttreatment showed different dynamics of re-infection prevalence in the different study settings, with significant difference between the two schistosome species. Interestingly, the re-infection rates were higher for S. haematobium at any of the follow-up time points posttreatment and in all study settings. In the areas of Bessoum and Ouro Doukoudje, the re-infections of children with S. mansoni were very low, and up to only 2% after one year post-treatment. One of the factors that might explain this low re-infection rate is the local malacological fauna encountered in these settings. Indeed, the snail intermediate hosts of S. haematobium (three different Bulinus species) were abundant, while the snail intermediate host for S. mansoni (i.e. Biomphalaria pfeifferi) was very rare and was found only at one occasion in one survey site in Bessoum, suggestive that opportunities for environmental transmission were low during this period. The re-infection patterns of schistosomiasis after anthelminthic chemotherapy vary between schistosome species and are governed by multiple factors such as local ecology and epidemiology, human exposure to water, intensity of transmission within a given community, geographical, environmental and socioeconomic factors (Kahama et al., 1999; Ernould et al., 2004; Cundill et al., 2011). In the present study, the re-infection with S. haematobium in the two northern Cameroon settings was higher than that with S. mansoni, similarly to observations in settings along the Niger River (Garba et al., 2013); and contrary to the general trend reporting more rapid re-infection with S. mansoni than S. haematobium (Daffalla and Fenwick, 1982; Ernould et al., 2004). Detailed analysis taking into account the pretreatment features/characteristics revealed significant differences of re-infection patterns between pretreatment intensity classes, with higher re-infection rates among children with heavy intensity of S. mansoni (≥400 EPG) before treatment (P < 0.05). No significant difference was observed between pretreatment intensity classes for S. haematobium. Also, no significant difference was observed between sex and age groups for both schistosome species. In conclusion, the present study revealed that PZQ is efficacious in the management of dual species schistosome infections. In the northern Cameroon setting, the drug was particularly effective against S. mansoni, lower efficacy was observed against S. haematobium. Re-infection patterns were significantly higher for S. haematobium, which may be explained in part by higher levels
of local transmission as evidenced by snail surveys and observed cercarial shedding. Our study showed that transmission dynamics and re-infection patterns posttreatment are complex and generalizations could not be made between foci in light of local changes in the malacological fauna. Acknowledgements We would like to thank the technicians, school headmasters, teachers and all people in the health districts of Lagdo and Makenene who contributed in any way for their assistance and help with the collection of information and data necessary for this study. We are grateful to Laurentine Sumo for her contribution in field surveys, and to Cesaire Kuete Fouodo and Jules Brice Tchatchueng Mbougua for their contribution in statistical analysis of data. References Augusto, G., Magnussen, P., Kristensen, T.K., Appleton, C.C., Vennervald, B.J., 2009. 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Please cite this article in press as: Tchuem Tchuenté, L.-A., et al., Efficacy of praziquantel and reinfection patterns in single and mixed infection foci for intestinal and urogenital schistosomiasis in Cameroon. Acta Trop. (2013), http://dx.doi.org/10.1016/j.actatropica.2013.06.007
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Please cite this article in press as: Tchuem Tchuenté, L.-A., et al., Efficacy of praziquantel and reinfection patterns in single and mixed infection foci for intestinal and urogenital schistosomiasis in Cameroon. Acta Trop. (2013), http://dx.doi.org/10.1016/j.actatropica.2013.06.007