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Delayed-Onset Hemolytic Anemia in Patients with Travel-Associated Severe Malaria Treated with Artesunate, France, 2011–2013 - Volume 21, Number 5—May 2015 - Emerging Infectious Disease journal - CDC

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Delayed-Onset Hemolytic Anemia in Patients with Travel-Associated Severe Malaria Treated with Artesunate, France, 2011–2013 - Volume 21, Number 5—May 2015 - Emerging Infectious Disease journal - CDC





Volume 21, Number 5—May 2015

Research

Delayed-Onset Hemolytic Anemia in Patients with Travel-Associated Severe Malaria Treated with Artesunate, France, 2011–2013

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Stéphane JauréguiberryComments to Author , Marc Thellier, Papa Alioune Ndour, Flavie Ader, Camille Roussel, Romain Sonneville, Julien Mayaux, Sophie Matheron, Adela Angoulvant, Benjamin Wyplosz, Christophe Rapp, Thierry Pistone, Bénédicte Lebrun-Vignes, Eric Kendjo, Martin Danis, Sandrine Houzé, François Bricaire, Dominique Mazier, Pierre Buffet, Eric Caumes, and French Artesunate Working Group
Author affiliations: Université Pierre et Marie Curie, Paris, France (S. Jauréguiberry, M. Thellier, P.A. Ndour, C. Roussel, M. Danis, D. Mazier, P. Buffet, E. Caumes); Hôpital Pitié-Salpêtrière, Assistance Publique des Hôpitaux de Paris (APHP), Paris (S. Jauréguiberry, M. Thellier, F. Ader, J. Mayaux, B. Lebrun-Vignes, M. Danis, F. Bricaire, D. Mazier, P. Buffet, E. Caumes); Centre National de Référence du Paludisme, Paris (S. Jauréguiberry, M. Thellier, E. Kendjo, M. Danis, D. Mazier, P. Buffet); Hôpital Bichat, APHP, Paris (R. Sonneville, S. Matheron, S. Houzé);Université Paris-Sud, Orsay, France (A. Angoulvant); Hôpital de Bicêtre, Le Kremlin Bicêtre, APHP, France (A. Angoulvant, B. Wyplosz); Hôpital d’Instruction des Armées Begin, St. Mandé, France (C. Rapp); Hôpital Pellegrin, Bordeaux, France (T. Pistone)

Abstract

Artesunate is the most effective treatment for severe malaria. However, delayed-onset hemolytic anemia has been observed in ≈20% of travelers who receive artesunate, ≈60% of whom require transfusion. This finding could discourage physicians from using artesunate. We prospectively evaluated a cohort of 123 patients in France who had severe imported malaria that was treated with artesunate; our evaluation focused on outcome, adverse events, and postartesunate delayed-onset hemolysis (PADH). Of the 123 patients, 6 (5%) died. Overall, 97 adverse events occurred. Among the 78 patients who received follow-up for >8 days after treatment initiation, 76 (97%) had anemia, and 21 (27%) of the 78 cases were recorded as PADH. The median drop in hemoglobin levels was 1.3 g/dL; 15% of patients with PADH had hemoglobin levels of <7 g/dL, and 1 required transfusion. Despite the high incidence of PADH, the resulting anemia remained mild in 85% of cases. This reassuring result confirms the safety and therapeutic benefit of artesunate.
Intravenous (IV) artesunate has been the recommended first-line treatment for severe malaria worldwide since 2010 (1). Two large randomized trials showed a 35.0% reduction (from 22.0% to 15.0%) in death rates among adults in Asia and a 22.5% (from 10.9% to 8.5%) reduction among children in Africa when artesunate was compared with parenteral quinine in the treatment of severe malaria (2,3). Four case series performed in Western countries reported death rates of <4% (4–7).
Artesunate is generally considered safe (8). However, its use in Western countries has shown that delayed hemolytic events occur in ≈20% of patients with severe imported malaria, and 60% of these patients require blood transfusion (4,6,7,9–11). Delayed-onset anemia (herein referred to as postartesunate delayed-onset hemolysis [PADH] pattern of anemia) has been observed to occur 2–3 weeks after initiation of IV artesunate, after complete clearance of parasites, and to resolve during weeks 3–6 (7). The mechanism of this anemia is hemolytic, as demonstrated by high serum lactate dehydrogenase (LDH) and low plasma haptoglobin levels. Across several studies, no common conventional cause of hemolysis was identified (4,6,12–14). In a comparative study, PADH anemia was described in 5 of 8 patients with hyperparasitemia treated with artesunate alone or combined with quinine; it was not seen in patients treated with quinine alone. This finding supports the assumption that this side effect is associated with artesunate (11). PADH anemia has not been reported in meta-analyses (8) nor observed in large clinical trials (2,3). However PADH has been reported recently in children in Africa (15).
This PADH is a matter of concern for the medical community. Without a systematic assessment of the incidence and outcome of artesunate-associated PADH anemia, a slowdown may occur in the ongoing change toward favoring treatment with artesunate rather than quinine, a less-efficient treatment for severe malaria. The World Health Organization recently recommended increased vigilance for PADH anemia and called for a more precise description of its incidence, time course, and severity (16). To determine the effectiveness and safety of artesunate in patients with severe imported malaria, we focused on PADH anemia cases detected through an existing artesunate surveillance program in France.

Dr. Jauréguiberry is a physician in the Department of Infectious and Tropical Diseases at the Pitié Salpêtrière University Hospital in Paris. His research interests include the pathophysiology and treatment of malaria and the epidemiology of imported diseases.

Acknowledgments


We thank Ipsita Sinha, Charlie Woodrow, and Muriel Vray for fruitful discussions. We are grateful to Elsa Boher and Françoise Mancel for constructive interactions.
This work was supported by grants from the Domaine d'Interêt Majeur Maladies Infectieuses Région Ile-de-France, the Worldwide Antimalarial Resistance Network Fast-Track Drugs & Biologics, LLC, the Bill and Melinda Gates Foundation, and the Follereau Foundation. Further support was provided by an Inserm-APHP France interface contract. S.J. has a grant from the Collège des Universitaires des Maladies Infectieuses et Tropicales.
S.J. and P.B. are engaged in a collaboration with Guilin Laboratories. P.B. provided expertise to Sigma-Tau Laboratories and Sanofi Aventis Group Research and Development. D.M., M.T., and T.P. provided expertise to Sigma-Tau Laboratories in France. M.D. has provided expertise to Sigma-Tau and Sanofi Laboratories.

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Figures

Tables

Technical Appendix

Suggested citation for this article: Jauréguiberry S, Thellier M, Ndour PA, Ader F, Roussel C, Sonneville R, et al. Delayed-onset hemolytic anemia in patients with severe malaria treated with artesunate, France, 2011–2013. Emerg Infect Dis. 2015 May [date cited]. http://dx.doi.org/10.3201/eid2105.141171
DOI: 10.3201/eid2105.141171
1Members of the French Artesunate Working Group are listed in the Technical Appendix.
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