Asymptomatic malaria infections: detectability, transmissibility and public health relevance

Abstract

Most Plasmodium falciparum infections that are detected in community surveys are characterized by low-density parasitaemia and the absence of clinical symptoms. Molecular diagnostics have shown that this asymptomatic parasitic reservoir is more widespread than previously thought, even in low-endemic areas. In this Opinion article, we describe the detectability of asymptomatic malaria infections and the relevance of submicroscopic infections for parasite transmission to mosquitoes and for community interventions that aim at reducing transmission. We argue that wider deployment of molecular diagnostic tools is needed to provide adequate insight into the epidemiology of malaria and infection dynamics to aid elimination efforts.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Sensitivity of malaria diagnostic methods in relation to parasite density and transmission intensity.

References

  1. 1

    World Health Organization. World Malaria Report (WHO, 2012).

  2. 2

    Murray, C. J. et al. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 379, 413–431 (2012).

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Hay, S. I. et al. Estimating the global clinical burden of Plasmodium falciparum malaria in 2007. PLoS Med. 7, e1000290 (2010).

    PubMed  PubMed Central  Google Scholar 

  4. 4

    Hermsen, C. C. et al. Testing vaccines in human experimental malaria: statistical analysis of parasitemia measured by a quantitative real-time polymerase chain reaction. Am. J. Trop. Med. Hyg. 71, 196–201 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Eichner, M. et al. Genesis, sequestration and survival of Plasmodium falciparum gametocytes: parameter estimates from fitting a model to malariatherapy data. Trans. R. Soc. Trop. Med. Hyg. 95, 497–501 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Bousema, T. et al. Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs. Malar. J. 9, 136 (2010).

    PubMed  PubMed Central  Google Scholar 

  7. 7

    Smalley, M. E. & Sinden, R. E. Plasmodium falciparum gametocytes: their longevity and infectivity. Parasitology 74, 1–8 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Greenwood, B. M. Asymptomatic malaria infections — do they matter? Parasitol. Today 3, 206–214 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Njama-Meya, D., Kamya, M. R. & Dorsey, G. Asymptomatic parasitaemia as a risk factor for symptomatic malaria in a cohort of Ugandan children. Trop. Med. Int. Health 9, 862–868 (2004).

    PubMed  PubMed Central  Google Scholar 

  10. 10

    Tran, T. M. et al. An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin. Infect. Dis. 57, 40–47 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Nsobya, S. L. et al. Molecular evaluation of the natural history of asymptomatic parasitemia in Ugandan children. J. Infect. Dis. 189, 2220–2226 (2004).

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Roucher, C. et al. Changing malaria epidemiology and diagnostic criteria for Plasmodium falciparum clinical malaria. PLoS ONE 7, e46188 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Belizario, V. Y. et al. Field epidemiological studies on malaria in a low endemic area in the Philippines. Acta Trop. 63, 241–256 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Okell, L. C. et al. Factors determining the occurrence of submicroscopic malaria infections and their relevance for control. Nature Commun. 3, 1237 (2012).

    Google Scholar 

  15. 15

    Cotter, C. et al. The changing epidemiology of malaria elimination: new strategies for new challenges. Lancet 382, 900–911 (2013).

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Bejon, P. et al. Thick blood film examination for Plasmodium falciparum malaria has reduced sensitivity and underestimates parasite density. Malar. J. 5, 104 (2006).

    PubMed  PubMed Central  Google Scholar 

  17. 17

    Wongsrichanalai, C., Barcus, M. J., Muth, S., Sutamihardja, A. & Wernsdorfer, W. H. A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT). Am. J. Trop. Med. Hyg. 77, 119–127 (2007).

    PubMed  PubMed Central  Google Scholar 

  18. 18

    Bell, D., Wongsrichanalai, C. & Barnwell, J. W. Ensuring quality and access for malaria diagnosis: how can it be achieved? Nature Rev. Microbiol. 4, 682–695 (2006).

    CAS  Google Scholar 

  19. 19

    Snounou, G., Viriyakosol, S., Jarra, W., Thaithong, S. & Brown, K. N. Identification of the four human malaria parasite species in field samples by the polymerase chain reaction and detection of a high prevalence of mixed infections. Mol. Biochem. Parasitol. 58, 283–292 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Schneider, P. et al. Real-time nucleic acid sequence-based amplification is more convenient than real-time PCR for quantification of Plasmodium falciparum. J. Clin. Microbiol. 43, 402–405 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Wampfler, R. et al. Strategies for detection of Plasmodium species gametocytes. PLoS ONE 8, e76316 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Schoone, G. J., Oskam, L., Kroon, N. C., Schallig, H. D. & Omar, S. A. Detection and quantification of Plasmodium falciparum in blood samples using quantitative nucleic acid sequence-based amplification. J. Clin. Microbiol. 38, 4072–4075 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Murphy, S. C. et al. Real-time quantitative reverse transcription PCR for monitoring of blood-stage Plasmodium falciparum infections in malaria human challenge trials. Am. J. Trop. Med. Hyg. 86, 383–394 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Mosha, J. F. et al. Epidemiology of subpatent Plasmodium falciparum infection: implications for detection of hotspots with imperfect diagnostics. Malar. J. 12, 221 (2013).

    PubMed  PubMed Central  Google Scholar 

  25. 25

    Thomas, C. J. & Lindsay, S. W. Local-scale variation in malaria infection amongst rural Gambian children estimated by satellite remote sensing. Trans. R. Soc. Trop. Med. Hyg. 94, 159–163 (2000).

    CAS  Google Scholar 

  26. 26

    Kalayjian, B. C., Malhotra, I., Mungai, P., Holding, P. & King, C. L. Marked decline in malaria prevalence among pregnant women and their offspring from 1996 to 2010 on the South Kenyan Coast. Am. J. Trop. Med. Hyg. 89, 1129–1134 (2013).

    PubMed  PubMed Central  Google Scholar 

  27. 27

    Satoguina, J. et al. Comparison of surveillance methods applied to a situation of low malaria prevalence at rural sites in The Gambia and Guinea Bissau. Malar. J. 8, 274 (2009).

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Atkinson, J. A. et al. Operational research to inform a sub-national surveillance intervention for malaria elimination in Solomon Islands. Malar. J. 11, 101 (2012).

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Alves, F. P. et al. High prevalence of asymptomatic Plasmodium vivax and Plasmodium falciparum infections in native Amazonian populations. Am. J. Trop. Med. Hyg. 66, 641–648 (2002).

    Google Scholar 

  30. 30

    Bousema, T. et al. Identification of hot spots of malaria transmission for targeted malaria control. J. Infect. Dis. 201, 1764–1774 (2010).

    PubMed  PubMed Central  Google Scholar 

  31. 31

    Bejon, P. et al. Stable and unstable malaria hotspots in longitudinal cohort studies in Kenya. PLoS Med. 7, e1000304 (2010).

    PubMed  PubMed Central  Google Scholar 

  32. 32

    Franks, S. et al. Frequent and persistent, asymptomatic Plasmodium falciparum infections in African infants, characterized by multilocus genotyping. J. Infect. Dis. 183, 796–804 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Wipasa, J. et al. Long-lived antibody and B cell memory responses to the human malaria parasites, Plasmodium falciparum and Plasmodium vivax. PLoS Pathog. 6, e1000770 (2010).

    PubMed  PubMed Central  Google Scholar 

  34. 34

    Clark, E. H. et al. Plasmodium falciparum malaria in the Peruvian Amazon, a region of low transmission, is associated with immunologic memory. Infect. Immun. 80, 1583–1592 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Roestenberg, M. et al. Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 377, 1770–1776 (2011).

    CAS  PubMed  Google Scholar 

  36. 36

    Warrell, D. A. in Essential Malariology (eds Warrell, D. A. & Gilles, H. M.) 191–205 (Arnold Publishers, 2002).

    Google Scholar 

  37. 37

    Collins, W. E. & Jeffery, G. M. A retrospective examination of sporozoite- and trophozoite-induced infections with Plasmodium falciparum in patients previously infected with heterologous species of Plasmodium: effect on development of parasitologic and clinical immunity. Am. J. Trop. Med. Hyg. 61, 36–43 (1999).

    CAS  Google Scholar 

  38. 38

    Felger, I. et al. The dynamics of natural Plasmodium falciparum infections. PLoS ONE 7, e45542 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Nassir, E. et al. Impact of genetic complexity on longevity and gametocytogenesis of Plasmodium falciparum during the dry and transmission-free season of eastern Sudan. Int. J. Parasitol. 35, 49–55 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Beshir, K. B. et al. Residual Plasmodium falciparum parasitemia in Kenyan children after artemisinin-combination therapy is associated with increased transmission to mosquitoes and parasite recurrence. J. Infect. Dis. 208, 2017–2024 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Pinkevych, M. et al. Decreased growth rate of P. falciparum blood stage parasitemia with age in a holoendemic population. J. Infect. Dis. 209, 1136–1143 (2013).

    PubMed  PubMed Central  Google Scholar 

  42. 42

    Douglas, A. D. et al. Substantially reduced pre-patent parasite multiplication rates are associated with naturally acquired immunity to Plasmodium falciparum. J. Infect. Dis. 203, 1337–1340 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Jeffery, G. M. Epidemiological significance of repeated infections with homologous and heterologous strains and species of Plasmodium. Bull. World Health Organ. 35, 873–882 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Chotivanich, K. et al. Parasite multiplication potential and the severity of falciparum malaria. J. Infect. Dis. 181, 1206–1209 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Takala, S. L. et al. Dynamics of polymorphism in a malaria vaccine antigen at a vaccine-testing site in Mali. PLoS Med. 4, e93 (2007).

    PubMed  PubMed Central  Google Scholar 

  46. 46

    Baird, J. K. Evidence and implications of mortality associated with acute Plasmodium vivax malaria. Clin. Microbiol. Rev. 26, 36–57 (2013).

    PubMed  PubMed Central  Google Scholar 

  47. 47

    Farnert, A., Snounou, G., Rooth, I. & Bjorkman, A. Daily dynamics of Plasmodium falciparum subpopulations in asymptomatic children in a holoendemic area. Am. J. Trop. Med. Hyg. 56, 538–547 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Bretscher, M. T. et al. Detectability of Plasmodium falciparum clones. Malar. J. 9, 234 (2010).

    PubMed  PubMed Central  Google Scholar 

  49. 49

    Sama, W., Owusu-Agyei, S., Felger, I., Dietz, K. & Smith, T. Age and seasonal variation in the transition rates and detectability of Plasmodium falciparum malaria. Parasitology 132, 13–21 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Bretscher, M. T. et al. The distribution of Plasmodium falciparum infection durations. Epidemics 3, 109–118 (2011).

    PubMed  PubMed Central  Google Scholar 

  51. 51

    Bousema, T. & Drakeley, C. Epidemiology and infectivity of Plasmodium falciparum and Plasmodium vivax gametocytes in relation to malaria control and elimination. Clin. Microbiol. Rev. 24, 377–410 (2011).

    PubMed  PubMed Central  Google Scholar 

  52. 52

    Jones, S. et al. Filter paper collection of Plasmodium falciparum mRNA for detecting low-density gametocytes. Malar. J. 11, 266 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Nwakanma, D. et al. High gametocyte complexity and mosquito infectivity of Plasmodium falciparum in the Gambia. Int. J. Parasitol. 38, 219–227 (2008).

    PubMed  PubMed Central  Google Scholar 

  54. 54

    Eziefula, A. C. et al. Single-dose primaquine for clearance of P. falciparum gametocytes in children with uncomplicated malaria in Uganda: a randomised controlled double-blinded dose-ranging trial. Lancet Infect. Dis. 14, 130–139 (2013).

    PubMed  PubMed Central  Google Scholar 

  55. 55

    Shekalaghe, S. A. et al. Submicroscopic Plasmodium falciparum gametocyte carriage is common in an area of low and seasonal transmission in Tanzania. Trop. Med. Int. Health 12, 547–553 (2007).

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Ouedraogo, A. L. et al. Age-dependent distribution of Plasmodium falciparum gametocytes quantified by Pfs25 real-time QT-NASBA in a cross-sectional study in Burkina Faso. Am. J. Trop. Med. Hyg. 76, 626–630 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Churcher, T. S. et al. Predicting mosquito infection from Plasmodium falciparum gametocyte density and estimating the reservoir of infection. eLife 2, e00626 (2013).

    PubMed  PubMed Central  Google Scholar 

  58. 58

    Bousema, T. et al. Mosquito feeding assays to determine the infectiousness of naturally infected Plasmodium falciparum gametocyte carriers. PLoS ONE 7, e42821 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Bousema, J. T. et al. Moderate effect of artemisinin-based combination therapy on transmission of Plasmodium falciparum. J. Infect. Dis. 193, 1151–1159 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Schneider, P. et al. Submicroscopic Plasmodium falciparum gametocyte densities frequently result in mosquito infection. Am. J. Trop. Med. Hyg. 76, 470–474 (2007).

    Google Scholar 

  61. 61

    Carter, R. & Graves, P. M. in Malaria: Principles and Practice of Malariology (eds Wernsorfer, W. H. & McGregor, I.) 253–305, (Churchill Livingstone, 1988).

    Google Scholar 

  62. 62

    Pichon, G., Awono-Ambene, H. P. & Robert, V. High heterogeneity in the number of Plasmodium falciparum gametocytes in the bloodmeal of mosquitoes fed on the same host. Parasitology 121, 115–120 (2000).

    Google Scholar 

  63. 63

    Miller, M. J. Observations on the natural history of malaria in the semi-resistant West African. Trans. R. Soc. Trop. Med. Hyg. 52, 152–168 (1958).

    CAS  Google Scholar 

  64. 64

    Okell, L. C. et al. The potential contribution of mass treatment to the control of Plasmodium falciparum malaria. PLoS ONE 6, e20179 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Bejon, P. et al. A micro-epidemiological analysis of febrile malaria in Coastal Kenya showing hotspots within hotspots. eLife 3, e02130 (2014).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    Bousema, T. et al. Hitting hotspots: spatial targeting of malaria for control and elimination. PLoS Med. 9, e1001165 (2012).

    PubMed  PubMed Central  Google Scholar 

  67. 67

    Sturrock, H. J. et al. Targeting asymptomatic malaria infections: active surveillance in control and elimination. PLoS Med. 10, e1001467 (2013).

    PubMed  PubMed Central  Google Scholar 

  68. 68

    Littrell, M. et al. Case investigation and reactive case detection for malaria elimination in northern Senegal. Malar. J. 12, 331 (2013).

    PubMed  PubMed Central  Google Scholar 

  69. 69

    Sturrock, H. J. et al. Reactive case detection for malaria elimination: real-life experience from an ongoing program in Swaziland. PLoS ONE 8, e63830 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Simon, C. et al. Malaria control in Botswana, 2008–2012: the path towards elimination. Malar. J. 12, 458 (2013).

    PubMed  PubMed Central  Google Scholar 

  71. 71

    Bousema, T. et al. The impact of hotspot-targeted interventions on malaria transmission: study protocol for a cluster-randomized controlled trial. Trials 14, 36 (2013).

    PubMed  PubMed Central  Google Scholar 

  72. 72

    Tiono, A. B. 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. 12, 79 (2013).

    PubMed  PubMed Central  Google Scholar 

  73. 73

    Poirot, E. et al. Mass drug administration for malaria. Cochrane Database Syst. Rev. 12, CD008846 (2013).

    Google Scholar 

  74. 74

    Hopkins, H. et al. Highly sensitive detection of malaria parasitemia in a malaria-endemic setting: performance of a new loop-mediated isothermal amplification kit in a remote clinic in Uganda. J. Infect. Dis. 208, 645–652 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Song, J. et al. Rapid and effective malaria control in Cambodia through mass administration of artemisinin–piperaquine. Malar. J. 9, 57 (2010).

    PubMed  PubMed Central  Google Scholar 

  76. 76

    Gamage-Mendis, A. C., Rajakaruna, J., Carter, R. & Mendis, K. N. Infectious reservoir of Plasmodium vivax and Plasmodium falciparum malaria in an endemic region of Sri Lanka. Am. J. Trop. Med. Hyg. 45, 479–487 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Boudin, C., Olivier, M., Molez, J. F., Chiron, J. P. & Ambroise-Thomas, P. High human malarial infectivity to laboratory-bred Anopheles gambiae in a village in Burkina Faso. Am. J. Trop. Med. Hyg. 48, 700–706 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Coleman, R. E. et al. Infectivity of asymptomatic Plasmodium-infected human populations to Anopheles dirus mosquitoes in western Thailand. J. Med. Entomol. 41, 201–208 (2004).

    PubMed  PubMed Central  Google Scholar 

  79. 79

    Ouédraogo, A. L. et al. Substantial contribution of submicroscopical Plasmodium falciparum gametocyte carriage to the infectious reservoir in an area of seasonal transmission. PLoS ONE 4, e8410 (2009).

    PubMed  PubMed Central  Google Scholar 

  80. 80

    Smith, D. L., McKenzie, F. E., Snow, R. W. & Hay, S. I. Revisiting the basic reproductive number for malaria and its implications for malaria control. PLoS Biol. 5, e42 (2007).

    PubMed  PubMed Central  Google Scholar 

  81. 81

    Babiker, H. A., Abdel-Muhsin, A. M., Ranford-Cartwright, L. C., Satti, G. & Walliker, D. Characteristics of Plasmodium falciparum parasites that survive the lengthy dry season in eastern Sudan where malaria transmission is markedly seasonal. Am. J. Trop. Med. Hyg. 59, 582–590 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Shekalaghe, S. et al. A cluster-randomized trial of mass drug administration with a gametocytocidal drug combination to interrupt malaria transmission in a low endemic area in Tanzania. Malar. J. 10, 247 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Fernando, S. D. et al. The importance of accuracy in diagnosis of positive malaria cases in a country progressing towards malaria elimination. J. Glob. Infect. Dis. 5, 127–130 (2013).

    PubMed  PubMed Central  Google Scholar 

  84. 84

    Wampfler, R. et al. Novel genotyping tools for investigating transmission dynamics of Plasmodium falciparum. J. Infect. Dis. http://dx.doi.org/10.1093/infdis/jiu236 (2014).

  85. 85

    Drakeley, C., Sutherland, C., Bousema, J. T., Sauerwein, R. W. & Targett, G. A. The epidemiology of Plasmodium falciparum gametocytes: weapons of mass dispersion. Trends Parasitol. 22, 424–430 (2006).

    PubMed  PubMed Central  Google Scholar 

  86. 86

    Muirhead-Thomson, R. C. Factors determining the true reservoir of infection of Plasmodium falciparum and Wuchereria bacnrofti in a West African village. Trans. R. Soc. Trop. Med. Hyg. 48, 208–225 (1954).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Stone, W. J. et al. The relevance and applicability of oocyst prevalence as a read-out for mosquito feeding assays. Sci. Rep. 3, 3418 (2013).

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Kafsack, B. F. et al. A transcriptional switch underlies commitment to sexual development in malaria parasites. Nature 507, 248–252 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Sinha, A. et al. A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium. Nature 507, 253–257 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Gouagna, L. C. et al. Genetic variation in human HBB is associated with Plasmodium falciparum transmission. Nature Genet. 42, 328–331 (2010).

    CAS  Google Scholar 

  91. 91

    Reece, S. E., Drew, D. R. & Gardner, A. Sex ratio adjustment and kin discrimination in malaria parasites. Nature 453, 609–614 (2008).

    CAS  Google Scholar 

  92. 92

    Paul, R. E., Brey, P. T. & Robert, V. Plasmodium sex determination and transmission to mosquitoes. Trends Parasitol. 18, 32–38 (2002).

    Google Scholar 

  93. 93

    Aingaran, M. et al. Host cell deformability is linked to transmission in the human malaria parasite Plasmodium falciparum. Cell. Microbiol. 14, 983–993 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Rupp, I. et al. Malaria parasites form filamentous cell-to-cell connections during reproduction in the mosquito midgut. Cell Res. 21, 683–696 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Van Den Berghe, L., Chardome, M. & Peel, E. Superiority of preparations from skin scarification over preparations of peripheral blood for the diagnosis of malaria. An. Inst. Med. Trop. 9, 553–562 (1952).

    CAS  Google Scholar 

  96. 96

    Aingaran, M. et al. Host cell deformability is linked to transmission in the human malaria parasite Plasmodium falciparum. Cell. Microbiol. 14, 983–993 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Molina-Cruz, A. et al. The human malaria parasite Pfs47 gene mediates evasion of the mosquito immune system. Science 340, 984–987 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Liebman, K. A. et al. Determinants of heterogeneous blood feeding patterns by aedes aegypti in Iquitos, Peru. PLoS Negl. Trop. Dis. 8, e2702 (2014).

    PubMed  PubMed Central  Google Scholar 

  99. 99

    Ansell, J., Hamilton, K. A., Pinder, M., Walraven, G. E. & Lindsay, S. W. Short-range attractiveness of pregnant women to Anopheles gambiae mosquitoes. Trans. R. Soc. Trop. Med. Hyg. 96, 113–116 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Verhulst, N. O. et al. Relation between HLA genes, human skin volatiles and attractiveness of humans to malaria mosquitoes. Infect. Genet. Evol. 18, 87–93 (2013).

    CAS  Google Scholar 

Download references

Acknowledgements

T.B. is supported by the Bill and Melinda Gates Foundation (grants OPP1024438 and OPP1034789). L.O. is supported by UK Medical Research Council Population Health Scientist Fellowship G1002387. I.F. is supported by the Swiss National Science Foundation (grant 3300C0-105994/1) and the Bill and Melinda Gates Foundation (grant 39777). C.D. is supported by the Bill and Melinda Gates Foundation (grant OPP1034789) and the Wellcome Trust (grant 091924). The authors thank R. Gosling, H. Sturrock, J. Mosha, G. Stresman, A. C. Eziefula and W. Moss for fruitful discussions. They also thank P. Bejon, A. van der Ven and G. Targett for critical reading of the manuscript.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Teun Bousema.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Artemisinin combination therapy

(ACT). A treatment in which an artemisinin derivative is combined with another antimalarial drug, which is often a schizonticidal drug.

Asymptomatic malaria infections

Malaria infections that lack typical clinical symptoms but are detectable by microscopy, rapid diagnostic test or molecular methods.

Gametocytogenesis

The developmental process that leads to the formation of male and female sexual gametocytes, which later fertilize after ingestion by the mosquito vector.

LAMP

(Loop-mediated isothermal amplification). A method for DNA amplification in which the entire reaction is carried out in a single tube and at a constant temperature.

Malaria receptivity

A term used to describe the degree to which infection occurs. In areas of high receptivity, the presence of abundant anopheline vectors and the existence of other ecological and climatic factors favour parasite transmission.

Mosquito larviciding

The treatment of breeding sites with insecticides that specifically target the larval life stage of mosquitoes.

Osmiophilic body

A membrane-bound vesicle that is predominantly found in female gametocytes.

Schizont stage

An asexual stage in the Plasmodium spp. life cycle, in which the parasite divides several times to produce daughter cells that go on to invade new red blood cells.

Submicroscopic gametocyte carriage

Infections in which sexual gametocytes that are detectable by molecular methods, but not microscopy, are produced.

Submicroscopic malaria infections

Infections that do not necessarily produce gametocytes and are detectable by molecular methods but not microscopy. Submicroscopic infections are almost exclusively asymptomatic.

Superinfections

Infections in which an Individual is infected by more than one parasite clone.

Symptomatic malaria infections

Infections that are accompanied by fever and/or other symptoms that are indicative of malaria. These infections are, almost without exception, detectable by microscopy or rapid diagnostic test.

Transmission hot spots

Areas in which transmission intensity is higher than that in the surrounding area.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bousema, T., Okell, L., Felger, I. et al. Asymptomatic malaria infections: detectability, transmissibility and public health relevance. Nat Rev Microbiol 12, 833–840 (2014). https://doi.org/10.1038/nrmicro3364

Download citation

Further reading