Haematological consequences of acute uncomplicated falciparum malaria: a WorldWide Antimalarial Resistance Network pooled analysis of individual patient data
Authors:   The WorldWide Antimalarial Resistance Network Falciparum Haematology Study Group, Mansoor Rashid , Commons Robert J. , Douglas Nicholas M. , Abuaku Benjamin , Achan Jane , Adam Ishag , Adjei George O. , Adjuik Martin , Alemayehu Bereket H. , Allan Richard , Allen Elizabeth N. , Anvikar Anupkumar R. , Arinaitwe Emmanuel , Ashley Elizabeth A. , Ashurst Hazel , Asih Puji B. S. , Bakyaita Nathan , Barennes Hubert , Barnes Karen I. , Basco Leonardo , Bassat Quique , Baudin Elisabeth , Bell David J , Bethell Delia , Bjorkman Anders , Boulton Caroline , Bousema Teun , Brasseur Philippe , Bukirwa Hasifa , Burrow Rebekah , Carrara Verena I. , Cot Michel , D’Alessandro Umberto , Das Debashish , Das Sabyasachi , Davis Timothy M. E. , Desai Meghna , Djimde Abdoulaye A. , Dondorp Arjen M. , Dorsey Grant , Drakeley Chris J. , Duparc Stephan , Espié Emmanuelle , Etard Jean-Francois , Falade Catherine , Faucher Jean Francois , Filler Scott , Fogg Carole , Fukuda Mark , Gaye Oumar , Genton Blaise , Ghulam Rahim Awab , Gilayeneh Julius , Gonzalez Raquel , Grais Rebecca F. , Grandesso Francesco , Greenwood Brian , Grivoyannis Anastasia , Hatz Christoph , Hodel Eva Maria , Humphreys Georgina S. , Hwang Jimee , Ishengoma Deus , Juma Elizabeth , Kachur S. Patrick , Kager Piet A. , Kamugisha Erasmus , Kamya Moses R. , Karema Corine , Kayentao Kassoum , Kazienga Adama , Kiechel Jean-René , Kofoed Poul-Erik , Koram Kwadwo , Kremsner Peter G. , Lalloo David G. , Laman Moses , Lee Sue J. , Lell Bertrand , Maiga Amelia W. , Mårtensson Andreas , Mayxay Mayfong , Mbacham Wilfred , McGready Rose , Menan Hervé , Ménard Didier , Mockenhaupt Frank , Moore Brioni R. , Müller Olaf , Nahum Alain , Ndiaye Jean-Louis , Newton Paul N. , Ngasala Billy E. , Nikiema Frederic , Nji Akindeh M. , Noedl Harald , Nosten Francois , Ogutu Bernhards R. , Ojurongbe Olusola , Osorio Lyda , Ouédraogo Jean-Bosco , Owusu-Agyei Seth , Pareek Anil , Penali Louis K. , Piola Patrice , Plucinski Mateusz , Premji Zul , Ramharter Michael , Richmond Caitlin L. , Rombo Lars , Roper Cally , Rosenthal Philip J. , Salman Sam , Same-Ekobo Albert , Sibley Carol , Sirima Sodiomon B. , Smithuis Frank M. , Somé Fabrice A. , Staedke Sarah G. , Starzengruber Peter , Strub-Wourgaft Nathalie , Sutanto Inge , Swarthout Todd D. , Syafruddin Din , Talisuna Ambrose O. , Taylor Walter R. , Temu Emmanuel A. , Thwing Julie I. , Tinto Halidou , Tjitra Emiliana , Touré Offianan A. , Tran T. Hien , Ursing Johan , Valea Innocent , Valentini Giovanni , van Vugt Michele , von Seidlein Lorenz , Ward Stephen A. , Were Vincent , White Nicholas J. , Woodrow Charles J. , Yavo William , Yeka Adoke , Zongo Issaka , Simpson Julie A. , Guerin Philippe J. , Stepniewska Kasia , Price Ric N. 
Published: March 2022

Abstract
Background
Plasmodium falciparum malaria is associated with anaemia-related morbidity, attributable to host, parasite and drug factors. We quantified the haematological response following treatment of uncomplicated P. falciparum malaria to identify the factors associated with malarial anaemia.

Methods
Individual patient data from eligible antimalarial efficacy studies of uncomplicated P. falciparum malaria, available through the WorldWide Antimalarial Resistance Network data repository prior to August 2015, were pooled using standardised methodology. The haematological response over time was quantified using a multivariable linear mixed effects model with nonlinear terms for time, and the model was then used to estimate the mean haemoglobin at day of nadir and day 7. Multivariable logistic regression quantified risk factors for moderately severe anaemia (haemoglobin < 7 g/dL) at day 0, day 3 and day 7 as well as a fractional fall ≥ 25% at day 3 and day 7.

Results
A total of 70,226 patients, recruited into 200 studies between 1991 and 2013, were included in the analysis: 50,859 (72.4%) enrolled in Africa, 18,451 (26.3%) in Asia and 916 (1.3%) in South America. The median haemoglobin concentration at presentation was 9.9 g/dL (range 5.0–19.7 g/dL) in Africa, 11.6 g/dL (range 5.0–20.0 g/dL) in Asia and 12.3 g/dL (range 6.9–17.9 g/dL) in South America. Moderately severe anaemia (Hb < 7g/dl) was present in 8.4% (4284/50,859) of patients from Africa, 3.3% (606/18,451) from Asia and 0.1% (1/916) from South America. The nadir haemoglobin occurred on day 2 post treatment with a mean fall from baseline of 0.57 g/dL in Africa and 1.13 g/dL in Asia. Independent risk factors for moderately severe anaemia on day 7, in both Africa and Asia, included moderately severe anaemia at baseline (adjusted odds ratio (AOR) = 16.10 and AOR = 23.00, respectively), young age (age < 1 compared to ≥ 12 years AOR = 12.81 and AOR = 6.79, respectively), high parasitaemia (AOR = 1.78 and AOR = 1.58, respectively) and delayed parasite clearance (AOR = 2.44 and AOR = 2.59, respectively). In Asia, patients treated with an artemisinin-based regimen were at significantly greater risk of moderately severe anaemia on day 7 compared to those treated with a non-artemisinin-based regimen (AOR = 2.06 [95%CI 1.39–3.05], p < 0.001).

Conclusions
In patients with uncomplicated P. falciparum malaria, the nadir haemoglobin occurs 2 days after starting treatment. Although artemisinin-based treatments increase the rate of parasite clearance, in Asia they are associated with a greater risk of anaemia during recovery.