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Published in: BMC Infectious Diseases 1/2017

Open Access 01-12-2017 | Research article

Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa

Authors: Julien Zwang, Umberto D’Alessandro, Jean-Louis Ndiaye, Abdoulaye A Djimdé, Grant Dorsey, Andreas A Mårtensson, Corine Karema, Piero L. Olliaro

Published in: BMC Infectious Diseases | Issue 1/2017

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Abstract

Background

Anaemia is common in malaria. It is important to quantitate the risk of anaemia and to distinguish factors related to the natural history of disease from potential drug toxicity.

Methods

Individual-patient data analysis based on nine randomized controlled trials of treatments of uncomplicated falciparum malaria from 13 sub-Saharan African countries. Risk factors for reduced haemoglobin (Hb) concentrations and anaemia on presentation and after treatment were analysed using mixed effect models.

Results

Eight thousand eight hundred ninety-seven patients (77.0% <5 years-old) followed-up through 28 days treated with artemisinin combination therapy (ACT, 90%, n = 7968) or non-ACT. At baseline, under 5’s had the highest risk of anaemia (77.6% vs. 32.8%) and higher parasitaemia (43,938 μl) than older subjects (2784 μl). Baseline anaemia increased the risk of parasitological recurrence.
Hb began to fall after treatment start. In under 5’s the estimated nadir was ~35 h (range 29–48), with a drop of −12.8% from baseline (from 9.8 g/dl to 8.7 g/dl, p = 0.001); in under 15’s, the mean Hb decline between day 0–3 was −4.7% (from 9.4 to 9.0 g/dl, p = 0.001). The degree of Hb loss was greater in patients with high pre-treatment Hb and parasitaemia and with slower parasite reduction rates, and was unrelated to age. Subsequently, Hb increased linearly (+0.6%/day) until day 28, to reach +13.8% compared to baseline.
Severe anaemia (<5 g/dl, 2 per 1000 patients) was transient and all patients recovered after day 14, except one case of very severe anaemia associated with parasite recurrence at day 28.
There was no systematic difference in Hb concentrations between treatments and no case of delayed anaemia.

Conclusion

On presentation with acute malaria young children with high parasitaemia have the highest risk of anaemia. The majority of patients experience a drop in Hb while on treatment as early as day 1–2, followed by a linear increase through follow-up. The degree of the early Hb dip is determined by pre-treatment parasitaemia and parasite clearance rates. Hb trends and rick of anaemia are independent of treatment.
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Literature
1.
go back to reference Perkins DJ, Were T, Davenport GC, Kempaiah P, Hittner JB, et al. Severe malarial anemia: innate immunity and pathogenesis. Int J Biol Sc. 2011;7:1427–42.CrossRef Perkins DJ, Were T, Davenport GC, Kempaiah P, Hittner JB, et al. Severe malarial anemia: innate immunity and pathogenesis. Int J Biol Sc. 2011;7:1427–42.CrossRef
2.
go back to reference Krystal JE, Hansen DS, van Rooijen N, Buckingham LA, Schofield L. Severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes. Blood. 2006;107:1192–9. Krystal JE, Hansen DS, van Rooijen N, Buckingham LA, Schofield L. Severe malarial anemia of low parasite burden in rodent models results from accelerated clearance of uninfected erythrocytes. Blood. 2006;107:1192–9.
4.
go back to reference Finaurini S, Ronzoni L, Colancecco A, Cattaneo A, Cappellini MD, et al. Selective toxicity of dihydroartemisinin on human CD34+ erythroid cell differentiation. Toxicology. 2010;276:128–34.CrossRefPubMed Finaurini S, Ronzoni L, Colancecco A, Cattaneo A, Cappellini MD, et al. Selective toxicity of dihydroartemisinin on human CD34+ erythroid cell differentiation. Toxicology. 2010;276:128–34.CrossRefPubMed
5.
go back to reference Rehman K, Lötsch F, Kremsner PG, Ramharter M. Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis. 2014;29:268–73.CrossRefPubMed Rehman K, Lötsch F, Kremsner PG, Ramharter M. Haemolysis associated with the treatment of malaria with artemisinin derivatives: a systematic review of current evidence. Int J Infect Dis. 2014;29:268–73.CrossRefPubMed
6.
go back to reference Adjuik M, Agnamey P, Babiker A, Borrmann S, Brasseur P, et al. Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial. Lancet. 2002;359:1365–72.CrossRefPubMed Adjuik M, Agnamey P, Babiker A, Borrmann S, Brasseur P, et al. Amodiaquine-artesunate versus amodiaquine for uncomplicated Plasmodium falciparum malaria in African children: a randomised, multicentre trial. Lancet. 2002;359:1365–72.CrossRefPubMed
7.
go back to reference Olliaro P, Nevill C, LeBras J, Ringwald P, Mussano P, et al. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet. 1996;348:1196–201.CrossRefPubMed Olliaro P, Nevill C, LeBras J, Ringwald P, Mussano P, et al. Systematic review of amodiaquine treatment in uncomplicated malaria. Lancet. 1996;348:1196–201.CrossRefPubMed
8.
go back to reference Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Cochrane Database Syst Rev. 2009;8:CD007483. Review Sinclair D, Zani B, Donegan S, Olliaro P, Garner P. Cochrane Database Syst Rev. 2009;8:CD007483. Review
9.
go back to reference Sirima SB, Tiono AB, Gansane A, Diarra A, Ouedraogo A, et al. The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum. Malar J. 2009;8:48.CrossRefPubMedPubMedCentral Sirima SB, Tiono AB, Gansane A, Diarra A, Ouedraogo A, et al. The efficacy and safety of a new fixed-dose combination of amodiaquine and artesunate in young African children with acute uncomplicated Plasmodium falciparum. Malar J. 2009;8:48.CrossRefPubMedPubMedCentral
10.
go back to reference Gasasira AF, Kamya MR, Achan J, Mebrahtu T, Kalyango JN, et al. High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. Clin Infect Dis. 2008;46:985–91.CrossRefPubMed Gasasira AF, Kamya MR, Achan J, Mebrahtu T, Kalyango JN, et al. High risk of neutropenia in HIV-infected children following treatment with artesunate plus amodiaquine for uncomplicated malaria in Uganda. Clin Infect Dis. 2008;46:985–91.CrossRefPubMed
11.
go back to reference Zwang J, Ndiaye JL, Djimdé A, Dorsey G, Mårtensson A, et al. Comparing changes in haematologic parameters occurring in patients included in randomized controlled trials of artesunate-amodiaquine vs single and combination treatments of uncomplicated falciparum in sub-Saharan Africa. Malar J. 2012;11:25.CrossRefPubMedPubMedCentral Zwang J, Ndiaye JL, Djimdé A, Dorsey G, Mårtensson A, et al. Comparing changes in haematologic parameters occurring in patients included in randomized controlled trials of artesunate-amodiaquine vs single and combination treatments of uncomplicated falciparum in sub-Saharan Africa. Malar J. 2012;11:25.CrossRefPubMedPubMedCentral
12.
go back to reference Bethell D, Se Y, Lon C, Socheat D, Saunders D, et al. Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria. Clin Infect Dis. 2010;51:e105–14.CrossRefPubMed Bethell D, Se Y, Lon C, Socheat D, Saunders D, et al. Dose-dependent risk of neutropenia after 7-day courses of artesunate monotherapy in Cambodian patients with acute Plasmodium falciparum malaria. Clin Infect Dis. 2010;51:e105–14.CrossRefPubMed
13.
go back to reference Four Artemisinin-Based Combinations (4ABC) Study Group. A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial. PLoS Med. 2011;8:e1001119.CrossRef Four Artemisinin-Based Combinations (4ABC) Study Group. A head-to-head comparison of four artemisinin-based combinations for treating uncomplicated malaria in African children: a randomized trial. PLoS Med. 2011;8:e1001119.CrossRef
14.
go back to reference Djimdé AA, Fofana B, Sagara I, Sidibe B, Toure S, Dembele D, Dama S, Ouologuem D, Dicko A, Doumbo OK (2008) Efficacy, safety, and selection of molecular markers of drug resistance by two ACTs in Mali: am J Trop med Hyg 78:455-461. Djimdé AA, Fofana B, Sagara I, Sidibe B, Toure S, Dembele D, Dama S, Ouologuem D, Dicko A, Doumbo OK (2008) Efficacy, safety, and selection of molecular markers of drug resistance by two ACTs in Mali: am J Trop med Hyg 78:455-461.
15.
go back to reference Dorsey G, Staedke S, Clark TD, Njama-Meya D, Nzarubara B, et al. Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial. JAMA. 2007;297:2210–9.CrossRefPubMed Dorsey G, Staedke S, Clark TD, Njama-Meya D, Nzarubara B, et al. Combination therapy for uncomplicated falciparum malaria in Ugandan children: a randomized trial. JAMA. 2007;297:2210–9.CrossRefPubMed
16.
go back to reference Karema C, Fanello CI, van Overmeir C, van Geertruyden JP, van Doren W, et al. Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg. 2006;100:1105–11.CrossRefPubMed Karema C, Fanello CI, van Overmeir C, van Geertruyden JP, van Doren W, et al. Safety and efficacy of dihydroartemisinin/piperaquine (Artekin) for the treatment of uncomplicated Plasmodium falciparum malaria in Rwandan children. Trans R Soc Trop Med Hyg. 2006;100:1105–11.CrossRefPubMed
17.
go back to reference Ndiaye JL, Randrianarivelojosia M, Sagara I, Brasseur P, Ndiaye I, et al. Randomized, multicentre assessment of the efficacy and safety of ASAQ – a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. Malar J. 2009;8:125.CrossRefPubMedPubMedCentral Ndiaye JL, Randrianarivelojosia M, Sagara I, Brasseur P, Ndiaye I, et al. Randomized, multicentre assessment of the efficacy and safety of ASAQ – a fixed-dose artesunate-amodiaquine combination therapy in the treatment of uncomplicated Plasmodium falciparum malaria. Malar J. 2009;8:125.CrossRefPubMedPubMedCentral
18.
go back to reference Rwagacondo CE, Karema C, Mugisha V, Erhart A, Dujardin JC, et al. Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria Trop Med Int Health. 2004;9:1091–8.PubMed Rwagacondo CE, Karema C, Mugisha V, Erhart A, Dujardin JC, et al. Is amodiaquine failing in Rwanda? Efficacy of amodiaquine alone and combined with artesunate in children with uncomplicated malaria Trop Med Int Health. 2004;9:1091–8.PubMed
19.
go back to reference Schramm B, Valeh P, Baudin E, Mazinda CS, Smith R, et al. Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia. Malar J. 2013;12:250.CrossRefPubMedPubMedCentral Schramm B, Valeh P, Baudin E, Mazinda CS, Smith R, et al. Tolerability and safety of artesunate-amodiaquine and artemether-lumefantrine fixed dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria: two open-label, randomized trials in Nimba County, Liberia. Malar J. 2013;12:250.CrossRefPubMedPubMedCentral
20.
go back to reference Schramm B, Valeh P, Baudin E, Mazinda CS, Smith R, et al. Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial. Malar J. 2013;12:251.CrossRefPubMedPubMedCentral Schramm B, Valeh P, Baudin E, Mazinda CS, Smith R, et al. Efficacy of artesunate-amodiaquine and artemether-lumefantrine fixed-dose combinations for the treatment of uncomplicated Plasmodium falciparum malaria among children aged six to 59 months in Nimba County, Liberia: an open-label randomized non-inferiority trial. Malar J. 2013;12:251.CrossRefPubMedPubMedCentral
21.
go back to reference Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, et al. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005;41:1079–86.CrossRefPubMed Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, et al. Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis. 2005;41:1079–86.CrossRefPubMed
23.
go back to reference Sagara I, Piarroux R, Djimde A, Giorgi R, Kayentao K, et al. Delayed anemia assessment in patients treated with oral artemisinin derivatives for uncomplicated malaria: a pooled analysis of clinical trials data from Mali. Malar J. 2014;13:358.CrossRefPubMedPubMedCentral Sagara I, Piarroux R, Djimde A, Giorgi R, Kayentao K, et al. Delayed anemia assessment in patients treated with oral artemisinin derivatives for uncomplicated malaria: a pooled analysis of clinical trials data from Mali. Malar J. 2014;13:358.CrossRefPubMedPubMedCentral
24.
go back to reference Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, et al. Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five-year-old Nigerian children. Am J Trop Med Hyg. 2014;91:925–35.CrossRefPubMedPubMedCentral Oguche S, Okafor HU, Watila I, Meremikwu M, Agomo P, et al. Efficacy of artemisinin-based combination treatments of uncomplicated falciparum malaria in under-five-year-old Nigerian children. Am J Trop Med Hyg. 2014;91:925–35.CrossRefPubMedPubMedCentral
25.
go back to reference Bouyou-Akotet MK, Mawili Mboumba DP, Kendjo E, Mbadinga F, Obiang-Bekale N, et al. Anaemia and severe malarial anaemia burden in febrile Gabonese children: a nine-year health facility based survey. J Infect Dev Ctries. 2013;7:983–9.CrossRefPubMed Bouyou-Akotet MK, Mawili Mboumba DP, Kendjo E, Mbadinga F, Obiang-Bekale N, et al. Anaemia and severe malarial anaemia burden in febrile Gabonese children: a nine-year health facility based survey. J Infect Dev Ctries. 2013;7:983–9.CrossRefPubMed
26.
go back to reference Maiga H, Djimde AA, Beavogui AH, Toure O, Tekete M, et al. Efficacy of sulphadoxine-pyrimethamine + artesunate, sulphadoxine-pyrimethamine + amodiaquine, and sulphadoxine-pyrimethamine alone in uncomplicated falciparum malaria in Mali. Malar J. 2015;14:64.CrossRefPubMedPubMedCentral Maiga H, Djimde AA, Beavogui AH, Toure O, Tekete M, et al. Efficacy of sulphadoxine-pyrimethamine + artesunate, sulphadoxine-pyrimethamine + amodiaquine, and sulphadoxine-pyrimethamine alone in uncomplicated falciparum malaria in Mali. Malar J. 2015;14:64.CrossRefPubMedPubMedCentral
27.
go back to reference Nambozi M, Malunga P, Mulenga M, Van Geertruyden JP, D'Alessandro U. Defining the malaria burden in Nchelenge District, northern Zambia using the World Health Organization malaria indicators survey. Malar J. 2014;13:220.CrossRefPubMedPubMedCentral Nambozi M, Malunga P, Mulenga M, Van Geertruyden JP, D'Alessandro U. Defining the malaria burden in Nchelenge District, northern Zambia using the World Health Organization malaria indicators survey. Malar J. 2014;13:220.CrossRefPubMedPubMedCentral
28.
go back to reference Nji AM, Ali IM, Moyeh MN, Ngongang EO, Ekollo AM, et al. Randomized non-inferiority and safety trial of dihydroartemisin-piperaquine and artesunate-amodiaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Cameroonian children. Malar J. 2015;14:27.CrossRefPubMedPubMedCentral Nji AM, Ali IM, Moyeh MN, Ngongang EO, Ekollo AM, et al. Randomized non-inferiority and safety trial of dihydroartemisin-piperaquine and artesunate-amodiaquine versus artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Cameroonian children. Malar J. 2015;14:27.CrossRefPubMedPubMedCentral
29.
go back to reference Olliaro P, Djimdé A, Dorsey G, Karema C, Mårtensson A, et al. Hematologic parameters in pediatric uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa. Am J Trop Med Hyg. 2011;85:619–25.CrossRefPubMedPubMedCentral Olliaro P, Djimdé A, Dorsey G, Karema C, Mårtensson A, et al. Hematologic parameters in pediatric uncomplicated Plasmodium falciparum malaria in sub-Saharan Africa. Am J Trop Med Hyg. 2011;85:619–25.CrossRefPubMedPubMedCentral
30.
go back to reference Zwang J, Dorsey G, Mårtensson A, d'Alessandro U, Ndiaye JL, Karema C, et al. Plasmodium falciparum clearance in clinical studies of artesunate-amodiaquine and comparator treatments in sub-Saharan Africa, 1999–2009. Malar J. 2014;13:114.CrossRefPubMedPubMedCentral Zwang J, Dorsey G, Mårtensson A, d'Alessandro U, Ndiaye JL, Karema C, et al. Plasmodium falciparum clearance in clinical studies of artesunate-amodiaquine and comparator treatments in sub-Saharan Africa, 1999–2009. Malar J. 2014;13:114.CrossRefPubMedPubMedCentral
31.
go back to reference Jauréguiberry S, Thellier M, Ndour PA, Ader F, Roussel C, et al. French Artesunate working group. Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011-2013. Emerg Infect Dis. 2015;21:804–12.CrossRefPubMedPubMedCentral Jauréguiberry S, Thellier M, Ndour PA, Ader F, Roussel C, et al. French Artesunate working group. Delayed-onset hemolytic anemia in patients with travel-associated severe malaria treated with artesunate, France, 2011-2013. Emerg Infect Dis. 2015;21:804–12.CrossRefPubMedPubMedCentral
32.
go back to reference Brooks MH, Malloy JP, Bartelloni PJ, Tigertt WD, Sheehy TW, Barry KG. Pathophysiology of acute falciparum malaria. I. Correlation of clinical and biochemical abnormalities. Am J Med. 1967 Nov;43(5):735–44.CrossRefPubMed Brooks MH, Malloy JP, Bartelloni PJ, Tigertt WD, Sheehy TW, Barry KG. Pathophysiology of acute falciparum malaria. I. Correlation of clinical and biochemical abnormalities. Am J Med. 1967 Nov;43(5):735–44.CrossRefPubMed
Metadata
Title
Haemoglobin changes and risk of anaemia following treatment for uncomplicated falciparum malaria in sub-Saharan Africa
Authors
Julien Zwang
Umberto D’Alessandro
Jean-Louis Ndiaye
Abdoulaye A Djimdé
Grant Dorsey
Andreas A Mårtensson
Corine Karema
Piero L. Olliaro
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Infectious Diseases / Issue 1/2017
Electronic ISSN: 1471-2334
DOI
https://doi.org/10.1186/s12879-017-2530-6

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