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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

Converting a Liability to an Asset: Using the Clearance of a Malaria Parasite Protein From the... (See the major article by Plucinski et al, on pages 685–92.) 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). Conclusions Finally, because clearance of the HRP2 protein from the blood of persons with malaria depends on the rate of parasite clearance rather than the antimalarial drug(s) that were used, this strategy should be applicable now (for artemisinin-based combination therapy in the current era) and in the future with other antimalarials structurally and mechanistically different from the artemisinins. For this reason, we hope it will be logistically and financially possible to obtain similarly sensitive and precise measurements of HRP2 blood levels in specimens from malaria-endemic areas in the near future, so these possibilities (hypotheses) can be tested as expeditiously as possible. Notes Acknowledgments. We thank Trevor Thompson for his review of this editorial and his thoughtful suggestions. Financial support. In previous years and currently, our research has been funded by the following: the Office of Orphan Product Development of the Food and Drug Administration (Grant Numbers FD R01-001692 and FD R01-003373), the National Institutes of Allergy and Infectious Diseases (Grant Numbers AI 25136, AI P50 39469, and AI U19-089696), the Centers for Disease Control and Prevention (grants UR3/CCU 418652 and UO1 CI 00211), Fogarty International Center (grant R25 TW 009340), the Department of State (Fulbright Award; to D. J. K.), Burroughs-Wellcome Fund (to D. J. K.), and the World Health Organization/TDR Special Programme for Research and Training in Tropical Diseases (grants TDR 92-0644 and TDR 92-0751). Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Rock EP , Marsh K, Saul AJet al.   Comparative analysis of the Plasmodium falciparum histidine-rich proteins HRP-I, HRP-II and HRP-III in malaria parasites of diverse origin. Parasitology  1987; 95 (Pt 2): 209– 27. Google Scholar CrossRef Search ADS PubMed  2. Parra ME , Evans CB, Taylor DW. Identification of Plasmodium falciparum histidine-rich protein 2 in the plasma of humans with malaria. J Clin Microbiol  1991; 29: 1629– 34. Google Scholar PubMed  3. World Health Organization. Guidelines for the Treatment of Malaria . Geneva: World Health Organization, 2010. Available at: https://apps.who.int/medicinedocs/documents/s19105en/s19105en.pdf. Accessed 15 December 2017. 4. Plucinski MM , Dimbu PR, Fortes Fet al.   Post-treatment HRP2 clearance in patients with uncomplicated Plasmodium falciparum malaria. J Infect Dis  2017. 5. Rogier E , Plucinski M, Lucchi Net al.   Bead-based immunoassay allows sub-picogram detection of histidine-rich protein 2 from Plasmodium falciparum and estimates reliability of malaria rapid diagnostic tests. PLoS One  2017; 12: e0172139. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Infectious Diseases Oxford University Press

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

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References (4)

Publisher
Oxford University Press
Copyright
© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
ISSN
0022-1899
eISSN
1537-6613
DOI
10.1093/infdis/jix623
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Abstract

(See the major article by Plucinski et al, on pages 685–92.) 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). Conclusions Finally, because clearance of the HRP2 protein from the blood of persons with malaria depends on the rate of parasite clearance rather than the antimalarial drug(s) that were used, this strategy should be applicable now (for artemisinin-based combination therapy in the current era) and in the future with other antimalarials structurally and mechanistically different from the artemisinins. For this reason, we hope it will be logistically and financially possible to obtain similarly sensitive and precise measurements of HRP2 blood levels in specimens from malaria-endemic areas in the near future, so these possibilities (hypotheses) can be tested as expeditiously as possible. Notes Acknowledgments. We thank Trevor Thompson for his review of this editorial and his thoughtful suggestions. Financial support. In previous years and currently, our research has been funded by the following: the Office of Orphan Product Development of the Food and Drug Administration (Grant Numbers FD R01-001692 and FD R01-003373), the National Institutes of Allergy and Infectious Diseases (Grant Numbers AI 25136, AI P50 39469, and AI U19-089696), the Centers for Disease Control and Prevention (grants UR3/CCU 418652 and UO1 CI 00211), Fogarty International Center (grant R25 TW 009340), the Department of State (Fulbright Award; to D. J. K.), Burroughs-Wellcome Fund (to D. J. K.), and the World Health Organization/TDR Special Programme for Research and Training in Tropical Diseases (grants TDR 92-0644 and TDR 92-0751). Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Rock EP , Marsh K, Saul AJet al.   Comparative analysis of the Plasmodium falciparum histidine-rich proteins HRP-I, HRP-II and HRP-III in malaria parasites of diverse origin. Parasitology  1987; 95 (Pt 2): 209– 27. Google Scholar CrossRef Search ADS PubMed  2. Parra ME , Evans CB, Taylor DW. Identification of Plasmodium falciparum histidine-rich protein 2 in the plasma of humans with malaria. J Clin Microbiol  1991; 29: 1629– 34. Google Scholar PubMed  3. World Health Organization. Guidelines for the Treatment of Malaria . Geneva: World Health Organization, 2010. Available at: https://apps.who.int/medicinedocs/documents/s19105en/s19105en.pdf. Accessed 15 December 2017. 4. Plucinski MM , Dimbu PR, Fortes Fet al.   Post-treatment HRP2 clearance in patients with uncomplicated Plasmodium falciparum malaria. J Infect Dis  2017. 5. Rogier E , Plucinski M, Lucchi Net al.   Bead-based immunoassay allows sub-picogram detection of histidine-rich protein 2 from Plasmodium falciparum and estimates reliability of malaria rapid diagnostic tests. PLoS One  2017; 12: e0172139. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Journal

The Journal of Infectious DiseasesOxford University Press

Published: Dec 6, 2017

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