The global threat of Zika virus to pregnancy: epidemiology, clinical perspectives, mechanisms, and impact
Zika virus (ZIKV) is a mosquito-borne flavivirus that has newly emerged as a significant global threat, especially to pregnancy. Recent major outbreaks in the Pacific and in Central and South America have been associated with an increased incidence of microcephaly and other abnormalities of the central nervous system in neonates. The causal link between ZIKV infection during pregnancy and microcephaly is now strongly supported. Over 2 billion people live in regions conducive to ZIKV transmission, with ~4 million infections in the Americas predicted for 2016. Given the scale of the current pandemic and the serious and long-term consequences of infection during pregnancy, the impact of ZIKV on health services and affected communities could be enormous. This further highlights the need for a rapid global public health and research response to ZIKV to limit and prevent its impact through the development of therapeutics, vaccines, and improved diagnostics. Here we review the epidemiology of ZIKV; the threat to pregnancy; the clinical consequences and broader impact of ZIKV infections; and the virus biology underpinning new interventions, diagnostics, and insights into the mechanisms of disease.
Keywords:
Biology, Pregnancy, Microcephaly, Placenta, Epidemiology, Economic cost, Pathogenesis, Public health
Autoři:
Phillipe Boeuf 1,2*; Heidi E. Drummer 1,3,4; Jack S. Richards 1,2,3; Michelle J. L. Scoullar 1,2; James G. Beeson 1,2,3*
Působiště autorů:
Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.
1; Department of Medicine, The University of Melbourne, Melbourne, Australia.
2; Department of Microbiology, Monash University, Clayton, Australia.
3; Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Australia.
4
Vyšlo v časopise:
BMC Medicine 2016, 14:112
Kategorie:
Review
prolekare.web.journal.doi_sk:
https://doi.org/10.1186/s12916-016-0660-0
© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
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The electronic version of this article is the complete one and can be found online at: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0660-0
Souhrn
Zika virus (ZIKV) is a mosquito-borne flavivirus that has newly emerged as a significant global threat, especially to pregnancy. Recent major outbreaks in the Pacific and in Central and South America have been associated with an increased incidence of microcephaly and other abnormalities of the central nervous system in neonates. The causal link between ZIKV infection during pregnancy and microcephaly is now strongly supported. Over 2 billion people live in regions conducive to ZIKV transmission, with ~4 million infections in the Americas predicted for 2016. Given the scale of the current pandemic and the serious and long-term consequences of infection during pregnancy, the impact of ZIKV on health services and affected communities could be enormous. This further highlights the need for a rapid global public health and research response to ZIKV to limit and prevent its impact through the development of therapeutics, vaccines, and improved diagnostics. Here we review the epidemiology of ZIKV; the threat to pregnancy; the clinical consequences and broader impact of ZIKV infections; and the virus biology underpinning new interventions, diagnostics, and insights into the mechanisms of disease.
Keywords:
Biology, Pregnancy, Microcephaly, Placenta, Epidemiology, Economic cost, Pathogenesis, Public health
Zdroje
1. Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, Pretrick M, Marfel M, Holzbauer S, Dubray C, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med. 2009;360(24):2536–43.
2. Deckard DT, Chung WM, Brooks JT, Smith JC, Woldai S, Hennessey M, Kwit N, Mead P. Male-to-male sexual transmission of Zika virus - Texas, January 2016. MMWR Morb Mortal Wkly Rep. 2016;65(14):372–4.
3. Foy BD, Kobylinski KC, Chilson Foy JL, Blitvich BJ, Travassos da Rosa A, Haddow AD, Lanciotti RS, Tesh RB. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis. 2011;17(5):880–2.
4. Musso D, Nhan T, Robin E, Roche C, Bierlaire D, Zisou K, Shan Yan A, Cao-Lormeau VM, Broult J. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill. 2014;19(14).
5. Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of Zika virus. Emerg Infect Dis. 2015;21(2):359–61.
6. Mansuy JM, Dutertre M, Mengelle C, Fourcade C, Marchou B, Delobel P, Izopet J, Martin-Blondel G. Zika virus: high infectious viral load in semen, a new sexually transmitted pathogen? Lancet Infect Dis. 2016;16(4):405.
7. Freour T, Mirallie S, Hubert B, Splingart C, Barriere P, Maquart M, Leparc-Goffart I. Sexual transmission of Zika virus in an entirely asymptomatic couple returning from a Zika epidemic area, France, April 2016. Euro Surveill. 2016;21(23). doi:10.2807/1560-7917.ES.2016.21.23.30254.
8. Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg. 1952;46(5):509–20.
9. Dick GW. Epidemiological notes on some viruses isolated in Uganda; Yellow fever, Rift Valley fever, Bwamba fever, West Nile, Mengo, Semliki forest, Bunyamwera, Ntaya, Uganda S and Zika viruses. Trans R Soc Trop Med Hyg. 1953;47(1):1348.
10. All Countries & Territories with Active Zika Virus Transmission [https://www.cdc.gov/zika/geo/active-countries.html]. Accessed 8 Jan 2016.
11. Passemard S, Kaindl AM, Verloes A. Microcephaly. Handb Clin Neurol. 2013;111:129–41.
12. Kliegman RM, Stanton BF, St Geme III JW, Schor NF. Nelson Textbook of Pediatrics. 20th ed. Philadelphia: Elsevier; 2016.
13. Rios A. Microcephaly. Pediatr Rev. 1996;17(11):386–7.
14. Society for Maternal-Fetal Medicine Publications Committee. Ultrasound screening for fetal microcephaly following Zika virus exposure. Am J Obstet Gynecol. 2016;214(6):B2–4.
15. Cavalheiro S, Lopez A, Serra S, Da Cunha A, da Costa MD, Moron A, Lederman HM. Microcephaly and Zika virus: neonatal neuroradiological aspects. Childs Nerv Syst. 2016;32(6):1057–60.
16. de Fatima Vasco Aragao M, van der Linden V, Brainer-Lima AM, Coeli RR, Rocha MA, Sobral da Silva P, Durce Costa Gomes de Carvalho M, van der Linden A, Cesario de Holanda A, Valenca MM. Clinical features and neuroimaging (CT and MRI) findings in presumed Zika virus related congenital infection and microcephaly: retrospective case series study. BMJ. 2016;353:i1901.
17. Hazin AN, Poretti A, Cruz DD, Tenorio M, van der Linden A, Pena LJ, Brito C, Gil LH, Miranda-Filho DB, Marques ET, et al. Computed tomographic findings in microcephaly associated with Zika virus. N Engl J Med. 2016;374(22):2193–5.
18. Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet. 2016; S0140-6736(16)00339-1. doi:10.1016/S0140-6736(16)00339-1. [Epub ahead of print].
19. Carod-Artal FJ, Wichmann O, Farrar J, Gascon J. Neurological complications of dengue virus infection. Lancet Neurol. 2013;12(9):906–19.
20. Cao-Lormeau V-M, Blake A, Mons S, Lastère S, Roche C, Vanhomwegen J, Dub T, Baudouin L, Teissier A, Larre P, et al. Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case–control study. Lancet. 2016;387(10027):1531–9.
21. Cauchemez S, Besnard M, Bompard P, Dub T, Guillemette-Artur P, Eyrolle-Guignot D, Salje H, Van Kerkhove MD, Abadie V, Garel C, et al. Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study. Lancet. 2016;387(10033):2152–32.
22. Kleber de Oliveira W, Cortez-Escalante J, De Oliveira WT, do Carmo GM, Henriques CM, Coelho GE, de Franca GV A. Increase in reported prevalence of microcephaly in infants born to women living in areas with confirmed Zika virus transmission during the first trimester of pregnancy - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(9):242–7.
23. Informe EpidemiolóGico No 32 [http://combateaedes.saude.gov.br/situacaoepidemiologica]. Accessed 8 Jan 2016.
24. Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika virus and birth defects - reviewing the evidence for causality. New Engl J Med. 2016;374(20):1981–7.
25. Frank C, Faber M, Stark K. Causal or not: applying the Bradford Hill aspects of evidence to the association between Zika virus and microcephaly. EMBO Mol Med. 2016;8(4):305–7.
26. Brasil P, Pereira JJP, Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro Nogueira RM, Carvalho de Sequeira P, Machado Siqueira A, Abreu de Carvalho LM, Cotrim da Cunha D, et al. Zika virus infection in pregnant women in Rio de Janeiro — preliminary report. New Engl J Med. 2016 [Epub ahead of print].
27. Mlakar J, Korva M, Tul N, Popovic M, Poljsak-Prijatelj M, Mraz J, Kolenc M, Resman Rus K, Vesnaver Vipotnik T, Fabjan Vodusek V, et al. Zika virus associated with microcephaly. N Engl J Med. 2016;374(10):951–8.
28. Wu KY, Zuo GL, Li XF, Ye Q, Deng YQ, Huang XY, Cao WC, Qin CF, Luo ZG. Vertical transmission of Zika virus targeting the radial glial cells affects cortex development of offspring mice. Cell Res. 2016;26(6):645–54.
29. Tang H, Hammack C, Ogden SC, Wen Z, Qian X, Li Y, Yao B, Shin J, Zhang F, Lee EM, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016;18(5):587–90.
30. Li C, Xu D, Ye Q, Hong S, Jiang Y, Liu X, Zhang N, Shi L, Qin CF, Xu Z. Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell. 2016;19(1):120–6.
31. da Silva SR, Gao SJ. Zika virus update II: recent development of animal models - proofs of association with human pathogenesis. J Med Virol. 2016 [Epub ahead of print].
32. Dowall SD, Graham VA, Rayner E, Atkinson B, Hall G, Watson RJ, Bosworth A, Bonney LC, Kitchen S, Hewson R. A susceptible mouse model for Zika virus infection. PLoS Negl Trop Dis. 2016;10(5), e0004658.
33. Lazear HM, Govero J, Smith AM, Platt DJ, Fernandez E, Miner JJ, Diamond MS. A mouse model of Zika virus pathogenesis. Cell Host Microbe. 2016;19(5):720–30.
34. Yazigi A, Eldin De Pecoulas A, Vauloup-Fellous C, Grangeot-Keros L, Ayoubi JM, Picone O. Fetal and neonatal abnormalities due to congenital rubella syndrome: a review of literature. J Matern Fetal Neonatal Med. 2016 [Epub ahead of print].
35. Feldman DM, Keller R, Borgida AF. Toxoplasmosis, parvovirus, and cytomegalovirus in pregnancy. Clin Lab Med. 2016;36(2):407–19.
36. Samarasekera U, Triunfol M. Concern over Zika virus grips the world. Lancet. 2016;387(10018):521–4.
37. Messina JP, Kraemer MUG, Brady OJ, Pigott DM, Shearer F, Weiss DJ, Golding N, Ruktanonchai CW, Gething PW, Cohn E, et al. Mapping global environmental suitability for Zika virus. eLife. 2016;5, e15272.
38. Basarab M, Bowman C, Aarons EJ, Cropley I. Zika virus. BMJ. 2016;352:i1049.
39. Karwowski MP, Nelson JM, Staples JE, Fischer M, Fleming-Dutra KE, Villanueva J, Powers AM, Mead P, Honein MA, Moore CA, et al. Zika virus disease: a CDC update for pediatric health care providers. Pediatrics. 2016;137(5). doi: 10.1542/peds.2016-0621. [Epub ahead of print].
40. Woods CG, Parker A. Investigating microcephaly. Arch Dis Child. 2013;98(9):707–13.
41. Marcdante K, Kliegman RM. Nelson Essentials of Pediatrics. 7th ed. Philadelphia: Elsevier; 2014.
42. Chan JF, Choi GK, Yip CC, Cheng VC, Yuen KY. Zika fever and congenital Zika syndrome: an unexpected emerging arboviral disease. J Infect. 2016;72(5):507–24.
43. Petersen E, Wilson ME, Touch S, McCloskey B, Mwaba P, Bates M, Dar O, Mattes F, Kidd M, Ippolito G, et al. Rapid spread of Zika virus in the Americas - implications for public health preparedness for mass gatherings at the 2016 Brazil Olympic Games. Int J Infect Dis. 2016;44:11–5.
44. World Health Organization, The World Bank. World report on disability. Geneva: WHO; 2011.
45. Xu K, Evans DB, Kawabata K, Zeramdini R, Klavus J, Murray CJL. Household catastrophic health expenditure: a multicountry analysis. Lancet. 2003;362(9378):111–7.
46. The potential economic impact of Zika virus [http://www.jhsph.edu/research/centers-and-institutes/ivac/IVACBlog/the-potential-economicimpact-of-the-zika-virus]. Accessed 8 Jan 2016.
47. Watts J. Brazil's health system woes worsen in economic crisis. Lancet. 2016;387:1603–4.
48. Shepard DS, Undurraga EA, Halasa YA, Stanaway JD. The global economic burden of dengue: a systematic analysis. Lancet Infect Dis. 2016. S1473-3099(16)00146-8. doi:10.1016/S1473-3099(16)00146-8. [Epub ahead of print].
49. Roth A, Mercier A, Lepers C, Hoy D, Duituturaga S, Benyon E, Guillaumot L, Souares Y. Concurrent outbreaks of dengue, chikungunya and Zika virus infections - an unprecedented epidemic wave of mosquito-borne viruses in the Pacific 2012–2014. Euro Surveill. 2014;19(41).
50. Sirohi D, Chen Z, Sun L, Klose T, Pierson TC, Rossmann MG, Kuhn RJ. The 3.8 A resolution cryo-EM structure of Zika virus. Science. 2016;352(6284):467–70.
51. Zhang Y, Corver J, Chipman PR, Zhang W, Pletnev SV, Sedlak D, Baker TS, Strauss JH, Kuhn RJ, Rossmann MG. Structures of immature flavivirus particles. EMBO J. 2003;22(11):2604–13.
52. Zhang W, Kaufmann B, Chipman PR, Kuhn RJ, Rossmann MG. Membrane curvature in flaviviruses. J Struct Biol. 2013;183(1):86–94.
53. Kuhn RJ, Zhang W, Rossmann MG, Pletnev SV, Corver J, Lenches E, Jones CT, Mukhopadhyay S, Chipman PR, Strauss EG, et al. Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell. 2002;108(5):717–25.
54. Beasley DW, Whiteman MC, Zhang S, Huang CY, Schneider BS, Smith DR, Gromowski GD, Higgs S, Kinney RM, Barrett AD. Envelope protein glycosylation status influences mouse neuroinvasion phenotype of genetic lineage 1 West Nile virus strains. J Virol. 2005;79(13):8339–47.
55. Larocca RA, Abbink P, Peron JP, Zanotto PM, Iampietro MJ, Badamchi-Zadeh A, Boyd M, Ng'ang'a D, Kirilova M, Nityanandam R, et al. Vaccine protection against Zika virus from Brazil. Nature. 2016. doi:10.1038/nature18952 [Epub ahead of print].
56. Cugola FR, Fernandes IR, Russo FB, Freitas BC, Dias JLM, Guimarães KP, Benazzato C, Almeida N, Pignatari GC, Romero S, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534(7606):267–71.
57. Waggoner JJ, Pinsky BA. Zika virus: diagnostics for an emerging pandemic threat. J Clin Microbiol. 2016;54(4):860–7.
58. Zumla A, Goodfellow I, Kasolo F, Ntoumi F, Buchy P, Bates M, Azhar EI, Cotten M, Petersen E. Zika virus outbreak and the case for building effective and sustainable rapid diagnostics laboratory capacity globally. Int J Infect Dis. 2016;45:92–4.
59. Petersen EE, Polen KN, Meaney-Delman D, Ellington SR, Oduyebo T, Cohn A, Oster AM, Russell K, Kawwass JF, Karwowski MP, et al. Update: Interim guidance for health care providers caring for women of reproductive age
with possible Zika virus exposure - United States, 2016. MMWR Morb Mortal Wkly Rep. 2016;65(12):315–22.
60. Lanciotti RS, Kosoy OL, Laven JJ, Velez JO, Lambert AJ, Johnson AJ, Stanfield SM, Duffy MR. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg Infect Dis. 2008;14(8):1232–9.
61. Monath TP, Craven RB, Muth DJ, Trautt CJ, Calisher CH, Fitzgerald SA. Limitations of the complement-fixation test for distinguishing naturally acquired from vaccine-induced yellow fever infection in flavivirushyperendemic areas. Am J Trop Med Hyg. 1980;29(4):624–34.
62. Pyke AT, Daly MT, Cameron JN, Moore PR, Taylor CT, Hewitson GR, Humphreys JL, Gair R. Imported zika virus infection from the cook islands into Australia, 2014. PLoS Curr. 2014;6. doi:10.1371/currents.outbreaks.4635a54dbffba2156fb2fd76dc49f65e.
63. Aubry M, Richard V, Green J, Broult J, Musso D. Inactivation of Zika virus in plasma with amotosalen and ultraviolet A illumination. Transfusion. 2016;56(1):33–40.
64. Faye O, Faye O, Diallo D, Diallo M, Weidmann M, Sall AA. Quantitative real-time PCR detection of Zika virus and evaluation with field-caught mosquitoes. Virol J. 2013;10:311.
65. Faye O, Faye O, Dupressoir A, Weidmann M, Ndiaye M, Alpha SA. One-step RT-PCR for detection of Zika virus. J Clin Virol. 2008;43(1):96–101.
66. Balm MN, Lee CK, Lee HK, Chiu L, Koay ES, Tang JW. A diagnostic polymerase chain reaction assay for Zika virus. J Med Virol. 2012;84(9):1501–5.
67. Musso D, Gubler DJ. Zika virus. Clin Microbiol Rev. 2016;29(3):487–524.
68. Calvet G, Aguiar RS, Melo AS, Sampaio SA, de Filippis I, Fabri A, Araujo ES, de Sequeira PC, de Mendonca MC, de Oliveira L, et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis. 2016;16(6):653–60.
69. Besnard M, Lastere S, Teissier A, Cao-Lormeau V, Musso D. Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill. 2014;19(13).
70. Dupont-Rouzeyrol M, Biron A, O'Connor O, Huguon E, Descloux E. Infectious Zika viral particles in breastmilk. Lancet. 2016;387(10023):1051.
71. D'Ortenzio E, Matheron S, de Lamballerie X, Hubert B, Piorkowski G, Maquart M, Descamps D, Damond F, Yazdanpanah Y, Leparc-Goffart I. Evidence of sexual transmission of Zika virus. N Engl J Med. 2016;374(22):2195–8.
72. Musso D, Roche C, Nhan TX, Robin E, Teissier A, Cao-Lormeau VM. Detection of Zika virus in saliva. J Clin Virol. 2015;68:53–5.
73. Gourinat AC, O'Connor O, Calvez E, Goarant C, Dupont-Rouzeyrol M. Detection of Zika virus in urine. Emerg Infect Dis. 2015;21(1):84–6.
74. Kutsuna S, Kato Y, Takasaki T, Moi M, Kotaki A, Uemura H, Matono T, Fujiya Y, Mawatari M, Takeshita N, et al. Two cases of Zika fever imported from French Polynesia to Japan, December 2013 to January 2014 [corrected]. Euro Surveill. 2014;19(4).
75. Alcantara D, O'Driscoll M. Congenital microcephaly. Am J Med Genet C Semin Med Genet. 2014;166C(2):124–39.
76. Faheem M, Naseer MI, Rasool M, Chaudhary AG, Kumosani TA, Ilyas AM, Pushparaj PN, Ahmed F, Algahtani HA, Al-Qahtani MH, et al. Molecular genetics of human primary microcephaly: an overview. BMC Medical Genomics. 2015;8(1):1–11.
77. Feldman HS, Jones KL, Lindsay S, Slymen D, Klonoff-Cohen H, Kao K, Rao S, Chambers C. Prenatal alcohol exposure patterns and alcohol-related birth defects and growth deficiencies: a prospective study. Alcohol Clin Exp Res. 2012;36(4):670–6.
78. Martines RB, Bhatnagar J, Keating MK, Silva-Flannery L, Muehlenbachs A, Gary J, Goldsmith C, Hale G, Ritter J, Rollin D, et al. Notes from the field: evidence of Zika virus infection in brain and placental tissues from two congenitally infected newborns and two fetal losses - Brazil, 2015. MMWR Morb Mortal Wkly Rep. 2016;65(6):159–60.
79. Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, Perera-Lecoin M, Surasombatpattana P, Talignani L, Thomas F, et al. Biology of Zika virus infection in human skin cells. J Virol. 2015;89(17):8880–96.
80. Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell. 2016;18(5):591–6.
81. McCarthy M. Severe eye damage in infants with microcephaly is presumed to be due to Zika virus. BMJ. 2016;352:i855.
82. Adibi JJ, Marques Jr ET, Cartus A, Beigi RH. Teratogenic effects of the Zika virus and the role of the placenta. Lancet. 2016;387(10027):1587–90.
83. Bayer A, Lennemann NJ, Ouyang Y, Bramley JC, Morosky S, Marques Jr ET, Cherry S, Sadovsky Y, Coyne CB. Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection. Cell Host Microbe. 2016;19(5):705–12.
84. Quicke KM, Bowen JR, Johnson EL, McDonald CE, Ma H, O’Neal JT, Rajakumar A, Wrammert J, Rimawi BH, Pulendran B, et al. Zika virus infects human placental macrophages. Cell Host Microbe. 2016;20:1–8.
85. D’Ortenzio E, Matheron S, de Lamballerie X, Hubert B, Piorkowski G, MaquartM, Descamps D, Damond F, Yazdanpanah Y, Leparc-Goffart I. Evidence of sexual transmission of Zika virus. New Engl J Med. 2016;374(22):2195–8.
86. Delorme-Axford E, Bayer A, Sadovsky Y, Coyne CB. Autophagy as a mechanism of antiviral defense at the maternal-fetal interface. Autophagy. 2013;9(12):2173–4.
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