DISPATCHESFigure. Maximum-likelihood bootstrap consensus phylogenetictree showing the relationship between rat lungworm sequencesgenerated in this study and other Angiostrongylus spp., UnitedStates. Tree was generated by using a Tamura 3-parametermodel. Value along the branch is a bootstrap value.parasite. Although wildlife might become infected with theparasite, not all wildlife are definitive hosts (5,11). Additionalfield and laboratory studies will clarify the role thatS. hispidus rats play in the spread of the rat lungworm.Because many terrestrial species remain taxonomicallynondescribed, there is strong potential for continual emergenceof unknown pathogens worldwide (14). Global travel,human encroachment into wildlife habitat, and climatechange will influence distribution and emergence of disease(2,15). By incorporating field epidemiology with moleculargenetic techniques to determine the geographic distributionof pathogens, major advances can be made in preventing thespread of wildlife diseases to human populations. Our resultsillustrate this point and highlight the need for future work toincorporate and refine these techniques and their applicationto epidemiology and wildlife disease surveillance.AcknowledgmentsWe thank Joshua York, Erica Judd, Elizabeth O’Bannon, andMichelle Haynie for helpful comments on earlier drafts of themanuscript and technical support; Mark Eberhard for providingadult A. cantonensis rat lungworms; the City of New OrleansMosquito, Termite, and Rodent Control Board for supplyingsamples and additional resources; and John Cross for being theinspiration for this project.This study was supported by the Office of Research and Grants,the W. Roger Webb Forensic Science Institute, and the Departmentof Biology at the University of Central Oklahoma.Mrs. York is an integrated pest management and collections specialistat the University of Oklahoma Sam Noble Museum of NaturalHistory. Her research interests include infectious disease surveillance,host–parasite ecology, and animal behavior/interactions.References1. Daszak P, Cunningham AA, Hyatt AD. Emerging infectiousdiseases of wildlife-threats to biodiversity and human health.Science. 2000;287:443–9. http://dx.doi.org/10.1126/science.287.5452.4432. Bengis RG, Leighton FA, Fischer JR, Artois M, Morner T,Tate CM. The role of wildlife in emerging and re-emergingzoonoses. Rev Sci Tech. 2004;23:497–511.3. Patz JA, Graczyk TK, Geller N, Vittor AY. Effects of environmentalchange on emerging parasitic diseases. Int J Parasitol. 2000;30:1395–405. http://dx.doi.org/10.1016/S0020-7519(00)00141-74. Prociv P, Spratt DM, Carlisle MS. Neuro-angiostrongyliasis:unresolved issues. Int J Parasitol. 2000;30:1295–303.http://dx.doi.org/10.1016/S0020-7519(00)00133-85. Duffy MS, Miller C, Kinsella J, Lahunta A. Parastrongyluscantonensis in a nonhuman primate, Florida. Emerg Infect Dis.2004;10:2207–10. http://dx.doi.org/10.3201/eid1012.0403196. Wang QP, Lai DH, Zhu XQ, Chen XG, Lun ZR. Humanangiostrongyliasis. Lancet Infect Dis. 2008;8:621–30.http://dx.doi.org/10.1016/S1473-3099(08)70229-97. Lindo JF, Waugh C, Hall J, Cunningham-Myrie C, Ashley D,Eberhard M, et al. Enzootic Angiostrongylus cantonensis in ratsand snails after an outbreak of human eosinophilic meningitis,Jamaica. Emerg Infect Dis. 2002;8:324–6. http://dx.doi.org/10.3201/eid0803.0103168. Kliks MM, Palumbo N. Eosinophilic meningitis beyond the PacificBasin: the global dispersal of a peridomestic zoonosis byAngiostrongylus cantonensis, the nematode lungworm of rats.Soc Sci Med. 1992;34:199–212. http://dx.doi.org/10.1016/0277-9536(92)90097-A9. York EM, Butler CJ, Lord WD. Global decline in suitablehabitat for Angiostrongylus (=Parastrongylus) cantonensis: the roleof climate change. PLoS ONE. 2014;9:e103831.http://dx.doi.org/10.1371/journal.pone.010383110. Qvarnstrom Y, Silva A, Teem J, Hollingsworth R, Bishop H,Graeff-Teixeira C, et al. Improved molecular detection ofAngiostrongylus cantonensis in mollusks and other environmentalsample with a species-specific ITS1-based TaqMan assay.Appl Environ Microbiol. 2010;76:5287–9. http://dx.doi.org/10.1128/AEM.00546-1011. Kim DY, Stewart T, Bauer R, Mitchell M. Parastrongylus(=Angiostrongylus) cantonensis now endemic in Louisiana.J Parasitol. 2002;88:1024–6. http://dx.doi.org/10.1645/0022-3395(2002)088[1024:PACNEI]2.0.CO;212. Rachowicz LJ, Hero JM, Alford RA, Taylor JW, Morgan JAT,Vredenburg VT, et al. The novel and endemic pathogen hypotheses:competing explanations for the origin of emerging infectiousdiseases of wildlife. Conservation Biology. 2005;19:1441–8.http://dx.doi.org/10.1111/j.1523-1739.2005.00255.x13. Whitaker JO Jr. National Audubon Society field guide toNorth American mammals. New York: Alfred A. Knopf, Inc.;1980. p. 745.14. Mora C, Tittensor DP, Adl S, Simpson AG, Worm B.How many species are there on Earth and in the ocean? PLoS Biol.2011;9:e1001127. http://dx.doi.org/10.1371/journal.pbio.100112715. Cunningham AA. A walk on the wild side–emerging wildlifediseases. BMJ. 2005;331:1214–5. http://dx.doi.org/10.1136/bmj.331.7527.1214Address for correspondence: Emily M. York, Sam Noble OklahomaMuseum of Natural History, University of Oklahoma, 2401 ChautauquaAve, Norman, OK 73072, USA; email: eyork@ou.edu1236 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 7, July 2015
Slow Clearance of Plasmodium falciparum inSevere Pediatric Malaria, Uganda, 2011–2013Michael Hawkes, Andrea L. Conroy,Robert O. Opoka, Sophie Namasopo,Kathleen Zhong, W. Conrad Liles,Chandy C. John, Kevin C. KainPlasmodium falciparum resistance to artemisinin derivativesis emerging in Asia. We examined molecular markersof resistance in 78 children in Uganda who had severe malariaand were treated with intravenous artesunate. We observedin the K13-propeller domain, A578S, a low-frequency(3/78), nonsynonymous, single-nucleotide polymorphismassociated with prolonged parasite clearance.Resistance of Plasmodium falciparum parasites to artemisininderivatives threatens the current first-linetreatment for severe malaria. Artemisinin resistance wasfirst reported in 2009 in Pailin, western Cambodia (1), andhas since become prevalent in the greater Mekong Delta,Vietnam, where standard 3-day courses of artemisinin combinationtherapies for uncomplicated P. falciparum malariaare now failing (2–4).Among several putative genetic determinants ofparasite resistance to artesunate (3,5), polymorphisms inthe propeller domain of a kelch gene on chromosome 13(PF3D7_1343700; K13) are now recognized as the majordeterminant of artemisinin resistance observed in P. falciparumisolates from patients in Southeast Asia (3,4,6,7).Various single amino acid substitutions in the K13 proteinare associated with a mean increase of 116% in theparasite clearance half-life (t 1/2) (4). The mechanism ofresistance has been illuminated by a recent study of theP. falciparum transcriptomes from >1,000 acute malariaepisodes (6). Slow-clearing parasites exhibited increasedexpression of unfolded protein response pathways (e.g.,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 GlobalHealth, Toronto (K.C. Kain)DOI: http://dx.doi.org/10.3201/eid2107.150213chaperone complexes); these pathways may mitigate proteindamage caused by artemisinin. Slow-clearing parasitesalso exhibited decreased expression of proteins involved inDNA replication and decelerated development at the youngring stage. Haplotype analysis suggests that K13 mutationsemerged independently in multiple geographic locations inSoutheast Asia, causing concerns about the ability to containresistant parasites (7).With the widespread use of artemisinin treatment, resultingin continued pressure for natural selection of themost resistant parasites, resistance may emerge in regionsbeyond Asia, including Africa. The possible increase ofparasite resistance to treatment highlights an urgent need tomap K13 mutations throughout the malaria-endemic world(7). Consequently, recent molecular epidemiologic analysesof K13 in Senegal (8) and Uganda (9) and in a largecollection of >1,100 infections from sub-Saharan Africa(10) have been undertaken, revealing the absence of nonsynonymoussingle-nucleotide polymorphisms (SNPs) associatedwith artemisinin resistance in Southeast Asia. Otherdistinct nonsynonymous SNPs have been discovered inparasites of African origin (9,10), but association of thesemutations with a resistance phenotype has not been shown.The StudyWe examined parasite clearance kinetics and sequenced theparasite K13 gene in a cohort of 78 children with severemalaria (including 8 children who died) from the placebogroup (being treated with artesunate alone) of a randomized,controlled trial conducted at the Jinja Regional ReferralHospital, Uganda, during July 12, 2011–June 14, 2013(11). Inclusion and exclusion criteria have been describedelsewhere (11). The median age of patients was 2.0 years(range 1.0–8.0 years), and 38 (49%) were female. Allpatients were treated intravenously with artesunate (GuilinPharmaceutical, Shanghai, China) prequalified by theWorld Health Organization and according to the Organization’sguidelines (12).Giemsa-stained peripheral blood smears (thin andthick) were assessed for quantitative malaria parasite densityby light microscopy at a quality-controlled centralresearch laboratory, the Makerere University–Johns HopkinsUniversity Research Collaboration Core Laboratory,which is certified by the College of American Pathologists.For each patient, 5 serial parasite densities were measuredaccording to the following sampling schedule: 1) admission;2) ≈12 hours later; 3) morning of the second day ofEmerging Infectious Diseases • www.cdc.gov/eid • Vol. 21, No. 7, July 2015 1237
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