Pre-treatment Infection Intensity Research Articles

Efficacy of Single-Dose Praziquantel for the Treatment of Schistosoma mansoni Infections among School Children in Rwanda.

Preventive chemotherapy with single-dose praziquantel is the WHO-recommended intervention strategy to eliminate schistosomiasis as a public health problem in endemic countries. Surveillance of drugs used in mass drug administration (MDA) programs is recommended to evaluate its effectiveness in reducing transmissions. After a decade-long implementation of a school-based MDA program in Rwanda, we conducted efficacy surveillance of single-dose praziquantel MDA against S. mansoni infection. Two weeks before MDA, stool examinations were performed to screen MDA-eligible school children (n = 4998) for S. mansoni infection using the Kato-Katz technique, and 265 (6.5%) children tested positive for the infection. All children received praziquantel and albendazole as preventive chemotherapy through the MDA campaign. Infected children were enrolled and followed for efficacy monitoring, and stool examination was repeated after three weeks post-MDA (n = 188). Before treatment, 173 (92%) had a light infection, and 15 (8%) had a moderate infection intensity. The primary and secondary outcomes were parasitological cure and egg reduction rates at three weeks post-treatment. The overall cure and egg reduction rates for S. mansoni infection were 97.9% (95% CI = 94.6-99.4) and 97.02%, respectively. Among the 173 children with light infection intensity, 170 (98.3%, 95% CI = 95.0-99.6) were cured, and among the 15 children who had moderate infection intensity, 14 (93.3%) were cured. No significant association between cure rate and pre-treatment infection intensity was observed. We conclude that single-dose praziquantel is efficacious against light-to-moderate S. mansoni infection. Preventive chemotherapy with praziquantel effectively reduces schistosome reservoirs and transmission among school-age children.

Efficacy and Safety of Praziquantel for Treatment of Schistosoma mansoni Infection among School Children in Tanzania.

Single-dose targeted praziquantel preventive chemotherapy is the WHO-recommended intervention for schistosomiasis control in endemic countries. The objective of this study was to assess the efficacy and safety of single-dose praziquantel among Schistosoma mansoni-infected children in north-western Tanzania. A prospective safety and efficacy surveillance study was conducted among 341 school-going children treated with a single-dose praziquantel 40 mg/kg body weight. Socio-demographic, pre-treatment, and post-treatment stool examination and safety data were collected. The primary and secondary outcomes were treatment efficacy (parasitological cure and egg reduction rates at three weeks post-treatment) and treatment-related adverse events, respectively. The overall cure rate and egg reduction rate were 81.2% (76.8–85.3%) and 95.0% (92.7–97.3%), respectively. There was no significant association between cure rate and pre-treatment infection intensity. The incidence of treatment-associated adverse events was 28.5% (23.7–33.3%), with abdominal pain being the most common. Post-treatment abdominal pain and vomiting were significantly associated with pre-treatment infection intensity (p < 0.001) and anemia (p = 0.03), respectively. Praziquantel single-dose is still safe and efficacious against Schistosoma mansoni infection. However, the lack of cure in about one-fifth and adverse events in a quarter, of the infected children indicate the need for close praziquantel safety monitoring and treatment optimization research to improve efficacy.

Population level changes in schistosome-specific antibody levels following chemotherapy.

SummaryAimsPrevious studies have reported that chemotherapy of schistosomiasis by praziquantel in humans boosts protective antibody responses against S mansoni and S haematobium. A number of studies have reported schistosome‐specific antibody levels before and after chemotherapy. Using these reports, a meta‐analysis was conducted to identify predictors of population level change in schistosome‐specific antibody levels after chemotherapy.Methods and resultsFollowing a systematic review, 92 observations from 26 articles published between 1988 and 2013 were included in this study. Observations were grouped by antigen type and antibody isotypes for the classification and regression tree (CART) analysis. The study showed that the change in antibody levels was variable: (a) between different human populations and (b) according to the parasite antigen and antibody isotypes. Thus, while anti‐worm responses predominantly increased after chemotherapy, anti‐egg responses decreased or did not show a significant trend. The change in antibody levels depended on a combination of age and infection intensity for anti‐egg IgA, IgM, IgG1, IgG2 and anti‐worm IgM and IgG.ConclusionThe study results are consistent with praziquantel treatment boosting anti‐worm antibody responses. However, there is considerable heterogeneity in post‐treatment changes in specific antibody levels that is related to host age and pre‐treatment infection intensity.

Safety, efficacy and acceptability of praziquantel in the treatment of Schistosoma haematobium in pre-school children of Kwale County, Kenya

BackgroundThe recommended strategy for control of schistosomiasis is preventive chemotherapy with praziquantel (PZQ). Pre-school children (PSC) are excluded from population treatment programs. In high endemic areas, these children are also at risk, and require treatment with PZQ. The Government of Kenya initiated the National School-Based Deworming Programme (NSBDP) where PSC in Early Childhood Development Education (ECDE) Centers are only eligible for treatment with albendazole (ABZ) but not with PZQ.Methodology/Principal findings400 PSC were enrolled, from 10 randomly selected ECDE Centers in Kwale County, Kenya where children were treated with crushed PZQ tablets mixed with orange juice, at a single dose of 40 mg/kg. Adverse events were assessed 24 hours post-treatment through questionnaires administered to the parents or guardians. Acceptability was determined by observing if the child spat and/ or vomited all or part of the PZQ dose immediately after treatment. Efficacy was assessed by examining urine samples for Schistosoma haematobium eggs in the 5 weeks post-treatment follow-up. Children testing negative for S. haematobium during the follow-up were considered cured. Egg reduction rate (ERR) was calculated as the decrement in the infection intensity (group’s geometric mean egg counts per 10 ml of urine) following treatment expressed as a proportion of the pre-treatment infection intensity. Before treatment, 80 out of the 400 children enrolled in the study tested positive for S. haematobium (20.0% (95% confidence interval (CI) 16.4–24.2%). Of these, 41 had infections of heavy intensity (51.3%) while the rest (48.7%) were of light intensity. Five weeks post-treatment, 10 children who had heavy intensity infection were diagnosed with S. haematobium (prevalence: 2.5% (95% CI 1.5–4.9%). Infection intensities decreased significantly from 45.9 (95% CI: 31.0–68.0) eggs/ 10 ml urine to1.4 (95% CI: 1.1–1.7) eggs/ 10 ml urine during pre-and post-treatment respectively. The ERR was 96.9%. There were no severe adverse events during follow up 24 hours post treatment. Treatment tolerability among the 400 children was high as none of the children spat and/ or vomited as observed in this study.Conclusion/SignificanceThe study revealed that crushed PZQ is safe and effective in the treatment of urogenital schistosomiasis in this age group. It is therefore recommended that PZQ should be administered to the PSC in Kwale County.

Rapidly Boosted Plasma IL-5 Induced by Treatment of Human Schistosomiasis haematobium Is Dependent on Antigen Dose, IgE and Eosinophils

BackgroundIgE specific to worm antigen (SWA) and pre-treatment eosinophil number, are associated with human immunity to re-infection with schistosomes after chemotherapeutic treatment. Treatment significantly elevates circulating IL-5 24-hr post-treatment of Schistosoma mansoni. Here we investigate if praziquantel treatment of human schistosomiasis haematobium also boosts circulating IL-5, the immunological and parasitological factors that predispose to this, and the relationship between these and subsequent immunity to post-treatment re-infection.Methodology/Principle FindingsThe relationship between pre-treatment SWA-IgE, eosinophil number and infection intensity and the 24-hr post-treatment IL-5 boost was investigated in a Malian cohort (aged 5–40 yrs), exposed to S. haematobium. Eotaxin levels were measured at 24-hr post-treatment as a proxy of eosinophil migration. The relationship between the 24-hr post-treatment IL-5 boost and later eosinophil numbers and SWA-IgE levels (9-wk post-treatment) was examined, then investigated in the context of subsequent levels of re-infection (2-yr post-treatment). Circulating IL-5 levels increased 24-hr post-treatment and were associated with pre-treatment infection intensity, SWA-IgE levels, eosinophil number, as well as 24-hr post-treatment eotaxin levels. 24-hr IL-5 levels were, in turn, significantly associated with eosinophil number and elevated SWA-IgE 9-wk later. These SWA-IgE levels were significantly associated with immunity to re-infection.Conclusions/SignificanceEarly IL-5 production after treatment-induced exposure to S. haematobium worm antigen is positively associated with antigen dose (infection intensity), IgE availability for arming of effector cells at time of treatment and subsequent eosinophil migration response (as indicated by eotaxin levels). The IL-5 produced is positively associated with increased downstream eosinophil number and increases in specific IgE levels, implicating this cytokine boost and its down-stream consequences in the production and maintenance of IgE, and subsequent re-infection immunity.

Efficacy of praziquantel syrup versus crushed praziquantel tablets in the treatment of intestinal schistosomiasis in Ugandan preschool children, with observation on compliance and safety

Preschool children (aged ≤5 years) have so far been overlooked by mass treatment campaigns targeting schistosomiasis, even though praziquantel (PZQ) has been shown to be well tolerated and effective within this age group. The WHO provided the Ugandan Ministry of Health with a syrup formulation of PZQ with the aim of assessing its safety and efficacy in comparison with crushed PZQ tablets for the treatment of intestinal schistosomiasis in preschool children. This study included 1144 preschool children randomly assigned to two treatment arms (PZQ syrup or crushed PZQ tablet) regardless of infection status for direct comparison. Diagnosis of intestinal schistosomiasis was assessed using single stool sample, double Kato–Katz smear examinations. Parasitological cure was assessed 3 weeks after treatment. The observed cure rate was 80.9% for the PZQ syrup arm and 81.7% for the crushed PZQ tablet arm, with egg reduction rates of 86.1% and 89.0%, respectively. Pre-treatment infection intensity was observed to influence cure rates significantly, with cure rates of 88.6% for light infections, 74.5% for moderate infections and 67.4% for heavy infections. No significant difference was found in non-compliance between the PZQ syrup (11.1%) and crushed PZQ tablet (14.7%) arms. PZQ syrup and crushed PZQ tablets have very similar efficacies in the treatment of intestinal schistosomiasis in preschool children.

Efficacy and side effects of praziquantel in the treatment of Schistosomiasis mansoni in schoolchildren in Shesha Kekele Elementary School, Wondo Genet, Southern Ethiopia

ObjectiveTo evaluate the efficacy and side effects of praziquantel (PZQ) in the treatment of schistosomiasis in Ethiopia. MethodsIn a cross-sectional study, stool specimens were collected from randomly selected 299 school children in Shesha Kekele Elementary School, Wondo Genet, Southern Ethiopia, in April 2010. Stool specimens were examined using a single Kato-Katz thick smear for Schistosoma mansoni (S. mansoni) ova. Children who were found positive for S. mansoni were treated with a single oral dose of PZQ at 40 mg/kg bw and interviewed for treatment-related symptoms 24 hours after drug administration. Four weeks post-treatment, stool specimens were collected from the same children and examined following the same procedure as in the pre-treatment. Drug efficacy was determined based on cure and egg reduction rates. ResultsPre-treatment prevalence of S. mansoni infection was 74.9% with geometric mean egg count of 268. The evaluated generic PZQ produced an overall cure rate of 73.6% (P<0.000 1, OR: 8.33, CI: 5.3–13.1) and egg reduction rate of 68.2% (P=0.03, F=0.64). The cure rate showed significant association with age (χ2=11, P=0.004), the highest rate being observed in the 15–22 age group. 83% of S. mansoni infected children showed various treatment-related symptoms, the most frequent being headache, nausea, and abdominal pain. These symptoms were associated with age (P<0.001) and pre-treatment intensity of infection (P<0.05). ConclusionsThe present observations revealed relatively lower cure and egg reduction rates of the PZQ evaluated as compared to previous reports for other PZQ brands in Ethiopia. Hence, in depth studies are recommended to clarify whether the present relatively lower cure rate is the actual cure rate of the praziquantel evaluated, treatment failure, or reduced susceptibility of the parasite. Treatment-related side effects observed were transient and tolerable.

Efficacy of two praziquantel treatments among primary school children in an area of highSchistosoma mansoniendemicity, Nile Delta, Egypt

Praziquantel is the cornerstone of schistosomiasis control. A number of reports from endemic areas suggest that resistance or tolerance to praziquantel might exist in Schistosoma mansoni. Several explanations were postulated. The present work was designed to test the hypothesis that a low praziquantel (pzq) cure rate in Egypt is due to survival and maturation of immature stages that escaped pzq, which is effective against mature S. mansoni worms only. The study sample included 1351 children attending El Rouse primary school located in El Rouse village, Nile Delta, Egypt. All children received 2 pzq doses (40 mg/kg) 4 weeks apart. Diagnosis of S. mansoni infection and cure assessment were based on examination of 2 Kato slides prepared from a single stool sample collected before and 4 weeks after the first and second treatments. The cure rate was 78·8% after the first treatment and increased significantly to 90·8% after the second treatment. Egg reduction rates were 71·2% and 77·2% after 1 and 2 treatments respectively. Pre-treatment intensity of infection has a great influence on cure and egg reduction rates. Our results confirmed that low praziquantel cure rate, in Egypt, might be attributed, even partially, to survival and maturation of the immature S. mansoni stages that escaped pzq that is effective against mature worms only.

Immunoglobulin E (IgE) Responses to Paramyosin Predict Resistance to Reinfection withSchistosoma japonicumand Are Attenuated by IgG4

Schistosomiasis remains a public health concern in developing countries, and rapid reinfection fostered by continued exposure to contaminated water sources necessitates a vaccine to augment current mass treatment-based control strategies. We report isotype-specific (immunoglobulin A [IgA], IgE, IgG1, IgG4, and IgG) antibody responses to soluble worm antigen preparation and the recombinant vaccine candidates rSj97, rSj67, and rSj22 from a Schistosoma japonicum-infected cohort in Leyte, the Philippines, where schistosomiasis is endemic. Sera were collected from infected individuals 1 month posttreatment with praziquantel, and antibody responses were measured using a bead-based multiplex platform. Reinfection was monitored by stool sampling every 3 months, and data up to 1 year were included in the analysis (n = 553). In repeated-measures models, individuals with detectible IgE responses to rSj97 had a 26% lower intensity of reinfection at 12 months posttreatment compared to nonresponders after adjusting for age, gender, village, exposure, pretreatment infection intensity, and clustering by household (P = 0.018). In contrast, IgG4 responses to rSj97 as well as rSj67 and rSj22 were associated with markedly increased reinfection intensity. When stratified by IgG4 and IgE responder status, individuals with IgE but not IgG4 responses to rSj97 (n = 16) had a 77% lower intensity of reinfection at 12 months compared to individuals with IgG4 responses but not IgE responses (n = 274), even after adjusting for potential confounders (P = 0.016). Together with our previously described protective cytokine responses, these data further support paramyosin as a leading vaccine candidate for human schistosomiasis japonica and underscore the importance of careful adjuvant selection to avoid the generation of blocking IgG4 antibody responses.

Anti-malaria humoral responses in children exposed to Plasmodium falciparum and Schistosoma haematobium

Antibody responses directed against the Plasmodium falciparum antigens, total extract, anti-merozoite surface protein-3 (MSP3b) and glutamate-rich protein (Glurp-R0) were studied in 42 children exposed to both Schistosoma haematobium and P. falciparum infections. The association between levels of the anti-malaria IgG subclasses and IgM with host age, sex, schistosome infection intensity and schistosome specific antibodies was studied before chemotherapeutic treatment of schistosome infections. This showed a significant negative association between schistosome infection intensity and levels of IgG1, IgG3, and IgG4 directed against malaria total extract antigen, and a positive association between levels of anti-schistosome soluble egg antigen IgG2, IgG3, and IgG4 and levels of the same subclasses directed against malaria total extract antigens. The effect of treating schistosome infections with praziquantel on malaria specific responses was also studied. This treatment resulted in increases in significant IgG4 levels against MSP3b and IgM against Glurp R0. Treatment also resulted in a significant decrease in IgG4 levels against Glurp R0. Host age, sex or pre-treatment infection intensity was not associated with the magnitude of change in the two IgG4 responses while males showed a significantly higher increase in levels of IgM. The results suggest cross reactivity between schistosome and malaria antigens in this population.

Increased Human IgE Induced by Killing Schistosoma mansoni In Vivo Is Associated with Pretreatment Th2 Cytokine Responsiveness to Worm Antigens

In schistosomiasis endemic areas, children are very susceptible to postchemotherapy reinfection, whereas adults are relatively resistant. Different studies have reported that schistosome-specific IL-4 and IL-5 responses, or posttreatment worm-IgE levels, correlate with subsequent low reinfection. Chemotherapy kills i.v. worms providing an in vivo Ag challenge. We measured anti-worm (soluble worm Ag (SWA) and recombinant tegumental Ag (rSm22.6)) and anti-egg (soluble egg Ag) Ab levels in 177 Ugandans (aged 7-50) in a high Schistosoma mansoni transmission area, both before and 7 wk posttreatment, and analyzed these data in relation to whole blood in vitro cytokine responses at the same time points. Soluble egg Ag-Ig levels were unaffected by treatment but worm-IgG1 and -IgG4 increased, whereas worm-IgE increased in many but not all individuals. An increase in worm-IgE was mainly seen in >15-year-olds and, unlike in children, was inversely correlated to pretreatment infection intensities, suggesting this response was associated both with resistance to pretreatment infection, as well as posttreatment reinfection. The increases in SWA-IgE and rSm22.6-IgE positively correlated with pretreatment Th2 cytokines, but not IFN-gamma, induced by SWA. These relationships remained significant after allowing for the confounding effects of pretreatment infection intensity, age, and pretreatment IgE levels, indicating a link between SWA-specific Th2 cytokine responsiveness and subsequent increases in worm-IgE. An exceptionally strong relationship between IL-5 and posttreatment worm-IgE levels in < 15-year-olds suggested that the failure of younger children to respond to in vivo Ag stimulation with increased levels of IgE, is related to their lack of pretreatment SWA Th2 cytokine responsiveness.

Chemotherapy for schistosomiasis in Ugandan fishermen: treatment can cause a rapid increase in interleukin-5 levels in plasma but decreased levels of eosinophilia and worm-specific immunoglobulin E.

Chemotherapy for blood-dwelling schistosomes kills the worms and exposes parasite antigen to the circulation. In many people from areas of endemicity, this treatment increases parasite-specific immunoglobulin E (IgE) and other Th2 responses in the months following therapy, responses that have been associated with subsequent resistance to reinfection. Here we investigate much earlier changes in immune reactions after praziquantel therapy in Schistosoma mansoni-infected fishermen working in an area of high transmission in Uganda. The subjects gave blood before treatment and at 1 and 21 days posttreatment. Blood cultures were incubated with schistosome soluble worm antigen (SWA) or soluble egg antigen (SEA). Interleukin-4 (IL-4), IL-5, IL-10, IL-13, gamma interferon, and transforming growth factor beta levels were measured in the cultures and in plasma. A marked transient increase in plasma IL-5 levels was observed in 75% of the subjects (n = 48) by 1 day posttreatment. This response was dependent on pretreatment intensity of infection and was accompanied by a transient decrease in eosinophil numbers. One day posttreatment, blood cultures from the 16 subjects with the greatest increase in plasma IL-5 level (>100 pg/ml) displayed reduced IL-5, IL-13, and IL-10 responses to SWA, and in contrast to the rest of the cohort, these high-IL-5 subjects displayed reduced levels of SWA-specific IgE in plasma 21 days posttreatment. Twenty months after treatment, the intensity of reinfection was positively correlated with the increase in plasma IL-5 level seen 1 day posttreatment. These studies describe the heterogeneity in early immune reactions to treatment, identifying subgroups who have different patterns of reaction and who may have different capacities to mount the responses that have been associated with resistance to reinfection.

Human IgE responses to rSm22.6 are associated with infection intensity rather than age per se, in a recently established focus of Schistomiasis mansoni.

In studies of schistosomasis mansoni-endemic communities, individuals with IgE responses to a 22 kD adult worm antigen (rSm22.6) suffered lower intensities of reinfection after treatment. It is of interest to define the factors that lead to the production of rSm22.6-specific IgE because it is a marker for resistant individuals and it may be involved in the development of resistance to reinfection. In endemic populations rSm22.6-specific IgE increases linearly with age. However, it is not possible to distinguish between age per se and 'history of infection' in endemic populations because individuals are exposed to the parasite at an early age. We have, therefore, quantified pre- and post-treatment isotype responses to rSm22.6 in a comparatively 'epidemic' Senegalese community where the patients were infected at different ages and where pre-treatment intensity of infection can be taken as a reasonable measure of antigen exposure. Post-treatment isotype responses to rSm22.6 correlated positively with pre-treatment intensities of infection but were not shown to be related to age. IgG1, IgG4 and IgE responses to rSm22.6 were significantly higher after treatment with the difference increasing with the pre-treatment level of infection. These results from a recently established focus of infection suggest that isotype responses to rSm22.6 are antigen-exposure dependent rather than dependent on age per se.

Chemotherapy-Based Control of Schistosomiasis Haematobia

To determine the relative efficacy of metrifonate and praziquantel in controlling urinary tract morbidity due to Schistosoma haematobium infection, a random allocation treatment trial was performed among 1,813 school age S. haematobium-infected children from the Msambweni area of Coast Province, Kenya. Following baseline examination for infection, hematuria, proteinuria, and ultrasonographic urinary tract abnormalities, oral treatment with either metrifonate (10 mg/kg, repeated at 4 month intervals) or praziquantel (1 dose of 40 mg/kg) was given to infected subjects. Prevalence of morbidity was reassessed 12 months later for each treatment group. Results indicated equivalent patient improvement in response to either regimen: prevalence of hematuria fell from 75% to 17% after either praziquantel or metrifonate therapy. Similarly, prevalence of proteinuria was significantly reduced from 73% to 29% (metrifonate) or 27% (praziquantel) after therapy. Metrifonate and praziquantel caused similar reductions in bladder granulomata and bladder thickening; however, no reduction in hydronephrosis was noted with either drug. Analysis of outcomes in population subgroups defined by age, sex, pretreatment intensity of infection, or severity of pretreatment morbidity showed no consistent advantage for either drug. In this endemic area, both agents provide effective control of morbidity due to urinary schistosomiasis.

Efficacy of metrifonate in a highly endemic area of urinary schistosomiasis in Kenya.

In a community in Kwale district, Kenya, selective mass chemotherapy with metrifonate caused a marked reduction in the intensity of Schistosoma haematobium infection from 46.5 to 9.4 eggs/hr and a sharp fall in prevalence of gross hematuria from 18.3% to 5.1%, although overall prevalence was reduced only slightly from 67.4% to 54%. The effect of metrifonate on cure rate and reduction of infection intensity was limited by both age and pretreatment infection intensity. Rate of improvement from gross hematuria was similar in all ages and in all classes of intensity of infection. Two doses of metrifonate reduced the prevalence of gross hematuria as much as 3 doses did, while the effect of a single dose on morbidity remains to be clarified.