Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis

Papa Alioune Ndour, Sébastien Larréché, Oussama Mouri, Nicolas Argy, Frédérick Gay, Camille Roussel, Stéphane Jauréguiberry, Claire Perillaud, Dominique Langui, Sylvestre Biligui, Nathalie Chartrel, Audrey Mérens, Eric Kendjo, Aniruddha Ghose, Md Mahtab Uddin Hassan, Md Amir Hossain, Hugh W.F. Kingston, Katherine Plewes, Arjen M. Dondorp, Martin Danis & 5 others Sandrine Houzé, Serge Bonnefoy, Marc Thellier, Charles J. Woodrow, Pierre A. Buffet

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Artesunate, the recommended drug for severe malaria, rapidly clears the malaria parasite from infected patients but frequently induces anemia - called post-artesunate delayed hemolysis (PADH) - for which a simple predictive test is urgently needed. The underlying event in PADH is the expulsion of artesunate-exposed parasites from their host erythrocytes by pitting. We show that the histidine-rich protein 2 (HRP2) of the malaria parasite Plasmodium falciparum persists in the circulation of artesunate-treated malaria patients in Bangladesh and in French travelers who became infected with malaria in Africa. HRP2 persisted in whole blood (not plasma) of artesunate-treated patients with malaria at higher levels compared to quinine-treated patients. Using an optimizedmembrane permeabilization method, HRP2 was observed by immunofluorescence, Western blotting, and electron microscopy to persist in once-infected red blood cells fromartesunate-treated malaria patients. HRP2 was deposited at themembrane of once-infected red blood cells in a pattern similar to that for ring erythrocyte surface antigen (RESA), a parasite invasion marker. On the basis of these observations, we developed a semiquantitative titration method using a widely available HRP2-based rapid diagnostic dipstick test. Positivity on this test using a 1:500 dilution ofwhole blood from artesunate-treated patients with malaria collected shortly after parasite clearance predicted subsequent PADH with 89% sensitivity and 73% specificity. These results suggest that adapting an existing HRP2-based rapid diagnostic dipstick test may enable prediction of PADH several days before it occurs in artesunate-treated patients with malaria.

Original languageEnglish
Article numbereaaf9377
Pages (from-to)1-11
Number of pages11
JournalScience Translational Medicine
Volume9
Issue number397
DOIs
Publication statusPublished - 5 Jul 2017

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Plasmodium falciparum
Hemolysis
Malaria
Blood Proteins
Parasites
Erythrocytes
Routine Diagnostic Tests
artesunate
histidine-rich proteins
Quinine
Bangladesh
Falciparum Malaria
Surface Antigens
Fluorescent Antibody Technique
Anemia
Electron Microscopy
Western Blotting
Sensitivity and Specificity

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Ndour, Papa Alioune ; Larréché, Sébastien ; Mouri, Oussama ; Argy, Nicolas ; Gay, Frédérick ; Roussel, Camille ; Jauréguiberry, Stéphane ; Perillaud, Claire ; Langui, Dominique ; Biligui, Sylvestre ; Chartrel, Nathalie ; Mérens, Audrey ; Kendjo, Eric ; Ghose, Aniruddha ; Hassan, Md Mahtab Uddin ; Hossain, Md Amir ; Kingston, Hugh W.F. ; Plewes, Katherine ; Dondorp, Arjen M. ; Danis, Martin ; Houzé, Sandrine ; Bonnefoy, Serge ; Thellier, Marc ; Woodrow, Charles J. ; Buffet, Pierre A. / Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis. In: Science Translational Medicine. 2017 ; Vol. 9, No. 397. pp. 1-11.
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title = "Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis",
abstract = "Artesunate, the recommended drug for severe malaria, rapidly clears the malaria parasite from infected patients but frequently induces anemia - called post-artesunate delayed hemolysis (PADH) - for which a simple predictive test is urgently needed. The underlying event in PADH is the expulsion of artesunate-exposed parasites from their host erythrocytes by pitting. We show that the histidine-rich protein 2 (HRP2) of the malaria parasite Plasmodium falciparum persists in the circulation of artesunate-treated malaria patients in Bangladesh and in French travelers who became infected with malaria in Africa. HRP2 persisted in whole blood (not plasma) of artesunate-treated patients with malaria at higher levels compared to quinine-treated patients. Using an optimizedmembrane permeabilization method, HRP2 was observed by immunofluorescence, Western blotting, and electron microscopy to persist in once-infected red blood cells fromartesunate-treated malaria patients. HRP2 was deposited at themembrane of once-infected red blood cells in a pattern similar to that for ring erythrocyte surface antigen (RESA), a parasite invasion marker. On the basis of these observations, we developed a semiquantitative titration method using a widely available HRP2-based rapid diagnostic dipstick test. Positivity on this test using a 1:500 dilution ofwhole blood from artesunate-treated patients with malaria collected shortly after parasite clearance predicted subsequent PADH with 89{\%} sensitivity and 73{\%} specificity. These results suggest that adapting an existing HRP2-based rapid diagnostic dipstick test may enable prediction of PADH several days before it occurs in artesunate-treated patients with malaria.",
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Ndour, PA, Larréché, S, Mouri, O, Argy, N, Gay, F, Roussel, C, Jauréguiberry, S, Perillaud, C, Langui, D, Biligui, S, Chartrel, N, Mérens, A, Kendjo, E, Ghose, A, Hassan, MMU, Hossain, MA, Kingston, HWF, Plewes, K, Dondorp, AM, Danis, M, Houzé, S, Bonnefoy, S, Thellier, M, Woodrow, CJ & Buffet, PA 2017, 'Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis', Science Translational Medicine, vol. 9, no. 397, eaaf9377, pp. 1-11. https://doi.org/10.1126/scitranslmed.aaf9377

Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis. / Ndour, Papa Alioune; Larréché, Sébastien; Mouri, Oussama; Argy, Nicolas; Gay, Frédérick; Roussel, Camille; Jauréguiberry, Stéphane; Perillaud, Claire; Langui, Dominique; Biligui, Sylvestre; Chartrel, Nathalie; Mérens, Audrey; Kendjo, Eric; Ghose, Aniruddha; Hassan, Md Mahtab Uddin; Hossain, Md Amir; Kingston, Hugh W.F.; Plewes, Katherine; Dondorp, Arjen M.; Danis, Martin; Houzé, Sandrine; Bonnefoy, Serge; Thellier, Marc; Woodrow, Charles J.; Buffet, Pierre A.

In: Science Translational Medicine, Vol. 9, No. 397, eaaf9377, 05.07.2017, p. 1-11.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Measuring the Plasmodium falciparum HRP2 protein in blood from artesunate-treated malaria patients predicts post-artesunate delayed hemolysis

AU - Ndour, Papa Alioune

AU - Larréché, Sébastien

AU - Mouri, Oussama

AU - Argy, Nicolas

AU - Gay, Frédérick

AU - Roussel, Camille

AU - Jauréguiberry, Stéphane

AU - Perillaud, Claire

AU - Langui, Dominique

AU - Biligui, Sylvestre

AU - Chartrel, Nathalie

AU - Mérens, Audrey

AU - Kendjo, Eric

AU - Ghose, Aniruddha

AU - Hassan, Md Mahtab Uddin

AU - Hossain, Md Amir

AU - Kingston, Hugh W.F.

AU - Plewes, Katherine

AU - Dondorp, Arjen M.

AU - Danis, Martin

AU - Houzé, Sandrine

AU - Bonnefoy, Serge

AU - Thellier, Marc

AU - Woodrow, Charles J.

AU - Buffet, Pierre A.

PY - 2017/7/5

Y1 - 2017/7/5

N2 - Artesunate, the recommended drug for severe malaria, rapidly clears the malaria parasite from infected patients but frequently induces anemia - called post-artesunate delayed hemolysis (PADH) - for which a simple predictive test is urgently needed. The underlying event in PADH is the expulsion of artesunate-exposed parasites from their host erythrocytes by pitting. We show that the histidine-rich protein 2 (HRP2) of the malaria parasite Plasmodium falciparum persists in the circulation of artesunate-treated malaria patients in Bangladesh and in French travelers who became infected with malaria in Africa. HRP2 persisted in whole blood (not plasma) of artesunate-treated patients with malaria at higher levels compared to quinine-treated patients. Using an optimizedmembrane permeabilization method, HRP2 was observed by immunofluorescence, Western blotting, and electron microscopy to persist in once-infected red blood cells fromartesunate-treated malaria patients. HRP2 was deposited at themembrane of once-infected red blood cells in a pattern similar to that for ring erythrocyte surface antigen (RESA), a parasite invasion marker. On the basis of these observations, we developed a semiquantitative titration method using a widely available HRP2-based rapid diagnostic dipstick test. Positivity on this test using a 1:500 dilution ofwhole blood from artesunate-treated patients with malaria collected shortly after parasite clearance predicted subsequent PADH with 89% sensitivity and 73% specificity. These results suggest that adapting an existing HRP2-based rapid diagnostic dipstick test may enable prediction of PADH several days before it occurs in artesunate-treated patients with malaria.

AB - Artesunate, the recommended drug for severe malaria, rapidly clears the malaria parasite from infected patients but frequently induces anemia - called post-artesunate delayed hemolysis (PADH) - for which a simple predictive test is urgently needed. The underlying event in PADH is the expulsion of artesunate-exposed parasites from their host erythrocytes by pitting. We show that the histidine-rich protein 2 (HRP2) of the malaria parasite Plasmodium falciparum persists in the circulation of artesunate-treated malaria patients in Bangladesh and in French travelers who became infected with malaria in Africa. HRP2 persisted in whole blood (not plasma) of artesunate-treated patients with malaria at higher levels compared to quinine-treated patients. Using an optimizedmembrane permeabilization method, HRP2 was observed by immunofluorescence, Western blotting, and electron microscopy to persist in once-infected red blood cells fromartesunate-treated malaria patients. HRP2 was deposited at themembrane of once-infected red blood cells in a pattern similar to that for ring erythrocyte surface antigen (RESA), a parasite invasion marker. On the basis of these observations, we developed a semiquantitative titration method using a widely available HRP2-based rapid diagnostic dipstick test. Positivity on this test using a 1:500 dilution ofwhole blood from artesunate-treated patients with malaria collected shortly after parasite clearance predicted subsequent PADH with 89% sensitivity and 73% specificity. These results suggest that adapting an existing HRP2-based rapid diagnostic dipstick test may enable prediction of PADH several days before it occurs in artesunate-treated patients with malaria.

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U2 - 10.1126/scitranslmed.aaf9377

DO - 10.1126/scitranslmed.aaf9377

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JF - Science Translational Medicine

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