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Converting a Liability to an Asset: Using the Clearance of a Malaria Parasite Protein From the Blood of Infected Subjects to Predict the Outcome of Treatment

Plasmodium falciparum histidine-rich protein 2 (HRP2) is a water-soluble protein in the food vacuole of the malaria parasite that is released (secreted) into the plasma during bloodstream infection [1]. Because it is secreted into the extracellular space by red cells with asexual parasites and can be detected in the plasma of P falciparum-infected individuals, Parra et al [2] originally suggested it might be useful as a marker for human P falciparum infection. During the past 15 years, the rapid diagnostic test (RDT) for malaria based on HRP2 has transformed malaria control in areas where P falciparum is the only (or major) parasite producing human disease. Using RDTs now available commercially with 1 drop of blood, persons with P falciparum malaria can be identified within 10–15 minutes and treated in the field. Based on this technology, the HRP2-based RDT has become the focal point of the revised World Health Organization Guidelines for the diagnosis and treatment of malaria [3]. As a result, persons with positive RDTs now receive oral treatment at the time of diagnosis. In contrast, persons with negative RDTs do not receive antimalarials and are referred for evaluation to identify an alternative explanation and treatment for their fever and clinical illness. The strength of the report from Plucinski et al [4] in this issue of The Journal of Infectious Diseases is that they have converted a liability of the HRP2-based RDT (its persistent positivity for weeks after the successful treatment of a malarial illness) to an asset. By using a quantitative and more sensitive bead-based assay for HRP2 in human blood [5], they have shown that the rate at which HRP2 blood levels fall after successful treatment is similar in subjects treated successfully at study sites in Angola, Tanzania, and Senegal (based on clearance constants or half-lives). In contrast, the peak HRP2 levels in individual subjects varied substantially and were related to the total parasite mass at the time of diagnosis. These results make sense and are logical conceptually. In addition, they have the potential to improve the follow-up care of persons with P falciparum malaria. As noted by the authors, day 3 and day 7 HRP2 blood levels greater than 96% or 80% of the day 0 blood levels successfully predicted recrudescence (with 90% and 80% sensitivity) [4]. If those predictions are accurate and this testing can be performed reproducibly in the field, this approach has the potential to identify treatment failure earlier than has been possible previously, to prevent the associated recrudescences and to reduce vector-borne transmission in the community. In summary, Plucinski et al [4] have provided new insights into the persistently positive assays for the P falciparum HPR2 protein after treatment, which have often been a clinical challenge because they have inadvertently been misinterpreted as new infections or evidence of treatment failure. These investigators and their colleagues have achieved a goal many of us share but few achieve: converting a shortcoming (liability) of a laboratory test to an asset while simultaneously increasing our understanding of the underlying mechanism (in this case, the decreasing levels of the HRP2 protein from P falciparum parasites in the bloodstream of patients who have been treated successfully for malaria as the number of asexual parasites declines).