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DISPATCHESTable. Characteristics of children infected with severe Plasmodium falciparum malaria parasites harboring the Kelch 13 A578Spolymorphism compared with children infected with wild-type parasites, UgandaCharacteristic A578S mutation, n = 3 Wild-type parasite, n = 75 p valueParasite clearance time, median (interquartile range), h 80 (71–200) 45 (40–64)* 0.033Clearance half-life, median, (interquartile range), h 5.9 (5.6–10.7) 4.5 (3.6–5.8)* 0.074Prior artemisinin exposure, no. (%) 1 (33.3) 19 (25.3) 1.000Deaths, no. (%) 0 8 (10.7) 1.000Recrudescence or reinfection 0 0 1.000*For 7 patients who died, parasite clearance time could not be calculated because of incomplete parasite clearance prior to death. For these same 7children, the parasite clearance half-time (t1/2) could not be calculated because of insufficient data points. For 1 child who died, clearance of parasitemiabefore death was documented; thus, the parasite clearance time and t1/2 could be computed. Estimates of parasite clearance time and clearance t1/2 arebased on the remaining 68 patients. All fatal cases were associated with wild-type parasites.admission; 4) morning of the third day of admission; and 5)morning of the fourth day of admission.To measure parasite clearance kinetics, we used astandardized tool, the parasite clearance estimator, whichexpresses parasite clearance as the parasite’s half-life (t 1/2),which was calculated by using the slope of the linear portionof the curve of log-transformed parasite densities over time(13). In addition, we computed the parasite clearance time,defined as the interval between the start of treatment and thefirst of 2 sequential negative peripheral blood films (14).To determine molecular markers of resistance, we amplifiedand sequenced the PF3D7_1343700 gene by usingthe nested PCR method, as described (3), with some modifications.DNA was extracted from cryopreserved erythrocytefractions by using QIAGEN columns (QIAGEN, Valencia,CA, USA) according to the manufacturer’s instructions.The K13-propeller domain was amplified by using K13-1 5′-CGGAGTGACCAAATCTGGGA-3′ and 5′-K13-4GGGAATCTGGTGGTAACAGC-3′ for the primary PCRand K13-2 5′-GCCAAGCTGCCATTCATTTG-3′ andK13-3 5′-GCCTTGTTGAAAGAAGCAGA-3′ for thenested PCR. DNA sequencing of the 810-bp nested PCRproduct was performed to determine the amino acid haplotypeof residues. Results were aligned to reference PF3D7kelch protein, putative (PF13_0238) mRNA, completecoding sequence (National Center for Biotechnology Informationreference sequence XM_001350122.1).We identified limited diversity within the K13 gene.For 16 loci tested (amino acid positions 439, 441, 458, 465,467, 476, 493, 522, 539, 543, 557, 558, 580, 617, 619, and637), the wild-type sequence was found in all 78 parasiteamplicons. We did not observe any of the most commonamino acid substitutions in K13 associated with artemisininresistance in P. falciparum isolates from Cambodia(C580Y, R539T or Y493H) (3), nor the I543T and N458Ymutations most strongly associated with increased clearancet 1/2in another recent study (4), nor the M476I mutationselected in vitro under artemisinin pressure (3). Similarly,these point mutations were absent in isolates from Senegaland Uganda and in >1,100 P. falciparum parasites from 14sites across sub-Saharan Africa (8–10). However, a previouslyreported point mutation, A578S (9,15), was found in3 (3.8%) of 78 infections.The Table shows infections with A578S parasitescompared with infections caused by wild-type parasites.Parasite clearance time was prolonged in infections withA578S mutant parasites, and a similar trend was observedfor clearance t 1/2.These 2 types of infections showed nodifferences in prior artemisinin exposure, number ofdeaths, or recrudescence or reinfection at day 14 fromdate of admission.ConclusionsThe role of the A578S amino acid substitution is unclear,but it occurs near the most common K13-propellermutation (C580Y), which has been associated with delayedparasite clearance in Southeast Asia and with toleranceto artemisinin in vitro (3). Computational modelingsuggests that A578S should considerably affect the tertiarystructure of the K13 protein, thereby destabilizingthe domain scaffold and altering its function (15). Isolateswith A578S exhibited a phenotype of prolonged clearanceunder artesunate treatment in our study. Delayedclearance of A578S parasites was not observed in previousreports (4,9), although the number of isolates in ourstudy and in others was small. Because multiple independentmutations in K13 have arisen in geographic regionsengaged in intense treatment of malaria with artemisininderivatives (7) and because only 2 point mutations werenecessary to confer drug tolerance in vitro to a P. falciparumisolate from Tanzania (3), we are concernedthat parasites with the A578S mutation are already causingsevere malaria in children in Uganda, although withlow frequency.The nonsynonymous SNP A578S in the K13-propellerdomain may represent another putative marker of delayedresponse to artesunate, although this indicator occurredinfrequently in our cohort of children with severe malariain Uganda. Our study documents an association betweenA578S and prolonged parasite clearance time, a findingrelevant for future monitoring of P. falciparum response toparenteral artesunate in children in Africa.Trial operational costs were provided by the Sandra RotmanCentre for Global Health. This work was also supported by donationsfrom Kim Kertland, the Tesari Foundation, the Canadian1238 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 7, July 2015
Slow Clearance of Plasmodium falciparum, UgandaInstitutes 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 ResearchClinician–Scientist Training Award (M.H.), and a postdoctoralresearch award (A.L.C.).Dr. Hawkes is a clinician–scientist (pediatric infectious diseases)at the University of Alberta, Edmonton, Alberta, Canada. His currentresearch includes translational and clinical studies in globalpediatric infections (i.e., malaria and pneumonia).References1. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al.Artemisinin resistance in Plasmodium falciparum malaria.N Engl J Med. 2009;361:455–67. http://dx.doi.org/10.1056/NEJMoa08088592. Amaratunga C, Sreng S, Suon S, Phelps ES, Stepniewska K,Lim P, et al. Artemisinin-resistant Plasmodium falciparum in Pursatprovince, western Cambodia: a parasite clearance rate study.Lancet Infect Dis. 2012;12:851–8. http://dx.doi.org/10.1016/S1473-3099(12)70181-03. Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC,Khim N, et al. A molecular marker of artemisinin-resistantPlasmodium falciparum malaria. Nature. 2014;505:50–5.http://dx.doi.org/10.1038/nature128764. Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P,Suon S, et al. Spread of artemisinin resistance in Plasmodiumfalciparum malaria. N Engl J Med. 2014;371:411–23.http://dx.doi.org/10.1056/NEJMoa13149815. Venkatesan M, Gadalla NB, Stepniewska K, Dahal P,Nsanzabana C, Moriera C, et al. Polymorphisms in Plasmodiumfalciparum chloroquine resistance transporter and multidrugresistance 1 genes: parasite risk factors that affect treatmentoutcomes for P. falciparum malaria after artemether–lumefantrineand artesunate–amodiaquine. Am J Trop Med Hyg. 2015.http://dx.doi.org/10.4269/ajtmh.14-00316. Mok S, Ashley EA, Ferreira PE, Zhu L, Lin Z, Yeo T, et al.Population transcriptomics of human malaria parasites reveals themechanism of artemisinin resistance. Science. 2014.7. Takala-Harrison S, Jacob CG, Arze C, Cummings MP, Silva JC,Dondorp AM, et al. Independent emergence of artemisininresistance mutations among Plasmodium falciparum in SoutheastAsia. J Infect Dis. 2015.8. Torrentino-Madamet M, Fall B, Benoit N, Camara C, Amalvict R,Fall M, et al. Limited polymorphisms in k13 gene in Plasmodiumfalciparum isolates from Dakar, Senegal in 2012–2013. Malar J.2014;13:472. http://dx.doi.org/10.1186/1475-2875-13-4729. Conrad MD, Bigira V, Kapisi J, Muhindo M, Kamya MR,Havlir DV, et al. Polymorphisms in K13 and falcipain-2associated with artemisinin resistance are not prevalent in Plasmodiumfalciparum isolated from Ugandan children. PLoS ONE.2014;9:e105690. http://dx.doi.org/10.1371/journal.pone.010569010. Taylor SM, Parobek CM, DeConti DK, Kayentao K, Coulibaly SO,Greenwood BM, et al. Absence of putative artemisinin resistancemutations among Plasmodium falciparum in sub-Saharan Africa: amolecular epidemiologic study. J Infect Dis. 2015.11. Hawkes M, Opoka RO, Namasopo S, Miller C, Thorpe KE,Lavery JV, et al. Inhaled nitric oxide for the adjunctive therapy ofsevere malaria: protocol for a randomized controlled trial. Trials.2011;12:176. http://dx.doi.org/10.1186/1745-6215-12-17612. 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 JA, Guerin PJ, Nosten F, Ashley EA, Phyo AP, Dondorp AM,et al. Optimal sampling designs for estimation of Plasmodiumfalciparum clearance rates in patients treated with artemisininderivatives. Malar J. 2013;12:411. http://dx.doi.org/10.1186/1475-2875-12-41114. Maude RJ, Silamut K, Plewes K, Charunwatthana P, Ho M,Abul Faiz M, et al. Randomized controlled trial of levamisolehydrochloride as adjunctive therapy in severe falciparummalaria with high parasitemia. J Infect Dis. 2014;209:120–9.http://dx.doi.org/10.1093/infdis/jit41015. Mohon AN, Alam MS, Bayih AG, Folefoc A, Shahinas D,Haque R, et al. Mutations in Plasmodium falciparum K13 propellergene from Bangladesh (2009–2013). Malar J. 2014;13:431.http://dx.doi.org/10.1186/1475-2875-13-431Address for correspondence: Kevin C. Kain, Sandra Rotman Centre forGlobal Health, MaRS Centre, 101 College St TMDT 10-360A, Toronto,ON M5G 1L7, Canada; email: kevin.kain@uhn.caThe Public Health Image Library (PHIL)The Public Health Image Library (PHIL), Centersfor Disease Control and Prevention, containsthousands of public health-related images,including high-resolution (print quality)photographs, illustrations, and videos.PHIL collections illustrate current events andarticles, supply visual content for health promotionbrochures, document the effects of disease, andenhance instructional media.PHIL Images, accessible to PC and Macintosh users,are in the public domain and available without charge.Visit PHIL at http://phil.cdc.gov/philEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 7, July 2015 1239
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July 2015SynopsisOn the CoverMarian
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1240 Gastroenteritis OutbreaksCause
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