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

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Science Translational Medicine  05 Jul 2017:
Vol. 9, Issue 397, eaaf9377
DOI: 10.1126/scitranslmed.aaf9377

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A quick test to predict artesunate-induced anemia

Anemia frequently affects patients treated for severe malaria with artemisinin drugs. Artemisinin kills malaria parasites, which are then expelled from infected red blood cells. These “deparasitized” red blood cells persist in the blood but are later destroyed, resulting in anemia. Ndour et al. now show that the deparasitized red blood cells retain the parasite protein HRP2, which explains why HRP2 can still be detected in patients after the malaria infection has been cleared. The amount of HRP2 in the blood immediately after treatment with artemisinin correlates with the number of deparasitized red blood cells in the circulation. HRP2 can be measured with a rapid diagnostic dipstick test that then can be used to predict the risk for delayed hemolysis and anemia in malaria patients treated with artemisinin.

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 optimized membrane permeabilization method, HRP2 was observed by immunofluorescence, Western blotting, and electron microscopy to persist in once-infected red blood cells from artesunate-treated malaria patients. HRP2 was deposited at the membrane 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 of whole 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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