Ultraschall Med 2016; 37(02): 212-213
DOI: 10.1055/s-0042-106006
EFSUMB Newsletter
Georg Thieme Verlag KG Stuttgart · New York

A mild pathogen turned ugly: Zika virus and the case with microcephaly

Alexandros Sotiriadis
1   Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece
,
Wellington P. Martins
2   University of Sao Paulo, Department of Obstetrics and Gynecology, Ribeirao Preto Medical School (FMRP-USP), Ribeirao Preto, Brazil
,
Jailson Costa Lima
1   Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece
,
Kimon Chatzistamatiou
1   Second Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki, Thessaloniki, Greece
› Author Affiliations
Further Information

Publication History

Publication Date:
08 April 2016 (online)

 

Zika virus (ZIKV) is a mosquito-bourne, dengue-like flavivirus (arbovirus), which has been causing transient outbreaks of mild, self-limited illness for about 70 years. Its recent notoriety has arisen from its association with Guillain-Barré syndrome in the general population and outbreak of babies with microcephaly in Brazil, particularly in the northeast region after September 2015 [1], [2].

Historically, ZIKV was first isolated in 1947-1948 in the namesake forest, a small (less than 1 square mile) isolated lake-shore forest in Uganda, from a sentinel rhesus monkey and a mosquito (Aedes [Stegomyia] Africanus) [3], [4]. In a 1964 field research paper studying the way of ZIKV transmission in its native source, it was concluded that infected mosquitos could be widely spread beyond the forest by convection currents above the tree-tops in the few hours following sunset [4]. After the original detection in A.(S.) Africanus, ZIKV has also been isolated in many other mosquito species, including A. Luteocephalus A. Aegypti, A. Albopictus, A. Apicoargenteus, A. Vitattus, A. Hensilli and A. Furcifer [5]-[10].

The first cases of human ZIKV infection were reported in the 1950s and 1960s [11], [12]; since then, Zika infection has been described as a mild and transient illness, its most common symptoms and signs including rash, fever, arthritis/arthralgia, conjunctivitis, myalgia, headache, retro-orbital pain, edema and vomiting [13].

Zika infection outside Africa was first reported in 1969 in Malaysia [14], and later in Indonesia [5], Pakistan [15] and a large outbreak in Oceania [13], [16]. We currently know that there are 2 main ZIKV lineages, an African and an Asian, and the strain that caused the Micronesia (Oceania) epidemic most likely originated in Southeast Asia [17]. At that time, a prophetic paper in Emerging Infectious Diseases highlighted the potential for transmission in Pacific Ocean and the Americas [10]. This indeed happened in French Polynesia, New Caledonia, Cook Islands and Easter Island by 2014 [18], and then from Cook Islands to Australia [19]. The first registered cases in the Americas were reported in 2014, in a woman who returned in Canada from Thailand [20] and then in Texas, in a woman who returned from vacation in Bora-Bora [21]. Shortly after, 2 cases were reported in Italy, in patients coming from French Polynesia [22].

Sporadic reports were published until the end of 2015, when several cases of congenital microcephaly were reported in Brazil, in association with a Zika outbreak [23], [24]. The first recorded cases in Brazil were reported in June 2015, originally in an area endemic for Dengue fever [25] and soon several reports followed, including cases from Venezuela [26] and Colombia [27].

Sonographic findings in the affected fetuses include microcephaly (more than 2.5 SD below mean, calcifications of the white matter, callosal and vermian dysgenesis, ventriculomegaly, thalamic hypoplasia and even arthrogryposis [28]) ([Fig. 1] and [2]). Approximately 1 third of affected neonates have ocular findings, including macular alterations and optic nerve abnormalities, usually bilateral [29], [30].

Zoom Image
Fig. 1 Microcephaly and ventriculomegaly in a 31-weeks ZIKV affected fetus in Brazil.
Zoom Image
Fig. 2 Biometric charts of the same fetus, illustrating the severe lag of head measurements (BPD: biparietal diameter; HC: head circumference), which is setting the diagnosis of microcephaly. The abdominal circumference (AC) shows a slighter delay; intrauterine growth restriction has also been described in ZIKV-affected fetuses. FL: femur length

Given that ZIKV had not been previously associated with fetal congenital defects, a crucial debate has been whether this relationship is truly causal or just statistical. The other 2 hot topics are whether ZIKV infection can be transmitted in ways other than mosquito bite (e.g. through sexual contact) and what are the potential protective strategies.

Regarding the first issue, the potential for vertical infection of ZIKV had already been described in 2 neonates in 2014; one of them was asymptomatic whereas the other developed a mild transient disease with fever and rash [31]. If ZIKV can be transmitted vertically, then the involvement of the central nervous system should not come as a complete surprise; the tropism of Zika for CNS had already been described in the first reports of Dick [3], [32], and experimental intracerebral inoculation of ZIKV in newborn mice resulted in replication of the virus in neurons and astroglial cells and eventually in their destruction, possibly though an immunological mechanism (at least partially) [33]. Although it is still not precisely known how ZIKV infection can damage the fetal brain, the paradigm of skin cells shows that the virus can infect immature dendritic cells (among others) and induce the formation of autophagosomes [34]. A more direct proof of causal relationship was provided in a recent autopsy report of a fetus with microcephaly and calcifications, in which Zika particles and RNA in were found in its brain, but no other organs [35]. However, confirmatory examinations are not the rule in ZIKV-attributed microcephaly and there are still publications highlighting the potential role of confounders (see at the end of this document).

As for potential alternative ZIKV infection routes, there is evidence for transmission via direct contact already since 2011; an American scientist who had contracted Zika when working in Senegal transmitted the virus to his wife after his return, probably through sexual contact [36]. Zika virus has been isolated from the human semen [37], saliva [18] and urine [38].

For as long as there is no vaccine, the only reasonable prevention measure recommended is through avoidance of mosquito bites [39]. In its interim guideline, the US Centers for Disease Control and Prevention (CDC) recommended testing of women who have travelled to endemic areas and have either developed symptoms or had ultrasound findings (microcephaly, endocranial calcifications) suggestive of fetal infection [40]. An update of the CDC guideline introduced the recommendation of preventive testing in women who have travelled in endemic areas, 2 to 12 weeks after their return from travel [41].

One of our current knowledge gaps refers to the effect of gestational age at infection and the exact magnitude of the risk. There is also no proof that mosquito control measures will succeed in controlling Zika, in the same way they did not succeed in controlling the –related in phylogenetic and epidemiological terms- Dengue virus [42].

The good news is that there is significant likelihood that a ZIKV vaccine could be produced in large quantities by the end of 2016 [43]. Until then, the Zika virus outbreak is regarded as a global public health emergency by the WHO [44], which has moreover issued a warning alert for European countries to control their populations of mosquitos of the Aedes genus in view of their expected activation during spring and summer [45].

Other interesting –and challenging–readings:

http://www.telegraph.co.uk/news/worldnews/zika/12157747/Zika-virus-Brazil-dismisses-link-between-larvicide-and-microcephaly.html

http://www.cdc.gov/mmwr/volumes/65/wr/mm6503e2.htm


#
  • References

  • 1 WHO. Zika virus. Updated February 2016. Available at: http://www.who.int/mediacentre/factsheets/zika/en/
  • 2 Brazil‘s government. Microcephaly. Updated February 2016. Available at: http://combateaedes.saude.gov.br/noticias/374-casos-suspeitos-chegam-a-4-107-em-todo-o-pais
  • 3 Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg 1952; 46: 509-520
  • 4 Haddow AJ, Williams MC, Woodall JP, Simpson DI, Goma LK. Twelve Isolations of Zika Virus from Aedes (Stegomyia) Africanus (Theobald) Taken in and above a Uganda Forest. Bull World Health Organ 1964; 31: 57-69
  • 5 Olson JG, Ksiazek TG Suhandiman Triwibowo Zika virus, a cause of fever in Central Java, Indonesia. Trans R Soc Trop Med Hyg 1981; 75: 389-393
  • 6 Lee VH, Moore DL. Vectors of the 1969 yellow fever epidemic on the Jos Plateau, Nigeria. Bull World Health Organ 1972; 46: 669-673
  • 7 Li MI, Wong PS, Ng LC, Tan CH. Oral susceptibility of Singapore Aedes (Stegomyia) aegypti (Linnaeus) to Zika virus. PLoS Negl Trop Dis 2012; 6: e1792
  • 8 Wong PS, Li MZ, Chong CS, Ng LC, Tan CH. Aedes (Stegomyia) albopictus (Skuse): a potential vector of Zika virus in Singapore. PLoS Negl Trop Dis 2013; 7: e2348
  • 9 Ledermann JP, Guillaumot L, Yug L, Saweyog SC, Tided M, Machieng P, Pretrick M, Marfel M, Griggs A, Bel M, Duffy MR, Hancock WT, Ho-Chen T, Powers AM. Aedes hensilli as a potential vector of Chikungunya and Zika viruses. PLoS Negl Trop Dis 2014; 8: e3188
  • 10 Hayes EB. Zika virus outside Africa. Emerg Infect Dis 2009; 15: 1347-1350
  • 11 Macnamara FN. Zika virus: a report on three cases of human infection during an epidemic of jaundice in Nigeria. Trans R Soc Trop Med Hyg 1954; 48: 139-145
  • 12 Simpson DI. Zika Virus Infection in Man. Trans R Soc Trop Med Hyg 1964; 58: 335-338
  • 13 Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, Pretrick M, Marfel M, Holzbauer S, Dubray C, Guillaumot L, Griggs A, Bel M, Lambert AJ, Laven J, Kosoy O, Panella A, Biggerstaff BJ, Fischer M, Hayes EB. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med 2009; 360: 2536-2543
  • 14 Marchette NJ, Garcia R, Rudnick A. Isolation of Zika virus from Aedes aegypti mosquitoes in Malaysia. Am J Trop Med Hyg 1969; 18: 411-415
  • 15 Darwish MA, Hoogstraal H, Roberts TJ, Ahmed IP, Omar F. A sero-epidemiological survey for certain arboviruses (Togaviridae) in Pakistan. Trans R Soc Trop Med Hyg 1983; 77: 442-445
  • 16 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: 1232-1239
  • 17 Haddow AD, Schuh AJ, Yasuda CY, Kasper MR, Heang V, Huy R, Guzman H, Tesh RB, Weaver SC. Genetic characterization of Zika virus strains: geographic expansion of the Asian lineage. PLoS Negl Trop Dis 2012; 6: e1477
  • 18 Musso D, Roche C, Nhan TX, Robin E, Teissier A, Cao-Lormeau VM. Detection of Zika virus in saliva. J Clin Virol 2015; 68: 53-55
  • 19 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
  • 20 Fonseca K, Meatherall B, Zarra D, Drebot M, MacDonald J, Pabbaraju K, Wong S, Webster P, Lindsay R, Tellier R. First case of Zika virus infection in a returning Canadian traveler. Am J Trop Med Hyg 2014; 91: 1035-1038
  • 21 Brust KB, Prince WS, Fader RC. Trouble in paradise. IDCases 2014; 1: 95-96
  • 22 Zammarchi L, Stella G, Mantella A, Bartolozzi D, Tappe D, Gunther S, Oestereich L, Cadar D, Munoz-Fontela C, Bartoloni A, Schmidt-Chanasit J. Zika virus infections imported to Italy: clinical, immunological and virological findings, and public health implications. J Clin Virol 2015; 63: 32-35
  • 23 Gatherer D, Kohl A. Zika virus: a previously slow pandemic spreads rapidly through the Americas. J Gen Virol 2015;
  • 24 Schuler-Faccini L, Ribeiro EM, Feitosa IM, Horovitz DD, Cavalcanti DP, Pessoa A, Doriqui MJ, Neri JI, Neto JM, Wanderley HY, Cernach M, El-Husny AS, Pone MV, Serao CL, Sanseverino MT. Brazilian Medical Genetics Society-Zika Embryopathy Task F. Possible Association Between Zika Virus Infection and Microcephaly - Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016; 65: 59-62
  • 25 Zanluca C, de Melo VC, Mosimann AL, Dos Santos GI, Dos Santos CN, Luz K. First report of autochthonous transmission of Zika virus in Brazil. Mem Inst Oswaldo Cruz 2015; 110: 569-572
  • 26 Valero N. [Zika virus: Another emerging arbovirus in Venezuela?]. Invest Clin 2015; 56: 241-242
  • 27 Sabogal-Roman JA, Murillo-Garcia DR, Yepes-Echeverri MC, Restrepo-Mejia JD, Granados-Alvarez S, Paniz-Mondolfi AE, Villamil-Gomez WE, Zapata-Cerpa DC, Barreto-Rodriguez K, Rodriguez-Morales AJ. Healthcare students and workersʼ knowledge about transmission, epidemiology and symptoms of Zika fever in four cities of Colombia. Travel Med Infect Dis 2015;
  • 28 Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?. Ultrasound Obstet Gynecol 2016; 47: 6-7
  • 29 Ventura CV, Maia M, Ventura BV, Linden VV, Araujo EB, Ramos RC, Rocha MA, Carvalho MD, Belfort Jr R, Ventura LO. Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection. Arq Bras Oftalmol 2016; 79: 1-3
  • 30 de Paula Freitas B, de Oliveira Dias JR, Prazeres J, Sacramento GA, Ko AI, Maia M, Belfort Jr. R. Ocular Findings in Infants With Microcephaly Associated With Presumed Zika Virus Congenital Infection in Salvador, Brazil. JAMA Ophthalmol 2016;
  • 31 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
  • 32 Tetro JA. Zika and microcephaly: causation, correlation, or coincidence?. Microbes Infect 2016;
  • 33 Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice. Arch Gesamte Virusforsch 1971; 35: 183-193
  • 34 Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, Perera-Lecoin M, Surasombatpattana P, Talignani L, Thomas F, Cao-Lormeau VM, Choumet V, Briant L, Despres P, Amara A, Yssel H, Misse D. Biology of Zika Virus Infection in Human Skin Cells. J Virol 2015; 89: 8880-8896
  • 35 Mlakar J, Korva M, Tul N, Popovic M, Poljsak-Prijatelj M, Mraz J, Kolenc M, Resman Rus K, Vesnaver Vipotnik T, Fabjan Vodusek V, Vizjak A, Pizem J, Petrovec M, Avsic Zupanc T. Zika Virus Associated with Microcephaly. N Engl J Med 2016;
  • 36 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: 880-882
  • 37 Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of Zika virus. Emerg Infect Dis 2015; 21: 359-361
  • 38 Shinohara K, Kutsuna S, Takasaki T, Moi ML, Ikeda M, Kotaki A, Yamamoto K, Fujiya Y, Mawatari M, Takeshita N, Hayakawa K, Kanagawa S, Kato Y, Ohmagari N. Zika fever imported from Thailand to Japan, and diagnosed by PCR in the urines. J Travel Med 2016; 23
  • 39 Oster AM, Brooks JT, Stryker JE, Kachur RE, Mead P, Pesik NT, Petersen LR. Interim Guidelines for Prevention of Sexual Transmission of Zika Virus - United States, 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 120-121
  • 40 Petersen EE, Staples JE, Meaney-Delman D, Fischer M, Ellington SR, Callaghan WM, Jamieson DJ. Interim Guidelines for Pregnant Women During a Zika Virus Outbreak - United States, 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 30-33
  • 41 Oduyebo T, Petersen EE, Rasmussen SA, Mead PS, Meaney-Delman D, Renquist CM, Ellington SR, Fischer M, Staples JE, Powers AM, Villanueva J, Galang RR, Dieke A, Munoz JL, Honein MA, Jamieson DJ. Update: Interim Guidelines for Health Care Providers Caring for Pregnant Women and Women of Reproductive Age with Possible Zika Virus Exposure - United States, 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 122-127
  • 42 Rubin EJ, Greene MF, Baden LR. Zika Virus and Microcephaly. N Engl J Med 2016;
  • 43 Dyer O. Zika vaccine could be in production by yearʼs end, says maker. BMJ 2016; 352: i630
  • 44 Gulland A. Zika virus is a global public health emergency, declares WHO. BMJ 2016; 352: i657
  • 45 Gulland A. WHO warns European countries to be on alert for Zika. BMJ 2016; 352: i753

  • References

  • 1 WHO. Zika virus. Updated February 2016. Available at: http://www.who.int/mediacentre/factsheets/zika/en/
  • 2 Brazil‘s government. Microcephaly. Updated February 2016. Available at: http://combateaedes.saude.gov.br/noticias/374-casos-suspeitos-chegam-a-4-107-em-todo-o-pais
  • 3 Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg 1952; 46: 509-520
  • 4 Haddow AJ, Williams MC, Woodall JP, Simpson DI, Goma LK. Twelve Isolations of Zika Virus from Aedes (Stegomyia) Africanus (Theobald) Taken in and above a Uganda Forest. Bull World Health Organ 1964; 31: 57-69
  • 5 Olson JG, Ksiazek TG Suhandiman Triwibowo Zika virus, a cause of fever in Central Java, Indonesia. Trans R Soc Trop Med Hyg 1981; 75: 389-393
  • 6 Lee VH, Moore DL. Vectors of the 1969 yellow fever epidemic on the Jos Plateau, Nigeria. Bull World Health Organ 1972; 46: 669-673
  • 7 Li MI, Wong PS, Ng LC, Tan CH. Oral susceptibility of Singapore Aedes (Stegomyia) aegypti (Linnaeus) to Zika virus. PLoS Negl Trop Dis 2012; 6: e1792
  • 8 Wong PS, Li MZ, Chong CS, Ng LC, Tan CH. Aedes (Stegomyia) albopictus (Skuse): a potential vector of Zika virus in Singapore. PLoS Negl Trop Dis 2013; 7: e2348
  • 9 Ledermann JP, Guillaumot L, Yug L, Saweyog SC, Tided M, Machieng P, Pretrick M, Marfel M, Griggs A, Bel M, Duffy MR, Hancock WT, Ho-Chen T, Powers AM. Aedes hensilli as a potential vector of Chikungunya and Zika viruses. PLoS Negl Trop Dis 2014; 8: e3188
  • 10 Hayes EB. Zika virus outside Africa. Emerg Infect Dis 2009; 15: 1347-1350
  • 11 Macnamara FN. Zika virus: a report on three cases of human infection during an epidemic of jaundice in Nigeria. Trans R Soc Trop Med Hyg 1954; 48: 139-145
  • 12 Simpson DI. Zika Virus Infection in Man. Trans R Soc Trop Med Hyg 1964; 58: 335-338
  • 13 Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, Pretrick M, Marfel M, Holzbauer S, Dubray C, Guillaumot L, Griggs A, Bel M, Lambert AJ, Laven J, Kosoy O, Panella A, Biggerstaff BJ, Fischer M, Hayes EB. Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med 2009; 360: 2536-2543
  • 14 Marchette NJ, Garcia R, Rudnick A. Isolation of Zika virus from Aedes aegypti mosquitoes in Malaysia. Am J Trop Med Hyg 1969; 18: 411-415
  • 15 Darwish MA, Hoogstraal H, Roberts TJ, Ahmed IP, Omar F. A sero-epidemiological survey for certain arboviruses (Togaviridae) in Pakistan. Trans R Soc Trop Med Hyg 1983; 77: 442-445
  • 16 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: 1232-1239
  • 17 Haddow AD, Schuh AJ, Yasuda CY, Kasper MR, Heang V, Huy R, Guzman H, Tesh RB, Weaver SC. Genetic characterization of Zika virus strains: geographic expansion of the Asian lineage. PLoS Negl Trop Dis 2012; 6: e1477
  • 18 Musso D, Roche C, Nhan TX, Robin E, Teissier A, Cao-Lormeau VM. Detection of Zika virus in saliva. J Clin Virol 2015; 68: 53-55
  • 19 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
  • 20 Fonseca K, Meatherall B, Zarra D, Drebot M, MacDonald J, Pabbaraju K, Wong S, Webster P, Lindsay R, Tellier R. First case of Zika virus infection in a returning Canadian traveler. Am J Trop Med Hyg 2014; 91: 1035-1038
  • 21 Brust KB, Prince WS, Fader RC. Trouble in paradise. IDCases 2014; 1: 95-96
  • 22 Zammarchi L, Stella G, Mantella A, Bartolozzi D, Tappe D, Gunther S, Oestereich L, Cadar D, Munoz-Fontela C, Bartoloni A, Schmidt-Chanasit J. Zika virus infections imported to Italy: clinical, immunological and virological findings, and public health implications. J Clin Virol 2015; 63: 32-35
  • 23 Gatherer D, Kohl A. Zika virus: a previously slow pandemic spreads rapidly through the Americas. J Gen Virol 2015;
  • 24 Schuler-Faccini L, Ribeiro EM, Feitosa IM, Horovitz DD, Cavalcanti DP, Pessoa A, Doriqui MJ, Neri JI, Neto JM, Wanderley HY, Cernach M, El-Husny AS, Pone MV, Serao CL, Sanseverino MT. Brazilian Medical Genetics Society-Zika Embryopathy Task F. Possible Association Between Zika Virus Infection and Microcephaly - Brazil, 2015. MMWR Morb Mortal Wkly Rep 2016; 65: 59-62
  • 25 Zanluca C, de Melo VC, Mosimann AL, Dos Santos GI, Dos Santos CN, Luz K. First report of autochthonous transmission of Zika virus in Brazil. Mem Inst Oswaldo Cruz 2015; 110: 569-572
  • 26 Valero N. [Zika virus: Another emerging arbovirus in Venezuela?]. Invest Clin 2015; 56: 241-242
  • 27 Sabogal-Roman JA, Murillo-Garcia DR, Yepes-Echeverri MC, Restrepo-Mejia JD, Granados-Alvarez S, Paniz-Mondolfi AE, Villamil-Gomez WE, Zapata-Cerpa DC, Barreto-Rodriguez K, Rodriguez-Morales AJ. Healthcare students and workersʼ knowledge about transmission, epidemiology and symptoms of Zika fever in four cities of Colombia. Travel Med Infect Dis 2015;
  • 28 Oliveira Melo AS, Malinger G, Ximenes R, Szejnfeld PO, Alves Sampaio S, Bispo de Filippis AM. Zika virus intrauterine infection causes fetal brain abnormality and microcephaly: tip of the iceberg?. Ultrasound Obstet Gynecol 2016; 47: 6-7
  • 29 Ventura CV, Maia M, Ventura BV, Linden VV, Araujo EB, Ramos RC, Rocha MA, Carvalho MD, Belfort Jr R, Ventura LO. Ophthalmological findings in infants with microcephaly and presumable intra-uterus Zika virus infection. Arq Bras Oftalmol 2016; 79: 1-3
  • 30 de Paula Freitas B, de Oliveira Dias JR, Prazeres J, Sacramento GA, Ko AI, Maia M, Belfort Jr. R. Ocular Findings in Infants With Microcephaly Associated With Presumed Zika Virus Congenital Infection in Salvador, Brazil. JAMA Ophthalmol 2016;
  • 31 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
  • 32 Tetro JA. Zika and microcephaly: causation, correlation, or coincidence?. Microbes Infect 2016;
  • 33 Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice. Arch Gesamte Virusforsch 1971; 35: 183-193
  • 34 Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, Perera-Lecoin M, Surasombatpattana P, Talignani L, Thomas F, Cao-Lormeau VM, Choumet V, Briant L, Despres P, Amara A, Yssel H, Misse D. Biology of Zika Virus Infection in Human Skin Cells. J Virol 2015; 89: 8880-8896
  • 35 Mlakar J, Korva M, Tul N, Popovic M, Poljsak-Prijatelj M, Mraz J, Kolenc M, Resman Rus K, Vesnaver Vipotnik T, Fabjan Vodusek V, Vizjak A, Pizem J, Petrovec M, Avsic Zupanc T. Zika Virus Associated with Microcephaly. N Engl J Med 2016;
  • 36 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: 880-882
  • 37 Musso D, Roche C, Robin E, Nhan T, Teissier A, Cao-Lormeau VM. Potential sexual transmission of Zika virus. Emerg Infect Dis 2015; 21: 359-361
  • 38 Shinohara K, Kutsuna S, Takasaki T, Moi ML, Ikeda M, Kotaki A, Yamamoto K, Fujiya Y, Mawatari M, Takeshita N, Hayakawa K, Kanagawa S, Kato Y, Ohmagari N. Zika fever imported from Thailand to Japan, and diagnosed by PCR in the urines. J Travel Med 2016; 23
  • 39 Oster AM, Brooks JT, Stryker JE, Kachur RE, Mead P, Pesik NT, Petersen LR. Interim Guidelines for Prevention of Sexual Transmission of Zika Virus - United States, 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 120-121
  • 40 Petersen EE, Staples JE, Meaney-Delman D, Fischer M, Ellington SR, Callaghan WM, Jamieson DJ. Interim Guidelines for Pregnant Women During a Zika Virus Outbreak - United States, 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 30-33
  • 41 Oduyebo T, Petersen EE, Rasmussen SA, Mead PS, Meaney-Delman D, Renquist CM, Ellington SR, Fischer M, Staples JE, Powers AM, Villanueva J, Galang RR, Dieke A, Munoz JL, Honein MA, Jamieson DJ. Update: Interim Guidelines for Health Care Providers Caring for Pregnant Women and Women of Reproductive Age with Possible Zika Virus Exposure - United States, 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 122-127
  • 42 Rubin EJ, Greene MF, Baden LR. Zika Virus and Microcephaly. N Engl J Med 2016;
  • 43 Dyer O. Zika vaccine could be in production by yearʼs end, says maker. BMJ 2016; 352: i630
  • 44 Gulland A. Zika virus is a global public health emergency, declares WHO. BMJ 2016; 352: i657
  • 45 Gulland A. WHO warns European countries to be on alert for Zika. BMJ 2016; 352: i753

Zoom Image
Fig. 1 Microcephaly and ventriculomegaly in a 31-weeks ZIKV affected fetus in Brazil.
Zoom Image
Fig. 2 Biometric charts of the same fetus, illustrating the severe lag of head measurements (BPD: biparietal diameter; HC: head circumference), which is setting the diagnosis of microcephaly. The abdominal circumference (AC) shows a slighter delay; intrauterine growth restriction has also been described in ZIKV-affected fetuses. FL: femur length