Accepted Manuscript

Zika virus: what do we know ?

Didier Musso, David Baud, Duane J. Gubler
PII:

S1198-743X(16)30050-7

DOI:

10.1016/j.cmi.2016.03.032

Reference:

CMI 565

To appear in:

Clinical Microbiology and Infection

Received Date: 15 March 2016

Revised Date:

28 March 2016

Accepted Date: 31 March 2016

Please cite this article as: Musso D, Baud D, Gubler DJ, Zika virus: what do we know ?, Clinical
Microbiology and Infection (2016), doi: 10.1016/j.cmi.2016.03.032.
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Title: Zika virus: what do we know ?

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Article type: Hot topic

Authors: Didier Musso 1*, David Baud 2,3, Duane J Gubler 4

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Authors affiliations:

Unit of Emerging Infectious Diseases, Institut Louis Malard, Tahiti, French Polynesia.

Materno-fetal and Obstetrics Research Unit, Department Femme-Mre-Enfant, Maternity,

University Hospital, Lausanne, Switzerland.

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University Hospital, Lausanne, Switzerland.

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Singapore 169857.

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Institute of Microbiology, Faculty of Biology and Medicine, University of Lausanne and

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Program in Emerging Infectious Disease, Duke-NUS Medical School,8 College Road,

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*Corresponding author: Didier Musso, Institut Louis Malard, PO Box 30, 98713 Papeete,

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Tahiti, French Polynesia. Tel: (689) 40 416 470, E.mail: dmusso@ilm.pf

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Word count: 1337

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TEXT

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The global spread of epidemic Zika virus (ZIKV) began in Micronesia in 2007,
followed by epidemics in French Polynesia in 2013-14, other South Pacific islands in 2014-

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15, and the Americas in 2015-16 [1]. Only 14 humans infections were confirmed prior to

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2007 [1], but by early March 2016, 52 countries and Territories of the Americas, Africa, Asia

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and Pacific had reported autochthonous ZIKV transmission [2]. A dramatic increase in severe

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congenital malformations (microcephaly) potentially associated with ZIKV in Brazil,

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combined with the rapid geographical spread, led the World Health Organization to declare

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the ZIKV epidemic a Public Health Emergency of International Concern. Although ZIKV was

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first isolated nearly 70 years ago, very little was known about the biology, epidemiology and

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clinical manifestations because transmission has been sporadic and silent for most of that time

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[1]. Here we review what is and is not known about ZIKV, with emphasis on the gaps in

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knowledge about ZIKV and the possible inaccurate assumptions made based on what we

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know about related viruses.

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The increase in Guillain-Barr syndrome (GBS) [3] and potential materno fetal [4],
sexual (detection of ZIKV in semen) [5] and blood transfusion transmission [6] were first

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described in French Polynesia [1], but they were not taken seriously by the public health

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community until the dramatic increase in severe disease associated with the Brazil epidemic.

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The reasons for the recent emergence of ZIKV and its association with severe

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neurological complications remain unknown. However, the change in epidemiology fits the

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pattern seen with dengue (DENV), chikungunya and West Nile viruses, all of which have

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emerged as important global epidemic viruses in recent years [1]. It seems likely that the same

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demographic, environmental, technological and societal pressures that influenced the

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emergence of epidemic strains of these viruses may have also led to increased transmission,

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thus increasing viral genetic changes and the emergence of a ZIKV strain with increased

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epidemic potential and possibly virulence [1].

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The burden of ZIKV disease is unknown because there has been no laboratory-based
surveillance for the disease and laboratory diagnosis is challenging. In the Pacific area,

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several countries reported cases of "fever and rash" without specifically identifying the

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causative pathogen [1]. In many dengue endemic countries, dengue-like illness is not

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confirmed by laboratory testing. Thus, ZIKV infections could be misdiagnosed as dengue or

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chikungunya. This type of silent transmission was underscored in June 2015, when a ZIKV

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infection was detected in a traveler returning from the Maldives Islands where ZIKV had

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never been detected before [7], confirming that ZIKV was circulating undetected.

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Acute phase diagnosis of ZIKV relies on molecular tests, which may be limited or
used with poor quality assurance. In many endemic countries, capacity to perform molecular

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detection of ZIKV is very limited [8] and most of the cases are currently diagnosed clinically.

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The duration of the viremic phase of ZIKV is not well established, but the window of

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detection might be increased by the use of urine [9]. Serological diagnosis by

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immunoglobulin M detection (IgM) is limited by the occurrence of cross-reactions between

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members of the Flavivirus genus [10]. Serologic diagnosis by IgM detection requires

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confirmation by neutralization test, which is only available in highly specialized laboratories

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[1]. Thus, serological diagnosis of ZIKV infection remains problematic because all endemic

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areas for ZIKV are also endemic for DENV, and often other flaviviruses [1].

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It is assumed that mosquito transmission by urban/peridomestic species such as Aedes

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aegypti and Aedes albopictus is the predominant mode of transmission of ZIKV [1]. The

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epidemiological importance of other modes of transmission is unknown. For example, sexual

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transmission of ZIKV has been documented in areas with no mosquito vectors [11], but the

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frequency and duration of infectious semen is unknown [11]. Only time and good clinical and

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epidemiologic surveillance will answer that question.

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The increased severe disease could be due to mutation and increased virulence of the
infecting virus strain or could simply represent the iceberg rising farther out of the water as

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a result of increased transmission [1]. Recent data suggest that ZIKV can emerge even if the

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main vectors (Aedes aegypty an Aedes albopictus) are low competent [12].

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The link between ZIKV infection and severe neurological disease is still uncertain,
although the evidence is mounting. The increase in GBS, which has been observed in French

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Polynesia has now been reported in nine Countries and Territories [2], and its link with ZIKV

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has recently been confirmed by a case control study conducted in French Polynesia [13].

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Materno fetal transmission of ZIKV has been confirmed, but the association between ZIKV

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and microcephaly remains controversial. The number of cases of microcephaly related to

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ZIKV in Brazil is unknown because of reporting bias; although notification became

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mandatory in 2015, different notification systems were used and the microcephaly case

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definition changed during the outbreak. Moreover, very few cases have been confirmed as

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ZIKV infections [8]. This suspected link relies (i) on the temporal association between ZIKV

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outbreaks and increased incidence of microcephaly (Brazil and retrospectively in French

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Polynesia) and (ii) detection of ZIKV in microcephalic newborns. Even if a cohort study of

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pregnant women with confirmed ZIKV infection being conducted in Rio de Janeiro (Brazil)

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strongly supports the link between maternal ZIKV infection and fetal or placental

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abnormalities [14], there is an urgent need to conduct a case control study to definitively

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prove a causative association [15].

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Some guidelines regarding management of ZIKV infections in pregnant women

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recommend serological screening of pregnant women and amniocentesis if the results are

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positive or inconclusive [16]. In endemic areas these recommendations are questionable

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because, in most cases, serological confirmation will not be possible and amniocentesis

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conducted on the basis of false positive serological results will lead to unnecessary invasive

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testing of unaffected fetuses [17]. Molecular detection of ZIKV in the amniotic fluid requires

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advanced laboratory techniques, so amniocentesis should only be performed in advanced

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materno-fetal centers [18]. The predictive value of detecting ZIKV RNA in amniotic fluid on

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fetal outcome is unknown. Finally, there is no specific treatment for infected pregnant women

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and abortion is outlawed in several endemic countries [12]. Latin American country health

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authorities recommend postponing pregnancy in ZIKV infected areas, but the impact of this

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recommendation in countries where half of the pregnancies are unintended, is unknown [19].

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A recent phylogenetic genetic study found no similar amino acid changes in three

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microcephaly-case genomes [20]. However, this does not exclude genetic changes responsible

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for potential increased virulence and/or epidemic potential of ZIKV occurred on the ancestral

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branches to the French Polynesian and American lineages, since severe disease and epidemic

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transmission were reported in both locations.

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With more than half of the worlds human population living in areas infested with
Aedes Stegomyia mosquitoes, one of the main challenges is to develop new tools to control

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the mosquito vectors. Evidence suggests that ZIKV is maintained in both a sylvatic and

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urban/periurban cycle. Although the recent epidemic spread suggests that Aedes aegypti is the

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main vector, there is clearly a lack of information on the role of this and other species. For

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example, ZIKV has been isolated from Culex species in Africa, but no data are available on

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whether Culex species can transmit the virus [1].

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However, data suggests that any area infested with Stegomyia species is at risk for

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epidemic transmission. There is thus an urgent need to develop and implement more effective

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prevention strategies, including effective mosquito control, information about personal

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protection against mosquito bites, preventing sexual transmission, strengthening laboratory

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facilities, training medical staff to manage at risk pregnancies with multidisciplinary teams

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(materno-fetal specialists, sonographers, geneticists, pediatricians and neurologists), training

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neurologists for care of GBS patients (number of intensive care unit, adequate

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immunoglobulin stock, plasma exchanges capacity) [21], implementing measures to prevent

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ZIKV transmission by blood transfusion [22], and developing a contingency plan to deal with

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increased severe disease case load [23].

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Finally, microcepahly and GBS may only be the tip of the iceberg because other
complications are now reported in neonates (ocular and auditory) and adults (ocular,

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meningoencephalitis, acute myelitis), although the incidence is unknown.

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Acknowledgements

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We thank Manon Vouga for critical review of the manuscript.

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DB is supported by the Department Femme-Mre-Enfant, by the Fondation Leenaards

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through the Bourse pour la relve acadmique, and by the SNSF (no. 310030_156169/1).

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