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1.  Effect of praziquantel treatment of Schistosoma mansoni during pregnancy on immune responses to schistosome antigens among the offspring: results of a randomised, placebo-controlled trial 
BMC Infectious Diseases  2011;11:234.
Background
Offspring of women with schistosomiasis may exhibit immune responsiveness to schistosomes due to in utero sensitisation or trans-placental transfer of antibodies. Praziquantel treatment during pregnancy boosts maternal immune responses to schistosome antigens and reduces worm burden. Effects of praziquantel treatment during pregnancy on responses among offspring are unknown.
Methods
In a trial of anthelminthic treatment during pregnancy in Uganda (ISRCTN32849447; http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women with Schistosoma mansoni were examined for cytokine and antibody responses to schistosome worm (SWA) and egg (SEA) antigen, in cord blood and at age one year. Relationships to maternal responses and pre-treatment infection intensities were examined, and responses were compared between the offspring of women who did, or did not receive praziquantel treatment during pregnancy.
Results
Of 388 S. mansoni-infected women studied, samples were obtained at age one year from 215 of their infants. Stool examination for S. mansoni eggs was negative for all infants. Cord and infant samples were characterised by very low cytokine production in response to schistosome antigens with the exception of cord IL-10 responses, which were substantial. Cord and infant cytokine responses showed no association with maternal responses. As expected, cord blood levels of immunoglobulin (Ig) G to SWA and SEA were high and correlated with maternal antibodies. However, by age one year IgG levels had waned and were hardly detectable. Praziquantel treatment during pregnancy showed no effect on cytokine responses or antibodies levels to SWA or SEA either in cord blood or at age one year, except for IgG1 to SWA, which was elevated in infants of treated mothers, reflecting maternal levels. There was some evidence that maternal infection intensity was positively associated with cord blood IL-5 and IL-13 responses to SWA, and IL-5 responses to SEA, and that this association was modified by treatment with praziquantel.
Conclusions
Despite strong effects on maternal infection intensity and maternal immune responses, praziquantel treatment of infected women during pregnancy had no effect on anti-schistosome immune responses among offspring by age one year. Whether the treatment will impact upon the offspring's responses on exposure to primary schistosome infection remains to be elucidated.
Trial registration
ISRCTN: ISRCTN32849447
doi:10.1186/1471-2334-11-234
PMCID: PMC3176493  PMID: 21888656
2.  Effect of praziquantel treatment of Schistosoma mansoni during pregnancy on intensity of infection and antibody responses to schistosome antigens: results of a randomised, placebo-controlled trial 
Background
Praziquantel treatment of schistosomiasis during pregnancy was only recommended in 2002; hence the effects of treatment during pregnancy are not fully known. We have therefore evaluated the effects on infection intensity and the immunological effects of praziquantel treatment against Schistosoma mansoni during pregnancy, compared with treatment after delivery.
Methods
A nested cohort of 387 Schistosoma mansoni infected women was recruited within a larger trial of de-worming during pregnancy. Women were randomised to receive praziquantel or placebo during pregnancy. All women were treated after delivery. Infection intensity after treatment was assessed by a single Kato-Katz examination of stool samples with duplicate slides and categorised as undetected, light (1–99 eggs per gram (epg)), moderate (100–399 epg) or heavy (≥400 epg). Antibodies against S. mansoni worm and egg antigens were measured by ELISA. Results were compared between women first treated during pregnancy and women first treated after delivery.
Results
At enrolment, 252 (65.1%) of the women had light infection (median (IQR) epg: 35 (11, 59)), 75 (19.3%) moderate (median (IQR) epg: 179(131, 227)) and 60 (15.5%) had heavy infection (median (IQR) epg: 749 (521, 1169)) with S. mansoni. At six weeks after praziquantel treatment during pregnancy S. mansoni infection was not detectable in 81.9% of the women and prevalence and intensity had decreased to 11.8% light, 4.7% moderate and 1.6% heavy a similar reduction when compared with those first treated after delivery (undetected (88.5%), light (10.6%), moderate (0.9%) and heavy (0%), p = 0.16). Parasite specific antibody levels were lower during pregnancy than after delivery. Praziquantel treatment during pregnancy boosted anti-worm IgG isotypes and to a lesser extent IgE, but these boosts were less pronounced than in women whose treatment was delayed until after delivery. Praziquantel had limited effects on antibodies against egg antigens.
Conclusion
S mansoni antigen-specific antibody levels and praziquantel-induced boosts in antibody levels were broadly suppressed during pregnancy, but this was not associated with major reduction in the efficacy of praziquantel. Long-term implications of these findings in relation to resistance to re-infection remain to be explored.
Trial registration
International Standard Randomised Controlled Trial Number for the current study: ISRCTN32849447 http://www.controlled-trials.com/ISRCTN32849447/elliott
doi:10.1186/1471-2334-9-32
PMCID: PMC2666740  PMID: 19296834
3.  Effect of Maternal Schistosoma mansoni Infection and Praziquantel Treatment During Pregnancy on Schistosoma mansoni Infection and Immune Responsiveness among Offspring at Age Five Years 
Introduction
Offspring of Schistosoma mansoni-infected women in schistosomiasis-endemic areas may be sensitised in-utero. This may influence their immune responsiveness to schistosome infection and schistosomiasis-associated morbidity. Effects of praziquantel treatment of S. mansoni during pregnancy on risk of S. mansoni infection among offspring, and on their immune responsiveness when they become exposed to S. mansoni, are unknown. Here we examined effects of praziquantel treatment of S. mansoni during pregnancy on prevalence of S. mansoni and immune responsiveness among offspring at age five years.
Methods
In a trial in Uganda (ISRCTN32849447, http://www.controlled-trials.com/ISRCTN32849447/elliott), offspring of women treated with praziquantel or placebo during pregnancy were examined for S. mansoni infection and for cytokine and antibody responses to SWA and SEA, as well as for T cell expression of FoxP3, at age five years.
Results
Of the 1343 children examined, 32 (2.4%) had S. mansoni infection at age five years based on a single stool sample. Infection prevalence did not differ between children of treated or untreated mothers. Cytokine (IFNγ, IL-5, IL-10 and IL-13) and antibody (IgG1, Ig4 and IgE) responses to SWA and SEA, and FoxP3 expression, were higher among infected than uninfected children. Praziquantel treatment of S. mansoni during pregnancy had no effect on immune responses, with the exception of IL-10 responses to SWA, which was higher in offspring of women that received praziquantel during pregnancy than those who did not.
Conclusion
We found no evidence that maternal S. mansoni infection and its treatment during pregnancy influence prevalence and intensity of S. mansoni infection or effector immune response to S. mansoni infection among offspring at age five years, but the observed effects on IL-10 responses to SWA suggest that maternal S. mansoni and its treatment during pregnancy may affect immunoregulatory responsiveness in childhood schistosomiasis. This might have implications for pathogenesis of the disease.
Author Summary
Infections with the blood fluke Schistosoma mansoni that cause schistosomiasis (also called Bilharzia) were not usually treated during pregnancy until 2002, but in 2002 a World Health Organization (WHO) team of experts recommended that praziquantel treatment of S. mansoni during pregnancy should be done. However, there was limited information on the effects of maternal S. mansoni infection and treatment during pregnancy on the outcomes in the offspring. We conducted a study in the Entebbe peninsula within Lake Victoria in Uganda to examine whether maternal S. mansoni infection or its treatment during pregnancy may have effects on the children's susceptibility to the infection. The children were examined at age five years old for the level of S. mansoni infection and for immune responses to schistosomes. At five years old few of the children in our study cohort were infected with S. mansoni. Our findings suggest that maternal infection with, or praziquantel treatment of S. mansoni during pregnancy did not influence the level of S. mansoni infection among the offspring. However our findings suggest an influence on regulation of the body's immune responses to schistosomes, which may have some effect on the progress of disease manifestations. This is an issue that needs further investigation.
doi:10.1371/journal.pntd.0002501
PMCID: PMC3798616  PMID: 24147175
4.  Efficacy and Safety of Praziquantel in Preschool-Aged Children in an Area Co-Endemic for Schistosoma mansoni and S. haematobium 
Background
In sub-Saharan Africa the recommended strategy to control schistosomiasis is preventive chemotherapy. Emphasis is placed on school-aged children, but in high endemicity areas, preschool-aged children are also at risk, and hence might need treatment with praziquantel. Since a pediatric formulation (e.g., syrup) is not available outside of Egypt, crushed praziquantel tablets are used, but the efficacy and safety of this treatment regimen is insufficiently studied.
Methodology
We assessed the efficacy and safety of crushed praziquantel tablets among preschool-aged children (<6 years) in the Azaguié district, south Côte d'Ivoire, where Schistosoma mansoni and S. haematobium coexist. Using a cross-sectional design, children provided two stool and two urine samples before and 3 weeks after treatment. Crushed praziquantel tablets, mixed with water, were administered at a dose of 40 mg/kg. Adverse events were assessed and graded 4 and 24 hours posttreatment by interviewing mothers/guardians.
Principal Findings
Overall, 160 preschool-aged children had at least one stool and one urine sample examined with duplicate Kato-Katz thick smears and a point-of-care circulating cathodic antigen (POC-CCA) cassette for S. mansoni, and urine filtration for S. haematobium diagnosis before and 3 weeks after praziquantel administration. According to the Kato-Katz and urine filtration results, we found high efficacy against S. mansoni (cure rate (CR), 88.6%; egg reduction rate (ERR), 96.7%) and S. haematobium (CR, 88.9%; ERR, 98.0%). POC-CCA revealed considerably lower efficacy against S. mansoni (CR, 53.8%). Treatment was generally well tolerated, but moderately severe adverse events (i.e., body and face inflammation), were observed in four Schistosoma egg-negative children.
Conclusions/Significance
Crushed praziquantel administered to preschool-aged children at a dose of 40 mg/kg is efficacious against S. mansoni and S. haematobium in a co-endemic setting of Côte d'Ivoire. Further research is required with highly sensitive diagnostic tools and safety must be investigated in more depth.
Trial Registration
Controlled-Trials.com ISRCTN53172722
Author Summary
Schistosomiasis is a parasitic worm infection that plagues more than 200 million people in the developing world, particularly in sub-Saharan Africa. The current strategy to control schistosomiasis is to regularly administer the deworming drug praziquantel to school-aged children. Younger children before reaching school-age are not included in these deworming campaigns, because they are considered at low risk of schistosomiasis, and because the amount of available data to evaluate the safety of praziquantel in young children is insufficient. We conducted a study in two villages in southern Côte d'Ivoire and examined the stool and urine of more than 250 children (<6 years) for schistosome eggs and antigens. Children were treated with crushed praziquantel tablets (40 mg/kg) and the efficacy of this treatment was determined 3 weeks after treatment. The safety of the treatment was assessed by interviewing mothers of treated children for adverse events (e.g., abdominal pain, diarrhea, and headache). Complete data records were available for 160 children. Praziquantel cleared most of the infections. The treatment was generally well tolerated, but we observed four children who were not infected at the baseline survey who developed face and body inflammation that required close supervision by the study physician.
doi:10.1371/journal.pntd.0001917
PMCID: PMC3516585  PMID: 23236526
5.  Effectiveness of a Pre-treatment Snack on the Uptake of Mass Treatment for Schistosomiasis in Uganda: A Cluster Randomized Trial 
PLoS Medicine  2014;11(5):e1001640.
In a cluster randomized trial, Simon Muhumuza and colleagues examine the effectiveness of a pre-treament snack given to school-aged children on the uptake of mass treatment for schistosomiasis in Uganda.
Please see later in the article for the Editors' Summary
Background
School-based mass treatment with praziquantel is the cornerstone for schistosomiasis control in school-aged children. However, uptake of treatment among school-age children in Uganda is low in some areas. The objective of the study was to examine the effectiveness of a pre-treatment snack on uptake of mass treatment.
Methods and Findings
In a cluster randomized trial carried out in Jinja district, Uganda, 12 primary schools were randomized into two groups; one received education messages for schistosomiasis prevention for two months prior to mass treatment, while the other, in addition to the education messages, received a pre-treatment snack shortly before mass treatment. Four weeks after mass treatment, uptake of praziquantel was assessed among a random sample of 595 children in the snack schools and 689 children in the non-snack schools as the primary outcome. The occurrence of side effects and the prevalence and mean intensity of Schistosoma mansoni infection were determined as the secondary outcomes. Uptake of praziquantel was higher in the snack schools, 93.9% (95% CI 91.7%–95.7%), compared to that in the non-snack schools, 78.7% (95% CI 75.4%–81.7%) (p = 0.002). The occurrence of side effects was lower in the snack schools, 34.4% (95% CI 31.5%–39.8%), compared to that in the non-snack schools, 46.9% (95% CI 42.2%–50.7%) (p = 0.041). Prevalence and mean intensity of S. mansoni infection was lower in the snack schools, 1.3% (95% CI 0.6%–2.6%) and 38.3 eggs per gram of stool (epg) (95% CI 21.8–67.2), compared to that in the non-snack schools, 14.1% (95% CI 11.6%–16.9%) (p = 0.001) and 78.4 epg (95% CI 60.6–101.5) (p = 0.001), respectively.
Conclusions
Our results suggest that provision of a pre-treatment snack combined with education messages achieves a higher uptake compared to the education messages alone. The use a pre-treatment snack was associated with reduced side effects as well as decreased prevalence and intensity of S. mansoni infection.
Trial registration
www.ClinicalTrials.gov NCT01869465
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 240 million people are infected with schistosomes, a parasitic worm found in tropical and sub-tropical fresh water. Schistosomes reproduce in snails, which release free-swimming infectious parasites that burrow into the skin of people when they wash or swim in contaminated water. Once inside a person, the parasites turn into larvae and migrate to the liver, where they become juvenile worms. These mature into 10–20 mm long adult worms and take up residence in the veins draining the gut or bladder where they mate and release eggs, some of which pass into the feces and go back into water where they hatch and infect fresh snails. Most people have no symptoms when they are first infected with schistosomes but some develop a rash or itchy skin. Later symptoms include fever, chills, cough, and muscle aches. Without treatment, schistosomiasis can persist for years, eventually causing liver, gut, bladder, and spleen damage. In Africa alone, schistosomiasis kills about 280,000 people annually.
Why Was This Study Done?
Strategies for the control of schistosomiasis include the provision of clean water and adequate sanitation, and education. However, the cornerstone of control is the reduction of disease through periodic, targeted treatment with the anti-schistosomal drug praziquantel. One group that is targeted for treatment in countries affected by schistosomiasis is school-aged children. For this approach to be successful, experts recommend regular treatment of at least 75% of school-age children at risk of infection. Unfortunately, the uptake of the intervention is often low, partly because children fear praziquantel's side effects, which include diarrhea, and vomiting. The risk of developing side effects can be reduced by eating food just before taking the drug. In this cluster randomized trial (a study that compares outcomes in groups of people randomly assigned to receive different treatments), the researchers investigate whether the provision of a pre-treatment snack improves the uptake of praziquantel among school children in Jinja district of Uganda, a country that has adopted school-based mass drug administration as part of its national schistosomiasis control program. The researchers also investigated whether this intervention reduces the occurrence of side effects attributable to praziquantel, the prevalence of schistosomiasis (the proportion of the population that is infected), and the infection intensity (indicated by the density of eggs in stool).
What Did the Researchers Do and Find?
The researchers randomly assigned 12 primary schools to receive education messages for 2 months before mass treatment with praziquantel or the same education messages plus a mango juice and donut snack just before treatment. The education messages included information about the dangers of schistosome infection, the importance of preventative treatment with praziquantel, and information about taking the drug with food to avoid side effects. Four weeks after mass treatment, praziquantel uptake was assessed by self report in 595 children chosen randomly from the snack schools and 689 children from the no-snack schools. Uptake of praziquantel in the snack and no-snack schools was 93.9% and 78.7%, respectively, a significant difference in outcomes that is unlikely to be a chance event. The occurrence of self-reported side effects, the prevalence of schistosome infection, and the average intensity of infection were all significantly lower in the snack schools than in the no-snack schools.
What Do These Findings Mean?
These findings suggest that the provision of a pre-treatment snack combined with education messages improved uptake of mass treatment for schistosomiasis among school children in Uganda compared to education messages alone. The intervention also reduced the occurrence of side effects, the prevalence of infection, and the infection intensity. Because uptake and the occurrence of side effects were determined by self-report, some children may have provided socially desirable answers. That is, they may have said they took the drug when they didn't because they knew that is what the researchers wanted to hear. However, the infection prevalence and intensity findings validate the self-reported uptake. The researchers conclude that the provision of a snack to mitigate the side effects of praziquantel could have motivated the children to take the treatment. If future trials show that the intervention is cost-effective, the researchers suggest that the provision of pre-treatment food should be integrated into school-based mass treatment programs for schistosomiasis control at the national level in Uganda and in similar settings elsewhere in sub-Saharan Africa.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001640.
The World Health Organization provides detailed information about schistosomiasis (in several languages)
The US Centers for Disease Control and Prevention provides information for the public and for health professionals about all aspects of schistosomiasis (in English and Spanish)
The UK National Health Service Choices website also provides information about schistosomiasis
More information about the Evaluation of Strategies for Improved Uptake of Preventive Treatment for Intestinal Schistosomiasis trial is available
The End Fund, a US not-for-profit organization that aims to tackle schistosomiasis and other neglected tropical diseases, has a personal story about dealing with schistosomiasis
doi:10.1371/journal.pmed.1001640
PMCID: PMC4019501  PMID: 24824051
6.  Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial 
Lancet  2011;377(9759):52-62.
Summary
Background
Helminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections.
Methods
In this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447.
Findings
Data were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30–0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34–0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3–43·7), of diarrhoea was 134·1 (129·2–139·2), and of pneumonia was 22·3 (20·4–24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79–1.14], diarrhoea [1·06, 0·96–1·16], pneumonia [1·11, 0·90–1·38]) or praziquantel treatment (malaria [1·00, 0·84–1·20], diarrhoea [1·07, 0·98–1·18], pneumonia [1·00, 0·80–1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35–1·42) or praziquantel (0·60, 0·29–1·23) treatment.
Interpretation
These results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed.
Funding
Wellcome Trust.
doi:10.1016/S0140-6736(10)61457-2
PMCID: PMC3018567  PMID: 21176950
7.  Impact of Anthelminthic Treatment in Pregnancy and Childhood on Immunisations, Infections and Eczema in Childhood: A Randomised Controlled Trial 
PLoS ONE  2012;7(12):e50325.
Background
Helminth infections may modulate immune responses to unrelated pathogens and allergens; these effects may commence prenatally. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects.
Methods and Findings
A randomised, double-blind, placebo-controlled trial was conducted in Entebbe, Uganda [ISRCTN32849447]. In three independent randomisations, 2507 pregnant women were allocated to receive single-dose albendazole or placebo, and praziquantel or placebo; 2016 of their offspring were randomised to receive quarterly single-dose albendazole or placebo from age 15 months to 5 years. Primary outcomes were post-immunisation recall responses to BCG and tetanus antigens, and incidence of malaria, diarrhoea, and pneumonia; incidence of eczema was an important secondary outcome. Analysis was by intention-to-treat. Of 2345 live births, 1622 (69%) children remained in follow-up at age 5 years. 68% of mothers at enrolment, and 11% of five-year-olds, had helminth infections. Maternal hookworm and Schistosoma mansoni were effectively treated by albendazole and praziquantel, respectively; and childhood hookworm and Ascaris by quarterly albendazole. Incidence rates of malaria, diarrhoea, pneumonia, and eczema were 34, 65, 10 and 5 per 100 py, respectively. Albendazole during pregnancy caused an increased rate of eczema in the children (HR 1.58 (95% CI 1.15–2.17), p = 0.005). Quarterly albendazole during childhood was associated with reduced incidence of clinical malaria (HR 0.85 (95% CI 0.73–0.98), p = 0.03). There were no consistent effects of the interventions on any other outcome.
Conclusions
Routine use of albendazole in pregnancy may not always be beneficial, even in tropical developing countries. By contrast, regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic. Given the low helminth prevalence in our children, the effect of albendazole on malaria is likely to be direct.
Trial registration
Current Controlled Trials ISRCTN32849447
doi:10.1371/journal.pone.0050325
PMCID: PMC3517620  PMID: 23236367
8.  Thioredoxin Glutathione Reductase from Schistosoma mansoni: An Essential Parasite Enzyme and a Key Drug Target 
PLoS Medicine  2007;4(6):e206.
Background
Schistosomiasis—infection with helminth parasites in the genus Schistosoma, including S. mansoni—is a widespread, devastating tropical disease affecting more than 200 million people. No vaccine is available, and praziquantel, the only drug extensively utilized, is currently administered more than 100 million people yearly. Because praziquantel resistance may develop it is essential to identify novel drug targets. Our goal was to investigate the potential of a unique, selenium-containing parasite enzyme thioredoxin glutathione reductase (TGR) as a drug target.
Methods and Findings
Using RNA interference we found that TGR is essential for parasite survival; after silencing of TGR expression, in vitro parasites died within 4 d. We also found that auranofin is an efficient inhibitor of pure TGR (Ki = 10 nM), able to kill parasites rapidly in culture at physiological concentrations (5 μM), and able to partially cure infected mice (worm burden reductions of ~60%). Furthermore, two previously used antischistosomal compounds inhibited TGR activity, suggesting that TGR is a key target during therapy with those compounds.
Conclusions
Collectively, our results indicate that parasite TGR meets all the major criteria to be a key target for antischistosomal chemotherapy. To our knowledge this is the first validation of a Schistosoma drug target using a convergence of both genetic and biochemical approaches.
Using both genetic and biochemical approaches, David Williams and colleagues show that the parasite thioredoxin glutathione reductase meets all the major criteria to be a key target for antischistosomal chemotherapy.
Editors' Summary
Background.
More than 200 million people are infected with schistosomes, a type of parasitic worm. Schistosomes have a complex life cycle that starts with them reproducing in freshwater snails. The snails release free-swimming, infectious parasites that burrow into the skin of people who swim in the contaminated water. Once in the human host, the parasites turn into larvae and migrate to the liver where they become juvenile worms. These mature into 10- to 20-mm-long adult worms and take up long-term residence in the veins draining the gut (Schistosoma mansoni and S. japonicum) or bladder (S. haematobium). Here, the worms mate and release eggs, some of which pass into the feces and so back into water where they hatch and infect fresh snails. Schistosomiasis causes serious health problems (including chronic liver, gut, bladder, and spleen damage) in about 20 million people, making it a disease of great public-health and socioeconomic importance in the developing countries in which it mainly occurs.
Why Was This Study Done?
The only drug available to treat schistosomiasis is praziquantel. Although it is very effective, people regularly get reinfected and need to be retreated once or twice a year. All told, 100 million people are currently being treated with praziquantel. Reliance on a single drug, however, is problematic, as the parasites are likely to develop resistance to the drug over time. The identification of new drug targets in schistosomes is therefore an urgent goal. In this study, the researchers have investigated whether thioredoxin glutathione reductase (TGR), a parasitic enzyme with several functions, might be a key target for antischistosomal chemotherapy. They chose this enzyme because adult worms need to make antioxidants (chemicals that prevent oxygen from damaging cells) to protect themselves against the human immune response. Antioxidant production in these worms depends on TGR; in mammalian cells, two specialized enzymes do its job. The researchers reasoned, therefore, that TGR might be an essential parasite protein and a potentially important drug target.
What Did the Researchers Do and Find?
The researchers made large quantities of pure TGR and tested its activity against various substrates. The enzymatic properties and substrate preferences of TGR, they found, differed somewhat from those of its mammalian counterparts. They then screened different types of compounds for their ability to inhibit TGR. Praziquantel had no effect on TGR activity, but two antischistosomal compounds that are no longer used, potassium antimonyl tartrate and oltipraz, inhibited the enzyme. The most potent inhibitor of TGR, however, was a gold-containing complex called auranofin, low levels of which inhibited TGR in test tubes, completely killed larval, juvenile, and adult parasites living in laboratory dishes within hours, and more than halved the worm burden in infected mice. Finally, the researchers used a technique called RNA silencing to test the importance of TGR for worm survival. Fragments of double-stranded RNA (dsRNA) stop proteins being made from messenger RNA that contains an identical sequence. The addition of TGR dsRNA to larval parasites in a dish greatly reduced TGR enzyme activity and killed nearly all the parasites within days.
What Do These Findings Mean?
These findings suggest TGR as a key target for antischistosomal drug development. Indeed, the discovery that two previously used antischistosomal compounds inhibit TGR suggests that the enzyme has already served as a target protein. The RNA silencing experiment shows that TGR is essential for parasite survival, and the biochemical analyses indicate that TGR and its mammalian counterparts have different substrate specificities. Thus, it should be possible to find compounds that inhibit TGR but have much less effect on the mammalian enzymes. This is certainly true for auranofin, a drug used to treat rheumatoid arthritis. Whether auranofin will be an effective treatment for schistosomiasis remains to be seen—an agent that completely kills schistosomes in animals would be preferable. However, even a 50% reduction in worm burden would decrease the human health problems caused by schistosomiasis, and a combination of auranofin (or another TGR inhibitor) with an agent that works by a different mechanism might be more effective and would also reduce the chances of the parasite developing drug resistance.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040206.
World Health Organization provides information on schistosomiasis, including a fact sheet in English, Spanish, French, Arabic, Chinese, and Russian
US Centers for Disease Control and Prevention provide information for the public and for professionals on schistosomiasis
MedlinePlus encyclopedia includes an entry on schistosomiasis (in English and Spanish)
The Schistosomiasis Control Initiative has information on the disease and its control
Wikipedia has a page on schistosomiasis that is available in several languages (note: Wikipedia is a free online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0040206
PMCID: PMC1892040  PMID: 17579510
9.  Predicted Impact of Mass Drug Administration on the Development of Protective Immunity against Schistosoma haematobium 
Previous studies suggest that protective immunity against Schistosoma haematobium is primarily stimulated by antigens from dying worms. Praziquantel treatment kills adult worms, boosting antigen exposure and protective antibody levels. Current schistosomiasis control efforts use repeated mass drug administration (MDA) of praziquantel to reduce morbidity, and may also reduce transmission. The long-term impact of MDA upon protective immunity, and subsequent effects on infection dynamics, are not known. A stochastic individual-based model describing levels of S. haematobium worm burden, egg output and protective parasite-specific antibody, which has previously been fitted to cross-sectional and short-term post-treatment egg count and antibody patterns, was used to predict dynamics of measured egg output and antibody during and after a 5-year MDA campaign. Different treatment schedules based on current World Health Organisation recommendations as well as different assumptions about reductions in transmission were investigated. We found that antibody levels were initially boosted by MDA, but declined below pre-intervention levels during or after MDA if protective immunity was short-lived. Following cessation of MDA, our models predicted that measured egg counts could sometimes overshoot pre-intervention levels, even if MDA had had no effect on transmission. With no reduction in transmission, this overshoot occurred if protective immunity was short-lived. This implies that disease burden may temporarily increase following discontinuation of treatment, even in the absence of any reduction in the overall transmission rate. If MDA was additionally assumed to reduce transmission, a larger overshoot was seen across a wide range of parameter combinations, including those with longer-lived protective immunity. MDA may reduce population levels of immunity to urogenital schistosomiasis in the long-term (3–10 years), particularly if transmission is reduced. If MDA is stopped while S. haematobium is still being transmitted, large rebounds (up to a doubling) in egg counts could occur.
Author Summary
Urogenital schistosomiasis, caused by schistosome blood flukes, infects more than 100 million people in sub-Saharan Africa. Current control efforts involve regularly treating all school-aged children with the drug praziquantel, which kills schistosome worms. Earlier work by our group suggests that protective immunity against schistosomes is mainly stimulated by dying worms, and that in the short term, praziquantel treatment boosts immunity through killing worms. The longer-term impact upon the development of protective immunity is unknown. In this paper, we used a mathematical model which was able to replicate short-term patterns of infection and antibody to predict the long-term changes in antibody and infection levels that would occur during and after a 5-year treatment programme. We found that the longevity of protective immunity was particularly influential. Short-lived protective immunity was associated with levels of protective antibody declining below pre-treatment levels in the long term, and also with an increase in measured infection levels (eggs in urine) to peak above pre-treatment levels after the treatment programme finished. Antibody declines and infection peaks post-treatment were also predicted if treatment programmes reduced schistosome transmission. These results highlight the possible negative consequences of ceasing mass treatment programmes once they have commenced.
doi:10.1371/journal.pntd.0003059
PMCID: PMC4117464  PMID: 25079601
10.  Cytokine Responses to the Anti-schistosome Vaccine Candidate Antigen Glutathione-S-transferase Vary with Host Age and Are Boosted by Praziquantel Treatment 
Background
Improved helminth control is required to alleviate the global burden of schistosomiasis and schistosome-associated pathologies. Current control efforts rely on the anti-helminthic drug praziquantel (PZQ), which enhances immune responses to crude schistosome antigens but does not prevent re-infection. An anti-schistosome vaccine based on Schistosoma haematobium glutathione-S-transferase (GST) is currently in Phase III clinical trials, but little is known about the immune responses directed against this antigen in humans naturally exposed to schistosomes or how these responses change following PZQ treatment.
Methodology
Blood samples from inhabitants of a Schistosoma haematobium-endemic area were incubated for 48 hours with or without GST before (n = 195) and six weeks after PZQ treatment (n = 107). Concentrations of cytokines associated with innate inflammatory (TNFα, IL-6, IL-8), type 1 (Th1; IFNγ, IL-2, IL-12p70), type 2 (IL-4, IL-5, IL-13), type 17 (IL-17A, IL-21, IL-23p19) and regulatory (IL-10) responses were quantified in culture supernatants via enzyme-linked immunosorbent assay (ELISA). Factor analysis and multidimensional scaling were used to analyse multiple cytokines simultaneously.
Principal Findings
A combination of GST-specific type 2 (IL-5 and IL-13) and regulatory (IL-10) cytokines was significantly lower in 10–12 year olds, the age group at which S. haematobium infection intensity and prevalence peak, than in 4–9 or 13+ year olds. Following PZQ treatment there was an increase in the number of participants producing detectable levels of GST-specific cytokines (TNFα, IL-6, IL-8, IFNγ, IL-12p70, IL-13 and IL-23p19) and also a shift in the GST-specific cytokine response towards a more pro-inflammatory phenotype than that observed before treatment. Participant age and pre-treatment infection status significantly influenced post-treatment cytokine profiles.
Conclusions/Significance
In areas where schistosomiasis is endemic host age, schistosome infection status and PZQ treatment affect the cellular cytokine response to GST. Thus the efficacy of a GST-based vaccine may also be shaped by the demographic and epidemiological characteristics of targeted populations.
Author Summary
Schistosomiasis is caused by infection with Schistosoma spp. parasites, for which the main treatment is the drug praziquantel (PZQ). Since PZQ does not prevent reinfection, an anti-schistosome vaccine based on the Schistosoma haematobium enzyme glutathione-S-transferase (GST) is being developed. In this study we investigated the GST-specific immune responses of people naturally exposed to schistosomes and the affect that PZQ has on these responses. We cultured blood samples from a schistosome-exposed community with GST before and six weeks after PZQ treatment and measured a range of soluble proteins (cytokines) in culture supernatants as indicators of blood cell activation and phenotype. Before treatment, GST-specific cytokine responses varied with host age, particularly in children with high intensity schistosome infections. Following treatment, GST activated blood samples from more individuals to produce a broader range of cytokines and the combination of GST-specific cytokine responses reflected a more pro-inflammatory immune phenotype than that observed pre-treatment. Post-treatment responses varied according to host age and pre-treatment infection status. Taken together, our study suggests that current and future GST-based vaccine trials should take host age, schistosome infection status and PZQ treatment history into account since these factors influence GST-specific immune activation.
doi:10.1371/journal.pntd.0002846
PMCID: PMC4014416  PMID: 24810615
11.  Effects of Deworming during Pregnancy on Maternal and Perinatal Outcomes in Entebbe, Uganda: A Randomized Controlled Trial 
Background
Helminth infections during pregnancy may be associated with adverse outcomes, including maternal anemia, low birth weight, and perinatal mortality. Deworming during pregnancy has therefore been strongly advocated, but its benefits have not been rigorously evaluated.
Methods
In Entebbe, Uganda, 2507 pregnant women were recruited to a randomized, double-blind, placebo-controlled trial investigating albendazole and praziquantel in a 2 × 2 factorial design [ISRCTN32849447]. Hematinics and sulphadoxine-pyrimethamine for presumptive treatment of malaria were provided routinely. Maternal and perinatal outcomes were recorded. Analyses were by intention to treat.
Results
At enrollment, 68% of women had helminths, 45% had hookworm, 18% had Schistosoma mansoni infection; 40% were anemic (hemoglobin level, <11.2 g/dL). At delivery, 35% were anaemic; there was no overall effect of albendazole (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.79–1.15) or praziquantel (OR, 1.00; 95% CI, 0.83–1.21) on maternal anemia, but there was a suggestion of benefit of albendazole among women with moderate to heavy hookworm (OR, 0.45; 95% CI, 0.21–0.98; P = .15 for interaction). There was no effect of either anthelminthic treatment on mean birth weight (difference in mean associated with albendazole: −0.00 kg; 95% CI, −0.05 to 0.04 kg; difference in mean associated with praziquantel: −0.01 kg; 95% CI, −0.05 to 0.04 kg) or on proportion of low birth weight. Anthelminthic use during pregnancy showed no effect on perinatal mortality or congenital anomalies.
Conclusions
In our study area, where helminth prevalence was high but infection intensity was low, there was no overall effect of anthelminthic use during pregnancy on maternal anemia, birth weight, perinatal mortality, or congenital anomalies. The possible benefit of albendazole against anemia in pregnant women with heavy hookworm infection warrants further investigation.
doi:10.1086/649924
PMCID: PMC2857962  PMID: 20067426
12.  The effect of anthelminthic treatment during pregnancy on HIV plasma viral load; results from a randomised, double blinded, placebo-controlled trial in Uganda 
Background
To investigate the effect of helminth infections and their treatment during pregnancy on HIV load, we conducted a 2×2 factorial randomised controlled trial of albendazole versus placebo and praziquantel versus placebo in pregnant women in Entebbe, Uganda
Methods
Two hundred and sixty-four HIV-infected women from the Entebbe Mother and Baby Study (ISRCTN32849447) were included in this analysis. Women were tested for helminth infections at enrolment and mean HIV load was compared between infected and uninfected groups. The effect of anthelminthic treatment on HIV load was evaluated at six weeks post-treatment and at delivery using linear regression and adjusting for enrolment viral load.
Results
Hookworm and Trichuris infections were associated with higher mean viral load at enrolment (adjusted mean difference 0.24log10 copies/ml, 95% confidence interval (CI): 0.01 to 0.47, p=0.03 and 0.37log10 copies/ml, 95%CI: 0.00 to 0.74, p=0.05, respectively). There were no associations between viral load and other helminth species. There was some evidence that albendazole reduced viral load at six weeks post-treatment (adjusted mean difference −0.17, 95% CI: −0.36 to 0.01, p=0.07), however this effect did not differ according to mother’s hookworm infection status and had diminished at delivery (adjusted mean difference −0.11, 95% CI: −0.28 to 0.07, p=0.23). There was no effect of praziquantel treatment on HIV load at any time point.
Conclusions
Infection with some soil-transmitted helminth species is associated with increased HIV load in pregnancy. Treatment with albendazole causes a small decrease in HIV load, however this may not represent a direct effect of worm removal.
doi:10.1097/QAI.0b013e3182511e42
PMCID: PMC3383620  PMID: 22728750
HIV; viral load; helminths; anthelminthic treatment; clinical trial
13.  Transcriptional Responses of In Vivo Praziquantel Exposure in Schistosomes Identifies a Functional Role for Calcium Signalling Pathway Member CamKII 
PLoS Pathogens  2013;9(3):e1003254.
Treatment for clinical schistosomiasis has relied centrally on the broad spectrum anthelmintic praziquantel; however, there is limited information on its mode of action or the molecular response of the parasite. This paper presents a transcriptional and functional approach to defining the molecular responses of schistosomes to praziquantel. Differential gene expression in Schistosoma japonicum was investigated by transcriptome-wide microarray analysis of adult worms perfused from infected mice after 0.5 to 24 hours after oral administration of sub-lethal doses of praziquantel. Genes up-regulated initially in male parasites were associated with “Tegument/Muscle Repair” and “Lipid/Ion Regulation” functions and were followed by “Drug Resistance” and “Ion Regulation” associated genes. Prominent responses induced in female worms included up-regulation of “Ca2+ Regulation” and “Drug Resistance” genes and later by transcripts of “Detoxification” and “Pathogen Defense” mechanisms. A subset of highly over-expressed genes, with putative drug resistance/detoxification roles or Ca2+-dependant/modulatory functions, were validated by qPCR. The leading candidate among these was CamKII, a putative calcium/calmodulin-dependent protein kinase type II delta chain. RNA interference was employed to knockdown CamKII in S. japonicum to determine the role of CamKII in the response to praziquantel. After partial-knockdown, schistosomes were analysed using IC50 concentrations (50% worm motility) and quantitative monitoring of parasite movement. When CamKII transcription was reduced by 50–69% in S. japonicum, the subsequent effect of an IC50 dosage of praziquantel was exacerbated, reducing motility from 47% to 27% in female worms and from 61% to 23% in males. These observations indicated that CamKII mitigates the effects of praziquantel, probably through stabilising Ca2+ fluxes within parasite muscles and tegument. Together, these studies comprehensively charted transcriptional changes upon exposure to praziquantel and, notably, identified CamKII as potentially central to the, as yet undefined, mode of action of praziquantel.
Author Summary
Schistosome infected mice were treated orally with a single sub-lethal dose of the anthelmintic praziquantel. Parasites were subsequently isolated 0.5–24 hours later and analysed by gene expression microarray. The transcriptional pattern was influenced by the sex of the parasite. Males up-regulated genes associated with surface integrity, muscle function, ion regulation and drug resistance. While for female worms, genes associated with calcium regulation, drug resistance, detoxification and pathogen defense were transcriptionally elevated. Based on these findings, genes with putative ion homeostasis or drug metabolism roles were further investigated for their prospective roles praziquantel action, using the gene silencing procedure RNA interference. The leading gene was CamKII (calcium/calmodulin-dependent protein kinase type II), a member of the Calcium Signalling Pathway. A quantitative assay for parasite motility during praziquantel exposure was used to study worms in which the CamKII gene had been partially silenced. When CamKII transcription was reduced, the effects of praziquantel were augmented, visualised by reduced parasite movement. These functional studies indicate a key role for the kinase CamKII in the mode of action of the praziquantel, and suggest that future studies on this enzyme and other calcium signaling pathway components will be constructive in understanding how praziquantel kills schistosomes.
doi:10.1371/journal.ppat.1003254
PMCID: PMC3610926  PMID: 23555262
14.  Rapidly Boosted Plasma IL-5 Induced by Treatment of Human Schistosomiasis haematobium Is Dependent on Antigen Dose, IgE and Eosinophils 
Background
IgE 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 Findings
The 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/Significance
Early 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.
Author Summary
Partial human immunity to infection with trematode worms of the genus Schistosoma is associated with IgE specific to adult worm-derived antigens and eosinophils. Treatment studies of Schistosoma infection allow us to examine the temporal features of the immune response post-antigen exposure, their inter-dependence and their relationship with re-infection levels. Here the boosted levels of the cytokine IL-5, measured at 24-hrs post-treatment of a Malian cohort, aged 5–40 yrs, were found to be significantly associated with pre-treatment levels of IgE to worm-derived antigens and eosinophil number, linking this rapid response to two of the main correlates of human immunity to these parasites. The IL-5 levels at 24-hr were in turn related to increased eosinophil counts and SWA-IgE levels at 9-wks post-treatment. In line with previous studies SWA-IgE was associated with resistance to re-infection. The study therefore identifies temporal relationships between immune mediators prior to and post treatment induced antigen exposure that are associated with resistance to re-infection.
doi:10.1371/journal.pntd.0002149
PMCID: PMC3610616  PMID: 23556029
15.  Dual Targeting of Insulin and Venus Kinase Receptors of Schistosoma mansoni for Novel Anti-schistosome Therapy 
Background
Chemotherapy of schistosomiasis relies on a single drug, Praziquantel (PZQ) and mass-use of this compound has led to emergence of resistant strains of Schistosoma mansoni, therefore pointing out the necessity to find alternative drugs. Through their essential functions in development and metabolism, receptor tyrosine kinases (RTK) could represent valuable drug targets for novel anti-schistosome chemotherapies. Taking advantage of the similarity between the catalytic domains of S. mansoni insulin receptors (SmIR1 and SmIR2) and Venus Kinase Receptors (SmVKR1 and SmVKR2), we studied the possibility to fight schistosomes by targeting simultaneously the four receptors with a single drug.
Methodology/Principal Findings
Several commercial RTK inhibitors were tested for their potential to inhibit the kinase activities of SmIR1, SmIR2, SmVKR1 and SmVKR2 intracellular domains (ICD) expressed in Xenopus oocytes. We measured the inhibitory effect of chemicals on meiosis resumption induced by the active ICD of the schistosome kinases in oocytes. The IR inhibitor, tyrphostin AG1024, was the most potent inhibitory compound towards SmIR and SmVKR kinases. In vitro studies then allowed us to show that AG1024 affected the viability of both schistosomula and adult worms of S. mansoni. At micromolar doses, AG1024 induced apoptosis and caused schistosomula death in a dose-dependent manner. In adult worms, AG1024 provoked alterations of reproductive organs, as observed by confocal laser scanner microscopy. With 5 µM AG1024, parasites were no more feeding and laying eggs, and they died within 48 h with 10 µM.
Conclusion/Significance
IRs and VKRs are essential in S. mansoni for key biological processes including glucose uptake, metabolism and reproduction. Our results demonstrate that inhibiting the kinase potential and function of these receptors by a single chemical compound AG1024 at low concentrations, leads to death of schistosomula and adult worms. Thus, AG1024 represents a valuable hit compound for further design of anti-kinase drugs applicable to anti-schistosome chemotherapy.
Author Summary
Schistosomiasis is a chronic, debilitating disease that affects over 200 million people in the world. The pathology of schistosomiasis is caused mainly by host immune responses to parasite eggs and due to the formation of granulomas in liver and other tissues. There is no vaccine for schistosomiasis and treatment relies essentially on a single drug, Praziquantel. However, reduced susceptibility of schistosome isolates to Praziquantel has been reported, raising serious concerns about the need to develop new drugs against schistosomes. Receptor tyrosine kinases (RTKs) control many cellular and developmental processes and they are important targets in cancer therapy. In this paper, we have investigated the possibility to fight schistosomes by targeting with a single drug, insulin receptors (IRs) involved in parasite growth and metabolism and Venus Kinase Receptors (VKRs) which are unusual IR-like RTKs expressed in the parasite reproductive organs of Schistosoma mansoni. Diverse RTK inhibitors have been tested on kinase activities of these RTKs. The well-known IR inhibitor, tyrphostin AG1024, was demonstrated to be a potent inhibitor of both S. mansoni VKRs and IRs, able to induce in vitro death of larvae and adult worms at micromolar doses. AG1024 could represent a good hit compound for the development of novel drugs against schistosomes.
doi:10.1371/journal.pntd.0002226
PMCID: PMC3656120  PMID: 23696913
16.  Schistosomiasis Mansoni: Novel Chemotherapy Using a Cysteine Protease Inhibitor 
PLoS Medicine  2007;4(1):e14.
Background
Schistosomiasis is a chronic, debilitating parasitic disease infecting more than 200 million people and is second only to malaria in terms of public health importance. Due to the lack of a vaccine, patient therapy is heavily reliant on chemotherapy with praziquantel as the World Health Organization–recommended drug, but concerns over drug resistance encourage the search for new drug leads.
Methods and Findings
The efficacy of the vinyl sulfone cysteine protease inhibitor K11777 was tested in the murine model of schistosomiasis mansoni. Disease parameters measured were worm and egg burdens, and organ pathology including hepato- and splenomegaly, presence of parasite egg–induced granulomas in the liver, and levels of circulating alanine aminotransferase activity as a marker of hepatocellular function. K11777 (25 mg/kg twice daily [BID]), administered intraperitoneally at the time of parasite migration through the skin and lungs (days 1–14 postinfection [p.i.]), resulted in parasitologic cure (elimination of parasite eggs) in five of seven cases and a resolution of other disease parameters. K11777 (50 mg/kg BID), administered at the commencement of egg-laying by mature parasites (days 30–37 p.i.), reduced worm and egg burdens, and ameliorated organ pathology. Using protease class-specific substrates and active-site labeling, one molecular target of K11777 was identified as the gut-associated cathepsin B1 cysteine protease, although other cysteine protease targets are not excluded. In rodents, dogs, and primates, K11777 is nonmutagenic with satisfactory safety and pharmacokinetic profiles.
Conclusions
The significant reduction in parasite burden and pathology by this vinyl sulfone cysteine protease inhibitor validates schistosome cysteine proteases as drug targets and offers the potential of a new direction for chemotherapy of human schistosomiasis.
A significant reduction in parasite burden and pathology by a vinyl sulfone cysteine protease inhibitor suggests a new direction for chemotherapy of human schistosomiasis.
Editors' Summary
Background.
Schistosomiasis, a disease caused by a type of parasitic flatworm that lives in the blood, infects around 200 million people worldwide. The disease is a serious problem in sub-Saharan Africa, South America, China, and southeast Asia. Although this disease can kill, it is better known as a lifelong chronic infection with debilitating symptoms mainly due to an immune reaction raised against parasite eggs trapped in the liver, spleen, and gut. The worm's life cycle is complicated and involves a free-swimming form that emerges from certain types of snails that live in lakes and ponds. This can penetrate the skin of people in contact with the water. After a period spent in the skin and around the lungs, the parasites move to veins around the gut, and develop into adult worms that mate and lay eggs. These eggs eventually return to the water through the person's feces or urine. A particular group of proteins called cysteine proteases are thought to be very important in the biology of these worms, especially in their function as digestive enzymes in the parasite's gut. These proteases could represent an exciting opportunity for development of new drugs to treat schistosomiasis. The researchers are looking at whether it is possible to block the activity of cysteine proteases and, as a result, kill the worms or prevent them from developing and thriving.
Why Was This Study Done?
At the moment there is only one drug, praziquantel, in common use for treatment of schistosomiasis; it is cheap and effective. However many organizations are worried about relying on a single drug to treat a serious disease which affects so many people worldwide. The research group here has been looking at molecules that block cysteine protease activity, to see if any of these could be good drug candidates for schistosomiasis. One molecule they have been looking at goes by the name of K11777, which is under evaluation as a drug candidate for another parasitic infection (Chagas' disease). Here, the researchers wanted to find out whether K11777 had any activity against schistosome worms.
What Did the Researchers Do and Find?
In this study, the researchers deliberately infected laboratory mice with the schistosome parasite. These mice were then either injected with K11777 solution twice daily, or with equivalent volumes of water as a comparison. The researchers examined the effects of injecting K11777 either “early” in infection (using a 14 day course, starting 1 day after infection with the parasite) or “late” in the worms' development (using an 8 day treatment course starting 30 days after infection). The outcomes used as measures of success of treatment with K11777 included the number of worms recovered from mice after euthanasia, the number of worm eggs counted in the liver; the extent of the damage to the liver; and finally, the researchers also looked at activity levels of cysteine proteases in the worms themselves, in particular, those proteases associated with the parasite gut.
The results of the early-treatment experiment showed a substantial decrease in worm numbers and egg production. In five of the seven mice treated, eggs were eliminated entirely. Also, there was little measurable liver damage. For the late-treatment experiment, decreased burdens of worms and eggs in the livers of K11777 treated mice were also found, and there was less damage to the livers. Those worms surviving treatment and removed from mice also had much less activity of gut cysteine proteases suggesting that K11777 exerts its effects by targeting worm cysteine proteases.
What Do These Findings Mean?
These experiments show that K11777 is a potent antischistosomal agent in mice. It might therefore be a good ‘candidate' molecule for developing future treatments for human schistosomiasis. However, before that stage can be reached, it would be important to carry out clinical trials to test whether K11777 is both safe and effective in schistosomiasis patients. Full details as to which worm cysteine protease(s) is the critical target of K11777 would also need to be worked out, and more information would be needed as to whether the dosing plan used in this study (twice-daily injections for a week to 14 days) can be decreased.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040014.
World Health Organization pages about schistosomiasis including links to details on further research into the disease
Information from the US Centers for Disease Control for patients and health professionals about schistosomiasis
Wikipedia pages on schistosomiasis (Wikipedia is an internet encyclopedia anyone can edit)
PLoS Neglected Tropical Diseases is a new journal from the Public Library of Science that is devoted to publishing research on the world's most neglected tropical diseases, including schistosomiasis
doi:10.1371/journal.pmed.0040014
PMCID: PMC1764436  PMID: 17214506
17.  Examining the Relationship between Urogenital Schistosomiasis and HIV Infection 
Background
Urogenital schistosomiasis, caused by infection with Schistosoma haematobium, is widespread and causes substantial morbidity on the African continent. The infection has been suggested as an unrecognized risk factor for incident HIV infection. Current guidelines recommend preventive chemotherapy, using praziquantel as a public health tool, to avert morbidity due to schistosomiasis. In individuals of reproductive age, urogenital schistosomiasis remains highly prevalent and, likely, underdiagnosed. This comprehensive literature review was undertaken to examine the evidence for a cause-effect relationship between urogenital schistosomiasis and HIV/AIDS. The review aims to support discussions of urogenital schistosomiasis as a neglected yet urgent public health challenge.
Methodology/Principal Findings
We conducted a systematic search of the literature including online databases, clinical guidelines, and current medical textbooks. We describe plausible local and systemic mechanisms by which Schistosoma haematobium infection could increase the risk of HIV acquisition in both women and men. We also detail the effects of S. haematobium infection on the progression and transmissibility of HIV in co-infected individuals. We briefly summarize available evidence on the immunomodulatory effects of chronic schistosomiasis and the implications this might have for populations at high risk of both schistosomiasis and HIV.
Conclusions/Significance
Studies support the hypothesis that urogenital schistosomiasis in women and men constitutes a significant risk factor for HIV acquisition due both to local genital tract and global immunological effects. In those who become HIV-infected, schistosomal co-infection may accelerate HIV disease progression and facilitate viral transmission to sexual partners. Establishing effective prevention strategies using praziquantel, including better definition of treatment age, duration, and frequency of treatment for urogenital schistosomiasis, is an important public health priority. Our findings call attention to this pressing yet neglected public health issue and the potential added benefit of scaling up coverage of schistosomal treatment for populations in whom HIV infection is prevalent.
Author Summary
Urogenital schistosomiasis is a parasitic infection caused by a worm, Schistosoma haematobium, which lives in the bloodstream of infected individuals. It affects at least 112 million people, mostly in sub-Saharan Africa, and has been suggested to be a risk factor for becoming infected with HIV. We reviewed publications in order to examine whether it seems likely that this parasitic infection could be a risk factor for HIV. Evidence from many types of studies supports the hypothesis that urogenital schistosomiasis does increase a person's risk of becoming infected with HIV. Studies also suggest that individuals who have both urogenital schistosomiasis and HIV have a more aggressive HIV infection and can more easily transmit HIV to their sexual partners. Praziquantel is an oral, nontoxic, inexpensive medication that is safe in pregnancy and is recommended for treatment of schistosomiasis. In areas where both infections co-exist, regular administration of praziquantel both to young girls and to sexually-active women may be an important approach to reducing HIV transmission. Our findings support the importance of making praziquantel more available to people who live in areas of the world where both urogenital schistosomiasis and HIV infection are widespread.
doi:10.1371/journal.pntd.0001396
PMCID: PMC3232194  PMID: 22163056
18.  Efficacy of praziquantel and artemisinin derivatives for the treatment and prevention of human schistosomiasis: a systematic review and meta-analysis 
Parasites & Vectors  2011;4:201.
Background
Praziquantel has been used as first-line drug for chemotherapy of schistosomiasis since 1984. Besides praziquantel, artemether and artesunate have also been used for the control of this infectious disease since late 1990s. In this article, we conducted a systematic review and meta-analysis to evaluate the antischistosomal efficacy of different medication strategies including monotherapy or combination therapies of these drugs.
Results
A number of 52 trials from 38 articles published in peer-reviewed journals before July 2011 were selected for analysis after searching the following literature databases: the Cochrane Library, PubMed/Medline, ISI Web of Science, Chinese Biomedicine Literature Database, and China National Knowledge Infrastructure. Our meta-analyses showed that a dosage of 30-60 mg/kg praziquantel compared with placebo produced a protection rate of about 76% (95% CI: 67%-83%) for treating human schistosomiasis, which varied from 70% to 76% with no significant differences among the subspecies S. haematobium, S. japonicum or S. mansoni. Protection rates were higher when praziquantel doses were elevated, as concluded from the nRCTs results: the protection rate of praziquantel at 40 mg/kg was 52% (95% CI: 49%-55%), and it increased to 91% (95% CI: 88%-92%) when the dosages were elevated to 60/80/100 mg/kg divided two or more doses. Multiple doses of artemether or artesunate over 1- or 2-week intervals resulted in protection rates of 65% to 97% for preventing schistosomiasis, and increased doses and shorter medication intervals improved their efficacies. Praziquantel and artemisinin derivatives (artemether or artesunate) in combination resulted in a higher protection rate of 84% (95% CI: 64%-91%) than praziquantel monotherapy for treatment. praziquantel and artesunate in combination had a great protection rate of 96% (95% CI: 78%-99%) for preventing schistosomes infection.
Conclusions
According to the results, praziquantel remains effective in schistosomiasis treatment, and multiple doses would improve its efficacy; meanwhile, praziquantel is also a good drug for preventing acute schistosomiasis morbidity. It's better to use multiple doses of artemether or artesunate with 1- or 2-week intervals for prevention against schistosome infection. Praziquantel and artemether or artesunate in combination perform better in treatment than praziquantel monotherapy, and they are especially suitable for treating the patients with repeated exposure to infected water.
doi:10.1186/1756-3305-4-201
PMCID: PMC3207908  PMID: 22004571
human schistosomiasis; praziquantel; artemether; artesunate; efficacy; meta-analysis
19.  Integrated Analysis of Innate, Th1, Th2, Th17, and Regulatory Cytokines Identifies Changes in Immune Polarisation Following Treatment of Human Schistosomiasis 
The Journal of Infectious Diseases  2012;208(1):159-169.
Background. Schistosomiasis elicits cross-regulatory immune responses, but it is unclear how antihelminthic treatment affects this balance. This study integrates data on 13 cytokines elicited by 3 schistosome to examine how praziquantel treatment alters immune polarization and whether post-treatment cytokine profiles influence reinfection status.
Methods. Venous blood from 72 Schistosoma haematobium–exposed participants was cultured with schistosome egg, adult worm, and cercaria antigens pre– and 6 weeks post–praziquantel treatment. Innate inflammatory (tumor necrosis factor α [TNF-α], interleukin(IL-)-6, IL-8), Th1 (interferon γ [IFN-γ], IL-2, IL-12p70), Th2 (IL-4, IL-5, IL-13), Th17 (IL-17A, IL-21, IL-23p19), and regulatory (IL-10) cytokines were quantified via enzyme-linked immunosorbent assay. Cytokine data was integrated using nonmetric multidimensional scaling and factor analysis.
Results. Egg-specific cytokine phenotypes became more proinflammatory post-treatment due to increased TNF-α, IL-6, IL-8, IFN-γ, IL-12p70, and IL-23 levels. Post-treatment cercariae-specific responses were also more proinflammatory reflecting elevated IL-8. In contrast, post-treatment adult worm-specific responses were less inflammatory, reflecting lower post-treatment IL-6. A combination of egg-induced IL-6, IL-12p70, IL-21, and IL-23 and adult worm-induced IL-5 and IL-21 post-treatment was associated with reduced reinfection risk 18 months later.
Conclusions. Praziquantel treatment markedly alters polarization of schistosome-specific cytokine responses, and these changes, particularly in response to egg-stage parasites, may promote resistance to reinfection.
doi:10.1093/infdis/jis524
PMCID: PMC3666130  PMID: 23045617
Human; helminth; cytokine; schistosomiasis; immune response; praziquantel
20.  Schistosoma japonicum Soluble Egg Antigens Attenuate Invasion in a First Trimester Human Placental Trophoblast Model 
Background
Schistosomiasis affects nearly 40 million women of reproductive age, and is known to elicit a pro-inflammatory signature in the placenta. We have previously shown that antigens from schistosome eggs can elicit pro-inflammatory cytokine production from trophoblast cells specifically; however, the influence of these antigens on other characteristics of trophoblast function, particularly as it pertains to placentation in early gestation, is unknown. We therefore sought to determine the impact of schistosome antigens on key characteristics of first trimester trophoblast cells, including migration and invasion.
Methods
First trimester HTR8/SVneo trophoblast cells were co-cultured with plasma from pregnant women with and without schistosomiasis or schistosome soluble egg antigens (SEA) and measured cytokine, cellular migration, and invasion responses.
Results
Exposure of HTR8 cells to SEA resulted in a pro-inflammatory, anti-invasive signature, characterized by increased pro-inflammatory cytokines (IL-6, IL-8, MCP-1) and TIMP-1. Additionally, these cells displayed 62% decreased migration and 2.7-fold decreased invasion in vitro after treatment with SEA. These results are supported by increased IL-6 and IL-8 in the culture media of HTR8 cells exposed to plasma from Schistosoma japonica infected pregnant women.
Conclusions
Soluble egg antigens found in circulation during schistosome infection increase pro-inflammatory cytokine production and inhibit the mobility and invasive characteristics of the first trimester HTR8/SVneo trophoblast cell line. This is the first study to assess the impact of schistosome soluble egg antigens on the behavior of an extravillous trophoblast model and suggests that schistosomiasis in the pre-pregnancy period may adversely impact placentation and the subsequent health of the mother and newborn.
Author Summary
Approximately 40 million women of childbearing age suffer from schistosome infection globally at any given time. Multiple studies in rodent models, as well as a few reports in humans, suggest that schistosome infection results in poor pregnancy outcomes. We have previously shown that antigens released from schistosome eggs result in a pronounced pro-inflammatory response in syncytialized third trimester trophoblasts. Herein, we examine the effect of schistosome egg antigens on a first trimester trophoblast cell line, an accepted model for early placental development. Not only is the pro-inflammatory response recapitulated in this model system, but we also observed a decrease in migration and invasion of trophoblast cells after exposure to these antigens. Both migration and invasion are key aspects in early placental development, and inadequate invasion has been implicated in pregnancy-related diseases such as growth restriction and preeclampsia. This study is the first to examine the impact of schistosome antigens on early placental development, and may have implications for the subsequent health of both the pregnancy and the child.
doi:10.1371/journal.pntd.0002253
PMCID: PMC3675010  PMID: 23755313
21.  A Multicentre Randomized Controlled Trial of the Efficacy and Safety of Single-Dose Praziquantel at 40 mg/kg vs. 60 mg/kg for Treating Intestinal Schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil 
Background
Praziquantel at 40 mg/kg in a single dose is the WHO recommended treatment for all forms of schistosomiasis, but 60 mg/kg is also deployed nationally.
Methodology/Principal Findings
Four trial sites in the Philippines, Mauritania, Tanzania and Brazil enrolled 856 patients using a common protocol, who were randomised to receive praziquantel 40 mg/kg (n = 428) or 60 mg/kg (n = 428). While the sites differed for transmission and infection intensities (highest in Tanzania and lowest in Mauritania), no bias or heterogeneity across sites was detected for the main efficacy outcomes. The primary efficacy analysis was the comparison of cure rates on Day 21 in the intent-to-treat population for the pooled data using a logistic model to calculate Odd Ratios allowing for baseline characteristics and study site. Both doses were highly effective: the Day 21 cure rates were 91.7% (86.6%–98% at individual sites) with 40 mg/kg and 92.8% (88%–97%) with 60 mg/kg. Secondary parameters were eggs reduction rates (ERR), change in intensity of infection and reinfection rates at 6 and 12 months. On Day 21 the pooled estimate of the ERR was 91% in both arms. The Hazard Ratio for reinfections was only significant in Brazil, and in favour of 60 mg/kg on the pooled estimate (40 mg/kg: 34.3%, 60 mg/kg: 23.9%, HR = 0.78, 95%CI = [0.63;0.96]). Analysis of safety could not distinguish between disease- and drug-related events. 666 patients (78%) reported 1327 adverse events (AE) 4 h post-dosing. The risk of having at least one AE was higher in the 60 than in the 40 mg/kg group (83% vs. 73%, p<0.001). At 24 h post-dosing, 456 patients (54%) had 918 AEs with no difference between arms. The most frequent AE was abdominal pain at both 4 h and 24 h (40% and 24%).
Conclusion
A higher dose of 60 mg/kg of praziquantel offers no significant efficacy advantage over standard 40 mg/kg for treating intestinal schistosomiasis caused by either S. mansoni or S. japonicum. The results of this study support WHO recommendation and should be used to inform policy decisions in the countries.
Trial Registration
Controlled-Trials.com ISRCTN29273316 ClinicalTrials.gov NCT00403611
Author Summary
Control of urinary and intestinal schistosomiasis is based on mass administration of praziquantel at the World Health Organization (WHO) recommended dose of 40 mg/kg, though some countries use 60 mg/kg. This multi-country randomized clinical trial compared the efficacy (cure and egg reduction rates three weeks post-treatment) and safety of these two doses for treating intestinal schistosomiasis in 856 patients in Brazil, Mauritania and Tanzania (Schistosoma mansoni), and The Philippines (S. japonicum). Transmission and infection intensities varied across the sites, but there was no bias or heterogeneity in efficacy outcomes. The two doses are equally effective in curing intestinal schistosomiasis; the higher dose may be less well tolerated, though effects are generally mild and transient. In endemic areas people can be re-infected; one year post-treatment patients on 60 mg/kg had fewer re-infections but this finding is difficult to explain. This study was conducted to respond to the demand for evidence about the dose of praziquantel when deployed in endemic countries. The results, along with those of systematic reviews, support the current WHO recommendation for using praziquantel at 40 mg/kg and should inform policy decisions in countries. The Philippines has already changed from 60 to 40 mg/kg after this study.
doi:10.1371/journal.pntd.0001165
PMCID: PMC3114749  PMID: 21695161
22.  Effects of Treatment on IgE Responses against Parasite Allergen-Like Proteins and Immunity to Reinfection in Childhood Schistosome and Hookworm Coinfections 
Infection and Immunity  2013;81(1):23-32.
Naturally occurring human immunity to both schistosomiasis and hookworm infection has been associated with IgE responses against parasite allergen-like proteins. Since the two helminths frequently coinfect the same individuals, there is growing advocacy for their concurrent treatment. However, both helminths are known to exert strong immunomodulatory effects; therefore, coinfected individuals could have immune responses different from those characteristically seen in monoinfected individuals. In this study, we measured changes in IgE, IgG1, and IgG4 responses to schistosome and hookworm antigens, including the allergen-like proteins Schistosoma mansoni tegumental-allergen-like 1 protein (SmTAL1), SmTAL2, and Necator americanus Ancylostoma-secreted protein-2 (Na-ASP-2), following concurrent treatment of schoolchildren coinfected with Schistosoma mansoni and hookworm. Antibody responses to schistosome egg (soluble egg antigen and SmTAL2) or somatic adult hookworm (AHW) antigens either decreased after treatment or were unchanged, whereas those to schistosome worm antigens (soluble worm antigen and SmTAL1) increased. The observed different effects of treatment likely reflect the different modes of drug action and sites of infection for these two helminths. Importantly, there was no evidence that the simultaneous treatment of coinfected children with praziquantel and albendazole affected schistosome- and hookworm-specific humoral responses differently from those characteristic of populations in which only one organism is endemic; schistosome- and hookworm-specific responses were not associated, and there was no evidence for cross-regulation. Posttreatment increases in the levels of IgE to schistosome worm antigens were associated with lower Schistosoma mansoni reinfection intensity, while no associations between humoral responses to AHW antigen and protection from hookworm reinfection were observed in this sample of school-aged children.
doi:10.1128/IAI.00748-12
PMCID: PMC3536155  PMID: 23071136
23.  Clinical Efficacy and Tolerability of Praziquantel for Intestinal and Urinary Schistosomiasis—A Meta-analysis of Comparative and Non-comparative Clinical Trials 
Background
Extensive use of praziquantel for treatment and control of schistosomiasis requires a comprehensive understanding of efficacy and safety of various doses for different Schistosoma species.
Methodology/Principal Findings
A systematic review and meta-analysis of comparative and non-comparative trials of praziquantel at any dose for any Schistosoma species assessed within two months post-treatment. Of 273 studies identified, 55 were eligible (19,499 subjects treated with praziquantel, control treatment or placebo). Most studied were in school-aged children (64%), S. mansoni (58%), and the 40 mg/kg dose (56%); 68% of subjects were in Africa. Efficacy was assessed as cure rate (CR, n = 17,017) and egg reduction rate (ERR, n = 13,007); safety as adverse events (AE) incidence. The WHO-recommended dose of praziquantel 40 mg/kg achieved CRs of 94.7% (95%CI 92.2–98.0) for S. japonicum, 77.1% (68.4–85.1) for S. haematobium, 76.7% (95%CI 71.9–81.2) for S. mansoni, and 63.5% (95%CI 48.2–77.0) for mixed S. haematobium/S. mansoni infections. Using a random-effect meta-analysis regression model, a dose-effect for CR was found up to 40 mg/kg for S. mansoni and 30 mg/kg for S. haematobium. The mean ERR was 95% for S. japonicum, 94.1% for S. haematobium, and 86.3% for S. mansoni. No significant relationship between dose and ERR was detected. Tolerability was assessed in 40 studies (12,435 subjects). On average, 56.9% (95%CI 47.4–67.9) of the subjects receiving praziquantel 40 mg/kg experienced an AE. The incidence of AEs ranged from 2.3% for urticaria to 31.1% for abdominal pain.
Conclusions/Significance
The large number of subjects allows generalizable conclusions despite the inherent limitations of aggregated-data meta-analyses. The choice of praziquantel dose of 40 mg/kg is justified as a reasonable compromise for all species and ages, although in a proportion of sites efficacy may be lower than expected and age effects could not be fully explored.
Author Summary
Praziquantel is the drug used worldwide to treat intestinal and urinary schistosomiasis, diseases caused by the infection with different species of the parasitic worm Schistosoma. Summarizing findings of different studies is important in order to characterize how the parasite responds to treatment and to what extent humans can tolerate the medication. We found over 270 clinical trials on praziquantel, and, although less than one-third could be included in this analysis, the total number of subjects enrolled nears 20,000. This large number of subjects allows deriving general conclusions even though the methodologies used to conduct these studies (how the infection is diagnosed, how treatment effects are assessed) were not always uniform. These analyses confirm that the WHO-recommended praziquantel treatment (single dose of 40 mg/kg) works well on all species and at all ages, although in a proportion of study locations the levels of efficacy may be lower than expected.
doi:10.1371/journal.pntd.0003286
PMCID: PMC4238982  PMID: 25412105
24.  Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells 
The continual rise of asthma in industrialised countries stands in strong contrast to the situation in developing lands. According to the modified Hygiene Hypothesis, helminths play a major role in suppressing bystander immune responses to allergens, and both epidemiological and experimental studies suggest that the tropical parasitic trematode Schistosoma mansoni elicits such effects. The focus of this study was to investigate which developmental stages of schistosome infection confer suppression of allergic airway inflammation (AAI) using ovalbumin (OVA) as a model allergen. Moreover, we assessed the functional role and localization of infection-induced CD4+Foxp3+ regulatory T cells (Treg) in mediating such suppressive effects. Therefore, AAI was elicited using OVA/adjuvant sensitizations with subsequent OVA aerosolic challenge and was induced during various stages of infection, as well as after successful anti-helminthic treatment with praziquantel. The role of Treg was determined by specifically depleting Treg in a genetically modified mouse model (DEREG) during schistosome infection. Alterations in AAI were determined by cell infiltration levels into the bronchial system, OVA-specific IgE and Th2 type responses, airway hyper-sensitivity and lung pathology. Our results demonstrate that schistosome infection leads to a suppression of OVA-induced AAI when mice are challenged during the patent phase of infection: production of eggs by fecund female worms. Moreover, this ameliorating effect does not persist after anti-helminthic treatment, and depletion of Treg reverts suppression, resulting in aggravated AAI responses. This is most likely due to a delayed reconstitution of Treg in infected-depleted animals which have strong ongoing immune responses. In summary, we conclude that schistosome-mediated suppression of AAI requires the presence of viable eggs and infection-driven Treg cells. These data provide evidence that helminth derived products could be incorporated into treatment strategies that specifically target suppression of immune responses in AAI by inducing Treg cells.
Author Summary
Infections with schistosomes, such as S. mansoni, S. japonicum and S. haematobium, are considered a major public health concern. Morbidity arises through granulomatous responses to eggs that become trapped in infected tissues. Interestingly, schistosomes belong to the group of helminths that have been shown to reduce allergy or autoimmunity. Indeed, the evidence provided by epidemiological surveys and experimental animal models has been so overwhelming that such helminths are now included in the Hygiene Hypothesis. However, since helminths provoke immunological responses that are similar to those seen in allergy (increased eosinophilia and IgE) it is suggested that additional mechanisms dampen such allergic responses. Helminth-induced regulatory T cells (Treg) are considered a component of these modulatory networks. Using an allergic airway inflammation model, we have elucidated that schistosome-mediated protection requires patency, that is, active egg production from fecund female worms. In addition, protection was shown to be mediated by infection-induced Treg. Interestingly, in endemic countries it is usually individuals with strong patent infections that show reduced allergic prevalence. Thus, further research into the immunomodulatory capacity of schistosome-egg derived factors may elucidate novel drug candidates or enhance treatment strategies to reduce allergic responses on the cellular level.
doi:10.1371/journal.pntd.0002379
PMCID: PMC3744427  PMID: 23967364
25.  Anthelminthic treatment during pregnancy is associated with increased risk of infantile eczema: randomised-controlled trial results 
Pediatric Allergy and Immunology  2011;22(3):305-312.
Background
Allergy is commoner in developed than in developing countries. Chronic worm infections show inverse associations with allergy, and prenatal exposures may be critical to allergy risk.
Objective
To determine whether anthelminthic treatment during pregnancy increases the risk of allergy in infancy.
Methods
A randomised, double-blind, placebo-controlled trial on treatment in pregnancy with albendazole versus placebo and praziquantel versus placebo was conducted in Uganda, with a 2 × 2 factorial design; 2507 women were enrolled; infants’ allergy events were recorded prospectively. The main outcome was doctor-diagnosed infantile eczema.
Results
Worms were detected in 68% of women before treatment. Doctor-diagnosed infantile eczema incidence was 10.4/100 infant years. Maternal albendazole treatment was associated with a significantly increased risk of eczema [Cox HR (95% CI), p: 1.82 (1.26–2.64), 0.002]; this effect was slightly stronger among infants whose mothers had no albendazole-susceptible worms than among infants whose mothers had such worms, although this difference was not statistically significant. Praziquantel showed no effect overall but was associated with increased risk among infants of mothers with Schistosoma mansoni [2.65 (1.16–6.08), interaction p = 0.02]. In a sample of infants, skin prick test reactivity and allergen-specific IgE were both associated with doctor-diagnosed eczema, indicating atopic aetiology. Albendazole was also strongly associated with reported recurrent wheeze [1.58 (1.13–2.22), 0.008]; praziquantel showed no effect.
Conclusions
The detrimental effects of treatment suggest that exposure to maternal worm infections in utero may protect against eczema and wheeze in infancy. The results for albendazole are also consistent with a direct drug effect. Further studies are required to investigate mechanisms of these effects, possible benefits of worms or worm products in primary prevention of allergy, and the possibility that routine deworming during pregnancy may promote allergic disease in the offspring.
doi:10.1111/j.1399-3038.2010.01122.x
PMCID: PMC3130136  PMID: 21255083
albendazole; praziquantel; worms; infantile eczema; pregnancy; clinical trial

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