International Journal of Medical Sciences

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25 May 2019

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Int J Med Sci 2018; 15(13):1449-1457. doi:10.7150/ijms.27350

Research Paper

Plasmodium falciparum Treated with Artemisinin-based Combined Therapy Exhibits Enhanced Mutation, Heightened Cortisol and TNF-α Induction

Abel Olusola Idowu1,2, Sanjib Bhattacharyya4, Steve Gradus4, Wellington Oyibo3, Zenas George5, Carolyn Black5, Joseph Igietseme5, Anthony Ajayi Azenabor1✉

1. Department of Biomedical Sciences, University of Wisconsin, Milwaukee WI 53211 USA
2. Department of Pharmaceutics and Pharmaceutical Technology, University of Lagos, Nigeria
3. Department of Medical Microbiology and Parasitology, University of Lagos, Nigeria
4. City of Milwaukee Health Department Laboratories, Milwaukee, WI 53202 USA
5. Molecular Pathogenesis laboratory, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA


The artemisinin-based combined therapy (ACT) post-treatment illness in Plasmodium falciparum-endemic areas is characterized by vague malaria-like symptoms. The roles of treatment modality, persistence of parasites and host proinflammatory response in disease course are unknown. We investigated the hypothesis that ACT post-treatment syndrome is driven by parasite genetic polymorphisms and proinflammatory response to persisting mutant parasites. Patients were categorized as treated, untreated and malaria-negative. Malaria positive samples were analyzed for Pfcrt, Pfmdr1, K13 kelch gene polymorphisms, while all samples were evaluated for cytokines (TNF-α, IL-12p70, IL-10, TGF-β, IFN-γ) and corticosteroids (cortisol and dexamethasone) levels. The treated patients exhibited higher levels of parasitemia, TNF-α, and cortisol, increased incidence of parasite genetic mutations, and greater number of mutant alleles per patient. In addition, corticosteroid levels declined with increasing number of mutant alleles. TGF-β levels were negatively correlated with parasitemia, while IL-10 and TGF-β were negatively correlated with increasing number of mutant alleles. However, IL-12 displayed slight positive correlation and TNF-α exhibited moderate positive correlation with increasing number of mutant alleles. Since post-treatment management ultimately results in patient recovery, the high parasite gene polymorphism may act in concert with induced cortisol and TNF-α to account for ACT post-treatment syndrome.

Keywords: Proinflammation, corticosteroids, cortisol, dexamethasone, gene polymorphism, persistent malaria, ACT.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
How to cite this article:
Idowu AO, Bhattacharyya S, Gradus S, Oyibo W, George Z, Black C, Igietseme J, Azenabor AA. Plasmodium falciparum Treated with Artemisinin-based Combined Therapy Exhibits Enhanced Mutation, Heightened Cortisol and TNF-α Induction. Int J Med Sci 2018; 15(13):1449-1457. doi:10.7150/ijms.27350. Available from