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Schistosomiasis Treatment Failures with Single-dose Praziquantel
Abstract & Commentary
By Maria D. Mileno, MD, and Paul Trowbridge, MD
Dr. Mileno is Director, Travel Medicine, The Miriam Hospital, Associate Professor of Medicine, Brown University, Providence, RI.
Dr. Trowbridge is a resident, Internal Medicine, The Miriam Hospital, Brown University, Providence, RI.
Dr. Mileno and Dr. Trowbridge report no financial relationships relevant to this field of study.
This article originally appeared in the June 2010 issue of Travel Medicine Advisor. It was edited by Frank Bia, MD, MPH, and peer reviewed by Philip Fischer, MD, DTM&H.
Synopsis: Of 30 patients re-examined post-treatment with praziquantel (PZQ) for new schistosomiasis, only 10 were free of signs and symptoms, suggesting ongoing infection. Two-thirds of patients re-evaluated had an elevated blood eosinophil count or serum IgE level, increased antibody titer, or symptoms. Detectable ova were found on evaluation of urine or rectal biopsy in 20%. Re-evaluation is complicated by the lack of a diagnostic gold standard for schistosomiasis, especially for those with low parasite burdens.
Source: Helleberg M, Thybo S. High rate of failure in treatment of imported schistosomiasis. J Travel Med. 2010;17:94-99.
A retrospective observational study was conducted on 30 individuals from a possible 49 persons who were treated for schistosomiasis between 2003 and 2008 at Copenhagen University Hospital, Denmark. All patients had traveled to endemic areas and had been previously diagnosed by detection of ova or positive serologic studies associated with symptoms. All patients had subsequently been treated appropriately with at least 1 dose of praziquantel (40-60 mg/kg) at least 12 weeks post-exposure to avoid treatment at the invasive infection phase during which PZQ has limited effectiveness. Patients were offered re-evaluation 3 to 36 months post-treatment (mean 16 months). Nineteen of the 30 patients who accepted actually required re-evaluation, as 11 had already done so. Evaluation consisted of microscopy performed on 24-hour urine samples and/or rectal biopsies for direct visualization of ova, measurement of eosinophil count, IgE levels, and schistosomiasis serology by indirect hemagglutination assay and/or immunofluorescence testing. All patients were screened by history for potential re-exposure to freshwater from schistosomiasis-endemic regions prior to re-examination.
Viable schistosome ova were detected in 6 of 30 (20%) patients during re-examination following initial treatment, and these cases were considered treatment failures. This level of treatment failure is largely congruent with previous studies of schistosomiasis treatment among travelers. Notably, all of these patients had initially been diagnosed by detection of viable ova, not by a positive serology alone, potentially indicating higher initial parasite load. In addition, these patients were all tourists, expatriates, or immigrants from endemic areas. Treatment of schistosomiasis with praziquantel in patients from endemic areas has produced lower treatment failure rates. It has been hypothesized that this occurs because praziquantel only exposes parasitic antigens and requires host immunity in order to clear the adult organisms and obtain a cure. The latter would be more likely to occur in sensitized individuals from endemic areas than in travelers who were previously uninfected with the parasite.
In addition to known treatment failures, additional treatment failures were suspected in patients who did not have detectable schistosome ova, but were symptomatic two years after treatment and showed a rise in antibody titer of at least eightfold with an elevated serum IgE level. Only one-third of the study population (10 patients) had no confirmed ova or signs/symptoms suggesting potential ongoing schistosomiasis.
Other than direct detection of schistosome ova, no other parameters such as eosinophil count, serum IgE levels, or clinical symptoms could be shown to be a reliable indicator of infection, as none of them were found to show significant differences between patients in whom ova were detected and those in whom ova were not detected. Antibody titer, notably, was actually decreased in one patient who was subsequently found to have ova present on rectal biopsy. The diagnosis of schistosomiasis among individuals who do not have a heavy parasitic burden, and thus have limited excretion of ova, can be difficult; detection of ova, by any means, is fairly insensitive, elevations in serum IgE levels or eosinophil counts are non-specific, and serologic markers can remain elevated long after effective therapy. Although polymerase chain reaction (PCR) testing for parasite DNA may aid diagnosis in the future, empiric repeat treatment of travelers with schistosomiasis may be the best strategy, given the general safety of PZQ use.
There are several interesting aspects to this study. First of all, the high rate of treatment failure with PZQ is somewhat disturbing. With at least a 20% treatment failure rate in this study and the possibility that up to two of every three patients treated failed to clear the parasite, the drug of choice for schistosomiasis may require some new guidelines for its effective use, or it even may need to be replaced.
What may be of more interest than the results from this study is what we learn about what we simply do not know. Interestingly, even though this study points out that PZQ may be failing to treat some cases of schistosomiasis, we do not even understand how this medication works, much less how or why it fails. One of the hypothesized mechanisms of action is disruption of the parasitic surface membrane, allowing antigen exposure to the host's immune mechanisms. This hypothesized mechanism potentially could explain why there seems to be a higher rate of treatment failure among people exposed while traveling, including children, than among adults from endemic areas. However, this is not yet clear. Additional research on a larger scale than performed in this study would be useful for detailing the range of risk factors for treatment failure.
In addition to highlighting our lack of knowledge about treatment, this study also indicates that we currently lack a reliable method for choosing whom to treat or even re-treat. Our gold standard for detection of infection is quite insensitive, and our serologic methods often are not helpful during re-evaluation. PCR tests looking for parasitic DNA may be helpful in the future, but have not yet been studied sufficiently.