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Ahead of Print -Slow Clearance of Plasmodium falciparum in Severe Pediatric Malaria, Uganda, 2011–2013 - Volume 21, Number 7—July 2015 - Emerging Infectious Disease journal - CDC

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Ahead of Print -Slow Clearance of Plasmodium falciparum in Severe Pediatric Malaria, Uganda, 2011–2013 - Volume 21, Number 7—July 2015 - Emerging Infectious Disease journal - CDC



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Volume 21, Number 7—July 2015

Dispatch

Slow Clearance of Plasmodium falciparum in Severe Pediatric Malaria, Uganda, 2011–2013

Michael Hawkes, Andrea L. Conroy, Robert O. Opoka, Sophie Namasopo, Kathleen Zhong, W. Conrad Liles, Chandy C. John, and Kevin C. KainComments to Author 
Author affiliations: University of Alberta, Edmonton, Alberta, Canada (M. Hawkes)University of Toronto, Toronto, Ontario, Canada (M. Hawkes, A.L. Conroy, K.C. Kain)Mulago Hospital, Kampala, Uganda (R.O. Opoka); Makerere University, Kampala (R. Opoka)Jinja Regional Referral Hospital, Jinja, Uganda (S. Namasopo);University Health Network–Toronto General Hospital, Toronto (K. Zhong, K.C. Kain)University of Washington, Seattle, Washington, USA (W.C. Liles)University of Minnesota, St. Paul, Minnesota, USA (C.C. John)Sandra Rotman Centre for Global Health, Toronto (K.C. Kain)

Abstract

Plasmodium falciparum resistance to artemisinin derivatives is emerging in Asia. We examined molecular markers of resistance in 78 children in Uganda who had severe malaria and were treated with intravenous artesunate. We observed in the K13-propeller domain, A578S, a low-frequency (3/78), nonsynonymous, single-nucleotide polymorphism associated with prolonged parasite clearance.
Resistance of Plasmodium falciparum parasites to artemisinin derivatives threatens the current first-line treatment for severe malaria. Artemisinin resistance was first reported in 2009 in Pailin, western Cambodia (1), and has since become prevalent in the greater Mekong Delta, Vietnam, where standard 3-day courses of artemisinin combination therapies for uncomplicated P. falciparum malaria are now failing (24).
Among several putative genetic determinants of parasite resistance to artesunate (3,5), polymorphisms in the propeller domain of a kelch gene on chromosome 13 (PF3D7_1343700; K13) are now recognized as the major determinant of artemisinin resistance observed in P. falciparum isolates from patients in Southeast Asia (3,4,6,7). Various single amino acid substitutions in the K13 protein are associated with a mean increase of 116% in the parasite clearance half-life (t1/2) (4). The mechanism of resistance has been illuminated by a recent study of the P. falciparum transcriptomes from >1,000 acute malaria episodes (6). Slow-clearing parasites exhibited increased expression of unfolded protein response pathways (e.g., chaperone complexes); these pathways may mitigate protein damage caused by artemisinin. Slow-clearing parasites also exhibited decreased expression of proteins involved in DNA replication and decelerated development at the young ring stage. Haplotype analysis suggests that K13 mutations emerged independently in multiple geographic locations in Southeast Asia, causing concerns about the ability to contain resistant parasites (7).
With the widespread use of artemisinin treatment, resulting in continued pressure for natural selection of the most resistant parasites, resistance may emerge in regions beyond Asia, including Africa. The possible increase of parasite resistance to treatment highlights an urgent need to map K13 mutations throughout the malaria-endemic world (7). Consequently, recent molecular epidemiologic analyses of K13 in Senegal (8) and Uganda (9) and in a large collection of >1,100 infections from sub-Saharan Africa (10) have been undertaken, revealing the absence of nonsynonymous single-nucleotide polymorphisms (SNPs) associated with artemisinin resistance in Southeast Asia. Other distinct nonsynonymous SNPs have been discovered in parasites of African origin (9,10), but association of these mutations with a resistance phenotype has not been shown.

Dr. Hawkes is a clinician–scientist (pediatric infectious diseases) at the University of Alberta, Edmonton, Alberta, Canada. His current research includes translational and clinical studies in global pediatric infections (i.e., malaria and pneumonia).

Acknowledgment

Trial operational costs were provided by the Sandra Rotman Centre for Global Health. This work was also supported by donations from Kim Kertland, the Tesari Foundation, the Canadian Institutes of Health Research MOP-244701 and 13721 (K.C.K.), the Canada Research Chair in Molecular Parasitology (K.C.K.), the Canada Research Chair in Infectious Diseases and Inflammation (W.C.L.), the Canadian Institutes of Health Research Clinician–Scientist Training Award (M.H.), and a postdoctoral research award (A.L.C.).

References

  1. Dondorp AMNosten FYi PDas DPhyo APTarning JArtemisinin resistance in Plasmodium falciparum malaria. N Engl J Med2009;361:45567.DOIPubMed
  2. Amaratunga CSreng SSuon SPhelps ESStepniewska KLim PArtemisinin-resistant Plasmodium falciparum in Pursat province, western Cambodia: a parasite clearance rate study. Lancet Infect Dis2012;12:8518DOIPubMed
  3. Ariey FWitkowski BAmaratunga CBeghain JLanglois ACKhim NA molecular marker of artemisinin-resistant Plasmodium falciparum malaria.Nature2014;505:505DOIPubMed
  4. Ashley EADhorda MFairhurst RMAmaratunga CLim PSuon SSpread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med.2014;371:41123DOIPubMed
  5. Venkatesan MGadalla NBStepniewska KDahal PNsanzabana CMoriera CPolymorphisms in Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes: parasite risk factors that affect treatment outcomes for P. falciparum malaria after artemether–lumefantrine and artesunate–amodiaquine. Am J Trop Med Hyg2015.DOIPubMed
  6. Mok SAshley EAFerreira PEZhu LLin ZYeo TPopulation transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science2014.PubMed
  7. Takala-Harrison SJacob CGArze CCummings MPSilva JCDondorp AMIndependent emergence of artemisinin resistance mutations amongPlasmodium falciparum in Southeast Asia. J Infect Dis2015DOIPubMed
  8. Torrentino-Madamet MFall BBenoit NCamara CAmalvict RFall MLimited polymorphisms in k13 gene in Plasmodium falciparum isolates from Dakar, Senegal in 2012–2013. Malar J2014;13:472DOIPubMed
  9. Conrad MDBigira VKapisi JMuhindo MKamya MRHavlir DVPolymorphisms in K13 and falcipain-2 associated with artemisinin resistance are not prevalent in Plasmodium falciparum isolated from Ugandan children. PLoS ONE2014;9:e105690DOIPubMed
  10. Taylor SMParobek CMDeConti DKKayentao KCoulibaly SOGreenwood BMAbsence of putative artemisinin resistance mutations amongPlasmodium falciparum in sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis2015DOIPubMed
  11. Hawkes MOpoka RONamasopo SMiller CThorpe KELavery JVInhaled nitric oxide for the adjunctive therapy of severe malaria: protocol for a randomized controlled trial. Trials2011;12:176DOIPubMed
  12. World Health Organization. Guidelines for the treatment of malaria. 2nd ed. 2010 Mar [cited 2014 Dec 5].http://www.who.int/malaria/publications/en/
  13. Flegg JAGuerin PJNosten FAshley EAPhyo APDondorp AMOptimal sampling designs for estimation of Plasmodium falciparum clearance rates in patients treated with artemisinin derivatives. Malar J2013;12:411DOIPubMed
  14. Maude RJSilamut KPlewes KCharunwatthana PHo MAbul Faiz MRandomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia. J Infect Dis2014;209:1209DOIPubMed
  15. Mohon ANAlam MSBayih AGFolefoc AShahinas DHaque RMutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009–2013). Malar J2014;13:431DOIPubMed

Table

Suggested citation for this article: Hawkes M, Conroy AL, Opoka RO, Namasopo S, Zhong K, Liles WC, et al. Slow clearance of Plasmodium falciparum in severe pediatric malaria, Uganda, 2011–2013. Emerg Infect Dis. 2015 Jul [date cited]. http://dx.doi.org/10.3201/eid2107.150213
DOI: 10.3201/eid2107.150213

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