Mass campaigns with antimalarial drugs are potentially a powerful tool for local elimination of malaria, yet current diagnostic technologies are insufficiently sensitive to identify all individuals who harbor infections. At the same time, overtreatment of uninfected individuals increases the risk of accelerating emergence of drug resistance and losing community acceptance. Local heterogeneity in transmission intensity may allow campaign strategies that respond to index cases to successfully target subpatent infections while simultaneously limiting overtreatment. While selective targeting of hotspots of transmission has been proposed as a strategy for malaria control, such targeting has not been tested in the context of malaria elimination. Using household locations, demographics, and prevalence data from a survey of four health facility catchment areas in southern Zambia and an agent-based model of malaria transmission and immunity acquisition, a transmission intensity was fit to each household based on neighborhood age-dependent malaria prevalence. A set of individual infection trajectories was constructed for every household in each catchment area, accounting for heterogeneous exposure and immunity. Various campaign strategies—mass drug administration, mass screen and treat, focal mass drug administration, snowball reactive case detection, pooled sampling, and a hypothetical serological diagnostic—were simulated and evaluated for performance at finding infections, minimizing overtreatment, reducing clinical case counts, and interrupting transmission. For malaria control, presumptive treatment leads to substantial overtreatment without additional morbidity reduction under all but the highest transmission conditions. Compared with untargeted approaches, selective targeting of hotspots with drug campaigns is an ineffective tool for elimination due to limited sensitivity of available field diagnostics. Serological diagnosis is potentially an effective tool for malaria elimination but requires higher coverage to achieve similar results to mass distribution of presumptive treatment.
References
[1]
World Health Organization. World Malaria Report 2014. Geneva: World Health Organization; 2015.
[2]
Moonen B, Cohen JM, Snow RW, Slutsker L, Drakeley C, Smith DL, et al. Operational strategies to achieve and maintain malaria elimination. Lancet. 2010;376: 1592–1603. doi: 10.1016/S0140-6736(10)61269-X. pmid:21035841
[3]
Alonso PL, Brown G, Arévalo-Herrera M, Binka F, Chitnis C, Collins F, et al. A Research Agenda to Underpin Malaria Eradication. PLoS Med. 2011;8: e1000406. doi: 10.1371/journal.pmed.1000406.s002. pmid:21311579
[4]
Newby G, Hwang J, Koita K, Chen I, Greenwood B, Seidlein von L, et al. Review of Mass Drug Administration for Malaria and Its Operational Challenges. Am J Trop Med Hyg. 2015;93: 125–134. doi: 10.4269/ajtmh.14-0254. pmid:26013371
[5]
Gerardin J, Eckhoff P, Wenger EA. Mass campaigns with antimalarial drugs: a modelling comparison of artemether-lumefantrine and DHA-piperaquine with and without primaquine as tools for malaria control and elimination. BMC Infect Dis. 2015;15: 144. doi: 10.1186/s12879-015-0887-y. pmid:25887935
[6]
Okell LC, Griffin JT, Kleinschmidt I, Hollingsworth TD, Churcher TS, White MJ, et al. The Potential Contribution of Mass Treatment to the Control of Plasmodium falciparum Malaria. PLoS One. 2011;6: e20179. doi: 10.1371/journal.pone.0020179.s001. pmid:21629651
[7]
Maude RJ, Socheat D, Nguon C, Saroth P, Dara P, Li G, et al. Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance. PLoS One. 2012;7: e37166. doi: 10.1371/journal.pone.0037166. pmid:22662135
[8]
Slater HC, Walker PGT, Bousema T, Okell LC, Ghani AC. The potential impact of adding ivermectin to a mass treatment intervention to reduce malaria transmission: a modelling study. J Infect Dis. 2014;210: 1972–1980. doi: 10.1093/infdis/jiu351. pmid:24951826
[9]
Smith T, Maire N, Ross A, Penny M, Chitnis N, Schapira A, et al. Towards a comprehensive simulation model of malaria epidemiology and control. Parasitology. 2008;135: 1507. doi: 10.1017/S0031182008000371. pmid:18694530
[10]
Ouédraogo AL, Bousema T, Schneider P, de Vlas SJ, Ilboudo-Sanogo E, Cuzin-Ouattara N, et al. Substantial Contribution of Submicroscopical Plasmodium falciparum Gametocyte Carriage to the Infectious Reservoir in an Area of Seasonal Transmission. PLoS One. 2009;4: e8410. doi: 10.1371/journal.pone.0008410.t002. pmid:20027314
[11]
Schneider P, Bousema JT, Gouagna LC, Otieno S, van de Vegte-Bolmer M, Omar SA, et al. Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection. Am J Trop Med Hyg. 2007;76: 470–474. pmid:17360869
[12]
Seidlein von L, Greenwood BM. Mass administrations of antimalarial drugs. Trends Parasitol. 2003;19: 452–460. pmid:14519583 doi: 10.1016/j.pt.2003.08.003
[13]
Kay K, Hastings IM. Measuring windows of selection for anti-malarial drug treatments. Malar J. 2015;: 1–10. doi: 10.1186/s12936-015-0810-4. pmid:26228915
[14]
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: 455–467. doi: 10.1056/NEJMoa0808859. pmid:19641202
[15]
Greenwood BM. The microepidemiology of malaria and its importance to malaria control. Trans R Soc Trop Med Hyg. 1989;83 Suppl: 25–29. pmid:2576161
[16]
Bousema T, Griffin JT, Sauerwein RW, Smith DL, Churcher TS, Takken W, et al. Hitting Hotspots: Spatial Targeting of Malaria for Control and Elimination. PLoS Med. 2012;9: e1001165. doi: 10.1371/journal.pmed.1001165.t001. pmid:22303287
[17]
Bousema T, Okell L, Felger I, Drakeley C. Asymptomatic malaria infections: detectability, transmissibility and public health relevance. Nat Rev Microbiol. 2014;12: 833–840. doi: 10.1038/nrmicro3364. pmid:25329408
[18]
Tiono AB, Ouédraogo A, Ogutu B, Diarra A, Coulibaly S, Gansané A, et al. A controlled, parallel, cluster-randomized trial of community-wide screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso. Malar J. 2013;12: 79. doi: 10.1186/1475-2875-12-79. pmid:23442748
[19]
Larsen DA, Bennett A, Silumbe K, Hamainza B, Yukich JO, Keating J, et al. Population-Wide Malaria Testing and Treatment with Rapid Diagnostic Tests and Artemether-Lumefantrine in Southern Zambia: A Community Randomized Step-Wedge Control Trial Design. Am J Trop Med Hyg. 2015;92: 913–921. doi: 10.4269/ajtmh.14-0347. pmid:25802434
[20]
Cook J, Xu W, Msellem M, Vonk M, Bergstrom B, Gosling R, et al. Mass Screening and Treatment on the Basis of Results of a Plasmodium falciparum-Specific Rapid Diagnostic Test Did Not Reduce Malaria Incidence in Zanzibar. J Infect Dis. 2015;211: 1476–1483. doi: 10.1093/infdis/jiu655. pmid:25429102
[21]
Sutcliffe CG, Kobayashi T, Hamapumbu H, Shields T, Mharakurwa S, Thuma PE, et al. Reduced Risk of Malaria Parasitemia Following Household Screening and Treatment: A Cross-Sectional and Longitudinal Cohort Study. PLoS One. 2012;7: e31396. doi: 10.1371/journal.pone.0031396.s001. pmid:22319629
[22]
Gerardin J, Ouédraogo AL, McCarthy KA, Eckhoff PA, Wenger EA. Characterization of the infectious reservoir of malaria with an agent-based model calibrated to age-stratified parasite densities and infectiousness. Malar J. 2015;: 1–13. doi: 10.1186/s12936-015-0751-y. pmid:26037226
[23]
Seidlein von L. The failure of screening and treating as a malaria elimination strategy. PLoS Med. 2014;11: e1001595. doi: 10.1371/journal.pmed.1001595. pmid:24492211
[24]
The malERA Consultative Group on Diagnoses and Diagnostics. A Research Agenda for Malaria Eradication: Diagnoses and Diagnostics. PLoS Med. 2011;8: e1000396. doi: 10.1371/journal.pmed.1000396.t001. pmid:21311583
[25]
World Health Organization. Guidelines for the treatment of malaria. 2nd ed. Geneva: World Health Organization; 2010.
[26]
Stresman GH, Kamanga A, Moono P, Hamapumbu H, Mharakurwa S, Kobayashi T, et al. A method of active case detection to target reservoirs of asymptomatic malaria and gametocyte carriers in a rural area in Southern Province, Zambia. Malar J. 2010;9: 265. doi: 10.1186/1475-2875-9-265. pmid:20920328
[27]
Littrell M, Sow GD, Ngom A, Ba M, Mboup BM, Dieye Y, et al. Case investigation and reactive case detection for malaria elimination in northern Senegal. Malar J. 2013;12: 1–1. doi: 10.1186/1475-2875-12-331. pmid:24044506
[28]
Bejon P, Williams TN, Liljander A, Noor AM, Wambua J, Ogada E, et al. Stable and Unstable Malaria Hotspots in Longitudinal Cohort Studies in Kenya. PLoS Med. 2010;7: e1000304. doi: 10.1371/journal.pmed.1000304.s003. pmid:20625549
[29]
Stresman GH, Baidjoe AY, Stevenson J, Grignard L, Odongo W, Owaga C, et al. Focal screening to identify the subpatent parasite reservoir in an area of low and heterogeneous transmission in the Kenya highlands. J Infect Dis. 2015. doi: 10.1093/infdis/jiv302.
[30]
Mosha JF, Sturrock HJW, Greenhouse B, Greenwood B, Sutherland CJ, Gadalla N, et al. Epidemiology of subpatent Plasmodium falciparum infection: implications for detection of hotspots with imperfect diagnostics. Malar J. 2013;12: 221. doi: 10.1186/1475-2875-12-221. pmid:23815811
[31]
Okell LC, Bousema T, Griffin JT, Ouédraogo AL, Ghani AC, Drakeley CJ. Factors determining the occurrence of submicroscopic malaria infections and their relevance for control. Nat Commun. 2012;3: 1237. doi: 10.1038/ncomms2241. pmid:23212366
[32]
Stresman GH, Stevenson JC, Ngwu N, Marube E, Owaga C, Drakeley C, et al. High Levels of Asymptomatic and Subpatent Plasmodium falciparum Parasite Carriage at Health Facilities in an Area of Heterogeneous Malaria Transmission Intensity in the Kenyan Highlands. Am J Trop Med Hyg. 2014;91: 1101–1108. doi: 10.4269/ajtmh.14-0355. pmid:25331807
[33]
Walker PG, White MT, Griffin JT, Reynolds A, Ferguson NM, Ghani AC. Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis. Lancet Infect Dis. 2015;: 1–8. doi: 10.1016/S1473-3099(15)70124-6. pmid:25921597
[34]
Helb DA, Tetteh KKA, Felgner PL, Skinner J, Hubbard A, Arinaitwe E, et al. Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities. Proc Natl Acad Sci USA. 2015;: 201501705. doi: 10.1073/pnas.1501705112.
[35]
Daniels RF, Schaffner SF, Wenger EA, Proctor JL, Chang H-H, Wong W, et al. Modeling malaria genomics reveals transmission decline and rebound in Senegal. Proc Natl Acad Sci U S A. 2015. doi: 10.1073/pnas.1505691112.
[36]
Nkhoma SC, Nair S, Al-Saai S, Ashley E, McGready R, Phyo AP, et al. Population genetic correlates of declining transmission in a human pathogen. Mol Ecol. 2012;22: 273–285. doi: 10.1111/mec.12099. pmid:23121253
[37]
Pinchoff J, Henostroza G, Carter BS, Roberts ST, Hatwiinda S, Hamainza B, et al. Spatial patterns of incident malaria cases and their household contacts in a single clinic catchment area of Chongwe District, Zambia. Malar J. 2015;14: 305. doi: 10.1186/s12936-015-0793-1. pmid:26246383
[38]
Acevedo MA, Prosper O, Lopiano K, Ruktanonchai N, Caughlin TT, Martcheva M, et al. Spatial Heterogeneity, Host Movement and Mosquito-Borne Disease Transmission. PLoS One. 2015;10: e0127552. doi: 10.1371/journal.pone.0127552.s003. pmid:26030769
[39]
Silal SP, Little F, Barnes KI, White LJ. Predicting the impact of border control on malaria transmission: a simulated focal screen and treat campaign. Malar J. 2015: 1–14. doi: 10.1186/s12936-015-0776-2. pmid:26164675
[40]
Eckhoff PA. A malaria transmission-directed model of mosquito life cycle and ecology. Malar J. 2011;10: 303. doi: 10.1186/1475-2875-10-303. pmid:21999664
[41]
Eckhoff P. Mathematical Models of Within-Host and Transmission Dynamics to Determine Effects of Malaria Interventions in a Variety of Transmission Settings. Am J Trop Med Hyg. 2013;88: 817–827. doi: 10.4269/ajtmh.12-0007. pmid:23589530
[42]
Eckhoff PA. Malaria parasite diversity and transmission intensity affect development of parasitological immunity in a mathematical model. Malar J. 2012;11: 1–1. doi: 10.1186/1475-2875-11-419. pmid:23241282
[43]
Institute for Disease Modeling. Epidemiological Modeling Software. 2015.
[44]
Taylor SM, Juliano JJ, Trottman PA, Griffin JB, Landis SH, Kitsa P, et al. High-Throughput Pooling and Real-Time PCR-Based Strategy for Malaria Detection. J Clin Microbiol. 2010;48: 512–519. doi: 10.1128/JCM.01800-09. pmid:19940051
[45]
Gu W, Killeen GF, Mbogo CM, Regens JL, Githure JI, Beier JC. An individual-based model of Plasmodium falciparum malaria transmission on the coast of Kenya. Trans R Soc Trop Med Hyg. 2005;99:459–67. doi: 10.1016/s0035-9203(03)90018-6
[46]
Babiker HA, Schneider P, Reece SE. Gametocytes: insights gained during a decade of molecular monitoring. Trends Parasitol. 2008;24: 525–530. doi: 10.1016/j.pt.2008.08.001. pmid:18801702
[47]
Beier JC, Copeland RS, Mtalib R, Vaughan JA. Ookinete rates in Afrotropical anopheline mosquitoes as a measure of human malaria infectiousness. Am J Trop Med Hyg. 1992;47: 41–46. pmid:1636882
[48]
Smith DL, McKenzie FE. Statics and dynamics of malaria infection in Anopheles mosquitoes. Malar J. 2004;3: 13. doi: 10.1186/1475-2875-3-13. pmid:15180900
[49]
Smith DL, Dushoff J, Snow RW, Hay SI. The entomological inoculation rate and Plasmodium falciparum infection in African children. Nature. 2005;438: 492–495. doi: 10.1038/nature04024. pmid:16306991
