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Roussel C.,Paris-Sorbonne University | Caumes E.,Assistance Publique Hopitaux de Paris | Caumes E.,University Pierre and Marie Curie | Thellier M.,University Pierre and Marie Curie | And 6 more authors.
Journal of Travel Medicine | Year: 2016

Background: Artesunate (AS) is the WHO first-line treatment of severe malaria in endemic countries, in adults and children. However, despite solid evidence that AS is safe and more effective than quinine in endemic areas, its deployment in non-endemic areas has been slow, due in part to the absence of a full good manufacturing practice (GMP) qualification (although prequalification has been granted in 2010). Prospective comparative trials were not conducted in travellers, but several retrospective studies and case reports are providing insights into the efficacy and safety of AS in imported severe malaria. Methods: We performed a systematic review on AS use in non-endemic areas for the treatment of imported severe malaria, using the Prisma method for bibliographic reports. Post-AS delayed haemolysis (PADH) was defined by delayed haemolytic episodes occurring 7–30 days after treatment initiation. We summarized prescription guidelines and generated answers to frequently asked questions regarding the use of AS in travellers with severe malaria. Results: We analysed 12 retrospectives and 1 prospective study as well as 7 case reports of AS treatment in 624 travellers. Of 574 patients with reported outcome, 23 died (4%). No death was attributed to AS toxicity. Nonhaematological side effects were uncommon and mainly included mild hepatitis, neurological, renal, cutaneous and cardiac manifestations. PADH occurred in 15% of the treated patients. No death or sequelae were reported. Overall blood transfusion was administered in 50% of travellers with PADH. Conclusion: AS is highly efficacious in travellers with severe malaria. The frequency of PADH supports the need of weekly follow-up of haematological parameters during 1 month. Full GMP qualification for the drug and rapid approval by drug agencies is warranted, backed by clear recommendations for optimal use. © International Society of Travel Medicine, 2016


Ndour P.A.,CNRS Immunology and Infectious Disease Center | Ndour P.A.,Center National Of Reference Du Paludisme Site Pitie Salpetriere | Ndour P.A.,Laboratory of Excellence GR Ex | Lopera-Mesa T.M.,National Institute of Allergy and Infectious Diseases | And 21 more authors.
Journal of Infectious Diseases | Year: 2015

Background In Plasmodium falciparum-infected patients treated with artemisinins, parasitemia declines through so-called pitting, an innate splenic process that transforms infected red blood cells (iRBCs) into once-infected RBCs (O-iRBCs). Methods We measured pitting in 83 French travelers and 42 Malian children treated for malaria with artesunate. Results In travelers, O-iRBCs peaked at 107.7% initial parasitemia. In Malian children aged 1.5-4 years, O-iRBCs peaked at higher concentrations than in children aged 9-13 years (91.60% vs 31.95%; P =. 0097). The parasite clearance time in older children was shorter than in younger children (P =. 0001), and the decline in parasitemia in children aged 1.5-4 years often started 6 hours after treatment initiation, a lag phase generally absent in infants and older children. A 6-hour lag phase in artificial pitting of artesunate-exposed iRBCs was also observed in vitro. The proportion of iRBCs recognized by autologous immunoglobulin G (IgG) correlated with the parasite clearance time (r = -0.501; P =. 0006) and peak O-iRBC concentration (r = -0.420; P =. 0033). Conclusions Antimalarial immunity correlates with fast artemisinin-induced parasite clearance and low pitting rates. In nonimmune populations, artemisinin-induced P. falciparum clearance is related to pitting and starts after a 6-hour lag phase. In immune populations, passively and naturally acquired immune mechanisms operating faster than pitting may exist. This mechanism may mitigate the emergence of artemisinin-resistant P. falciparum in Africa. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.


Jaureguiberry S.,Assistance Publique Hopitaux de Paris | Jaureguiberry S.,CNRS Immunology and Infectious Disease Center | Jaureguiberry S.,Center National Of Reference Du Paludisme Site Pitie Salpetriere | Ndour P.A.,CNRS Immunology and Infectious Disease Center | And 23 more authors.
Blood | Year: 2014

Patients with severe malaria treated with artesunate sometimes experience a delayed hemolytic episode. Artesunate (AS) induces pitting, a splenic process whereby dead parasites are expelled from their host erythrocytes. These once-infected erythrocytes then return to the circulation. We analyzed hematologic parameters in 123 travelers treated with AS for severe malaria. Among 60 nontransfused patients observed for more than 8 days, 13 (22%) had delayed hemolysis. The peak concentration of circulating once-infected erythrocytes was measured during the first week in 21 patients and was significantly higher in 9 patients with delayed hemolysis than in 12 with other patterns of anemia (0.30 vs 0.07; P = .0001). The threshold of 180 million once-infected erythrocytes per liter discriminated patients with delayed hemolysis with 89% sensitivity and 83% specificity. Once-infected erythrocyte morphology analyzed by using ImageStream in 4 patients showed an 8.9% reduction in their projected area, an alteration likely contributing to their shorter lifespan. Delayed clearance of infected erythrocytes spared by pitting during AS treatment is an original mechanism of hemolytic anemia. Our findings consolidate a disease framework for posttreatment anemia in malaria in which delayed hemolysis is a new entity. The early concentration of once-infected erythrocytes is a solid candidate marker to predict post-AS delayed hemolysis © 2014 by The American Society of Hematology.

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