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Background. Age prevalence curves for areas in which schistosomiasis is endemic suggest that humans develop partial immunity to reinfection beginning in early adolescence. We conducted a 2-year longitudinal study to determine whether children infected with Schistosoma mansoni develop protection-related immune responses after treatment with praziquantel and whether the development of these immune responses is accelerated by frequent treatment after reinfection. Methods. Children (8-10 years old) were tested for S. tnansoni every 4 months and treated with praziquantel when positive (arm A; n = 68) or were tested and treated at the end of the 2-year follow-up period (arm B; n = 49). Results. Children in arm A who remained free of infection during follow-up had significantly higher baseline levels of schistosome-specific immunoglobulin E (IgE) than did children with ⩾2 repeat diagnoses of S. mansoni infection. Children with ⩾2 repeat diagnoses of S. mansoni infection had significantly increased levels of anti- schistosome IgE and CD23+ B cells after receiving ⩾3 praziquantel treatments over the course of follow-up. No increase in either parameter was seen in children who received only the baseline praziquantel treatment. Conclusions. B cell activation and anti-schistosome IgE are associated with resistance to S. mansoni in children, and these immunological parameters can be increased by multiple rounds of infections and praziquantel-induced cures. [ABSTRACT FROM AUTHOR]

Background: The near exclusive use of praziquantel (PZQ) for treatment of human schistosomiasis has raised concerns about the possible emergence of drug-resistant schistosomes. Methodology/Principal Findings: We measured susceptibility to PZQ of isolates of Schistosoma mansoni obtained from patients from Kisumu, Kenya continuously exposed to infection as a consequence of their occupations as car washers or sand harvesters. We used a) an in vitro assay with miracidia, b) an in vivo assay targeting adult worms in mice and c) an in vitro assay targeting adult schistosomes perfused from mice. In the miracidia assay, in which miracidia from human patients were exposed to PZQ in vitro, reduced susceptibility was associated with previous treatment of the patient with PZQ. One isolate ("KCW") that was less susceptible to PZQ and had been derived from a patient who had never fully cured despite multiple treatments was studied further. In an in vivo assay of adult worms, the KCW isolate was significantly less susceptible to PZQ than two other isolates from natural infections in Kenya and two lab-reared strains of S. mansoni. The in vitro adult assay, based on measuring length changes of adults following exposure to and recovery from PZQ, confirmed that the KCW isolate was less susceptible to PZQ than the other isolates tested. A sub-isolate of KCW maintained separately and tested after three years was susceptible to PZQ, indicative that the trait of reduced sensitivity could be lost if selection was not maintained. Conclusions/Significance: Isolates of S. mansoni from some patients in Kisumu have lower susceptibility to PZQ, including one from a patient who was never fully cured after repeated rounds of treatment administered over several years. As use of PZQ continues, continued selection for worms with diminished susceptibility is possible, and the probability of emergence of resistance will increase as large reservoirs of untreated worms diminish. The potential for rapid emergence of resistance should be an important consideration of treatment programs. Author Summary: The emergence of drug resistant pathogens is a great challenge to the control of infectious diseases. Schistosomiasis is one of the world's greatest neglected tropical diseases, and it is primarily controlled with the drug praziquantel. This drug is often used by repeatedly treating patients to maintain reduced worm burdens, an ideal situation to encourage the evolution of resistant worms. Although drug based control programs are increasing, monitoring efforts for drug resistance remain rare. We measured drug susceptibility of schistosomes from a cohort of patients in Kenya who are enrolled in a longitudinal study in which they are repeatedly treated with praziquantel. We found that schistosomes from previously treated patients were significantly less susceptible than those that were not. Also, schistosomes derived from a single patient who had been treated with praziquantel 18 times showed marked resistance. Although the findings of this study indicated that reduced drug susceptibility occurs in this population of schistosomes, this trait does not seem to be spreading widely or creating clinical levels of resistance. We hypothesize that the trait remains at low frequency because of the large population of schistosomes that are not exposed to the drug and/or potential fitness costs associated with reduced susceptibility. [ABSTRACT FROM AUTHOR]

Objective To investigate trends in the efficacy of praziquantel (PZQ) suggestive of the emergence of drug resistance against Schistosoma mansoni infection after 12.5 years of intense, repeated use in a small geographic area along the shores of Lake Victoria. Methods As part of a longitudinal study, 178 men occupationally exposed to schistosomes were repeatedly tested for S. mansoni infection at 4- to 6-week intervals and treated with PZQ at each reinfection. We compared cure rates by year of study and examined factors associated with cure failure in a multivariate logistic regression model. Results Overall, the cure rate after a single dose of PZQ was 66%, ranging annually from 36% to 82%. In multivariate analysis, failure to cure after 1 PZQ dose was significantly associated with high intensity of infection and having fewer previous exposures to dying worms. Even after adjustment for these factors, treatments administered in 2006 were significantly more likely to result in cure failures than treatments administered in 2004, the year in which PZQ efficacy was highest. While cure rates varied over the course of 12 years, there was no consistent downward trend towards decreased efficacy over time. In years for which malacological data were available, periods of low PZQ efficacy coincide with high rates of S. mansoni infection in nearby snail populations. Conclusion We did not find a pattern of cure failures consistent with development of clinical resistance to PZQ in our intensely treated cohort. [ABSTRACT FROM AUTHOR]

Background: Age prevalence curves for areas in which schistosomiasis is endemic suggest that humans develop partial immunity to reinfection beginning in early adolescence. We conducted a 2-year longitudinal study to determine whether children infected with Schistosoma mansoni develop protection-related immune responses after treatment with praziquantel and whether the development of these immune responses is accelerated by frequent treatment after reinfection., Methods: Children (8-10 years old) were tested for S. mansoni every 4 months and treated with praziquantel when positive (arm A; n=68) or were tested and treated at the end of the 2-year follow-up period (arm B; n=49)., Results: Children in arm A who remained free of infection during follow-up had significantly higher baseline levels of schistosome-specific immunoglobulin E (IgE) than did children with > or =2 repeat diagnoses of S. mansoni infection. Children with > or =2 repeat diagnoses of S. mansoni infection had significantly increased levels of anti-schistosome IgE and CD23(+) B cells after receiving > or =3 praziquantel treatments over the course of follow-up. No increase in either parameter was seen in children who received only the baseline praziquantel treatment., Conclusions: B cell activation and anti-schistosome IgE are associated with resistance to S. mansoni in children, and these immunological parameters can be increased by multiple rounds of infections and praziquantel-induced cures.

Background: The immunologic findings that most consistently correlate with resistance in human schistosomiasis are high levels of IgE and low levels of IgG4. We have genotyped gene and promoter polymorphisms of cytokines associated with regulation of these isotypes in a cohort of men occupationally exposed to Schistosoma mansoni in western Kenya and evaluated their patterns with respect to resistance and susceptibility to reinfection after treatment and cure with praziquantel (PZQ)., Methodology/principal Findings: In this cohort, polymorphisms in IL-4 (-590T high IgE), IL-13 (-1055T high producer) and IFN-gamma (+874A high producer) demonstrated several correlations with resistance to reinfection. Resistance to reinfection was significantly correlated with the heterozygous IL-4 -590 genotype C/T (OR 3.5, [CI 1.2, 10.2]) compared to T/T. Among men with a homozygous IL-13 genotype CC/TT, having a T allele at the IFN-gamma +874 position increased the odds of resistance relative to individuals with the IFN-gamma +874 A/A genotype (OR = 17.5 [CI 3.0, 101.5]). Among men with homozygous A/A IFN-gamma genotype, the heterozygous IL-13 genotype C/T was associated with resistance relative to the homozygous C/C or T/T genotypes (OR = 22.5 [CI 3.5, 144.4]). No increases in odds of resistance were found in relation to the IL-13 genotype among those with a T allele in the IFN-gamma gene or in relation to the IFN-gamma genotype among those with a heterozygous IL-13 genotype. Calculation of the attributable proportion of resistance showed a significant synergistic interaction between IL-13 -1055 C/T and IL-4 -590 C/T., Conclusions: The identified polymorphisms do not by themselves confer resistance or susceptibility, but we propose that these genotypes allow the resistant phenotype to be developed and expressed upon suitable immune exposure. Based on the literature, these polymorphisms contribute to the regulation of their respective cytokines, likely leading to downstream differences in the production and interrelationships of critical defense mechanisms.