Rosauro Varo and Valerie M. Crowley equally contributed to the work, and should share co-primary authorship
Kevin C. Kain and Quique Bassat equally contributed to the work, and should share co-senior authorship
Despite recent efforts and successes in reducing the malaria burden globally, this infection still accounts for an estimated 212 million clinical cases, 2 million severe malaria cases, and approximately 429,000 deaths annually. Even with the routine use of effective anti-malarial drugs, the case fatality rate for severe malaria remains unacceptably high, with cerebral malaria being one of the most life-threatening complications. Up to one-third of cerebral malaria survivors are left with long-term cognitive and neurological deficits. From a population point of view, the decrease of malaria transmission may jeopardize the development of naturally acquired immunity against the infection, leading to fewer total cases, but potentially an increase in severe cases. The pathophysiology of severe and cerebral malaria is not completely understood, but both parasite and host determinants contribute to its onset and outcomes. Adjunctive therapy, based on modulating the host response to infection, could help to improve the outcomes achieved with specific anti-malarial therapy.
In the last decades, several interventions targeting different pathways have been tested. However, none of these strategies have demonstrated clear beneficial effects, and some have shown deleterious outcomes. This review aims to summarize evidence from clinical trials testing different adjunctive therapy for severe and cerebral malaria in humans. It also highlights some preclinical studies which have evaluated novel strategies and other candidate therapeutics that may be evaluated in future clinical trials.
WHO. World malaria report 2016. Geneva: World Health Organization; 2016.
WHO. Severe malaria. Trop Med Int Health. 2014;19(Suppl 1):7–131.
Prasad K, Garner P. Steroids for treating cerebral malaria. Cochrane Database Syst Rev. 2000;2:Cd000972.
de Souza JB, Okomo U, Alexander ND, Aziz N, Owens BM, Kaur H, et al. Oral activated charcoal prevents experimental cerebral malaria in mice and in a randomized controlled clinical trial in man did not interfere with the pharmacokinetics of parenteral artesunate. PLoS ONE. 2010;5:e9867. PubMedPubMedCentralCrossRef
Boggild AK, Krudsood S, Patel SN, Serghides L, Tangpukdee N, Katz K, et al. Use of peroxisome proliferator-activated receptor gamma agonists as adjunctive treatment for Plasmodium falciparum malaria: a randomized, double-blind, placebo-controlled trial. Clin Infect Dis. 2009;49:841–9. PubMedCrossRef
Auer-Hackenberg L, Staudinger T, Bojic A, Locker G, Leitner GC, Graninger W, et al. Automated red blood cell exchange as an adjunctive treatment for severe Plasmodium falciparum malaria at the Vienna General Hospital in Austria: a retrospective cohort study. Malar J. 2012;11:158. PubMedPubMedCentralCrossRef
Kreeftmeijer-Vegter AR, Melo Mde M, de Vries PJ, Koelewijn R, van Hellemond JJ, van Genderen PJ. Manual blood exchange transfusion does not significantly contribute to parasite clearance in artesunate-treated individuals with imported severe Plasmodium falciparum malaria. Malar J. 2013;12:115. PubMedPubMedCentralCrossRef
Meremikwu M, Smith HJ. Blood transfusion for treating malarial anaemia. Cochrane Database Syst Rev. 2000;2:CD001475.
Dash SC, Bhuyan UN, Gupta A, Sharma LC, Kumar A, Agarwal SK. Falciparum malaria complicating cholestatic jaundice and acute renal failure. J Assoc Physicians India. 1994;42:101–2. PubMed
Mohanty D, Ghosh K, Pathare AV, Karnad D. Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria. Indian J Med Res. 2002;115:17–21. PubMed
Smith HJ, Meremikwu M. Iron chelating agents for treating malaria. Cochrane Database Syst Rev. 2003;2:Cd001474.
Meremikwu M, Marson AG. Routine anticonvulsants for treating cerebral malaria. Cochrane Database Syst Rev. 2002;2:Cd002152.
Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med. 1989;71:441–59. PubMed
von Seidlein L, Olaosebikan R, Hendriksen IC, Lee SJ, Adedoyin OT, Agbenyega T, et al. Predicting the clinical outcome of severe falciparum malaria in African children: findings from a large randomized trial. Clin Infect Dis. 2012;54:1080–90. CrossRef
Krishna S, Agbenyega T, Angus BJ, Bedu-Addo G, Ofori-Amanfo G, Henderson G, et al. Pharmacokinetics and pharmacodynamics of dichloroacetate in children with lactic acidosis due to severe malaria. QJM. 1995;88:341–9. PubMed
De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96:60–8. PubMedPubMedCentralCrossRef
Yeo TW, Lampah DA, Kenangalem E, Tjitra E, Price RN, Weinberg JB, et al. Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation. PLoS Pathog. 2015;11:e1004667. PubMedPubMedCentralCrossRef
Higgins SJ, Purcell LA, Silver KL, Tran V, Crowley V, et al. Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Sci Transl Med. 2016;8:128. CrossRef
- Adjunctive therapy for severe malaria: a review and critical appraisal
Valerie M. Crowley
Kevin C. Kain
- BioMed Central
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