Emerging sexually transmitted viral infections: 2. Review of Zika virus disease

Abstract

A sudden increase in the number of newborn infants with microcephaly in Brazil in 2015 brought Zika virus (ZIKV), a less-known infection, to public attention. The rapid increase in the number of cases across the Americas and the devastating complications of infection with ZIKV highlighted the gravity of the situation. Within a relatively short period of time, our knowledge of this infection has significantly increased. This includes the realisation that ZIKV can be sexually transmitted. The aim of the present article is to provide a concise summary on this novel sexually transmitted infection linked to human birth defects and Guillain–Barre Syndrome. According to World Health Organization, individuals living outside areas of ZIKV mosquito transmission where one or both partners have been exposed to ZIKV should abstain from sex or have sex with condoms for at least six months after the last day of possible exposure.

Keywords

Viral disease Zika virus

Background

Zika virus (ZIKV) belongs to the family of Flaviviridae, genus Flavivirus. Other flaviviruses include yellow fever, dengue, West Nile and Japanese encephalitis viruses. Flaviviruses are arboviruses – a descriptive term that refers to hundreds of RNA viruses that rely on arthropods such as mosquitoes or ticks for transmission.¹

ZIKV may be grouped into three genotypes: East Africa, West Africa and Asia.² All genotypes of ZIKV are capable of infecting humans. The recent outbreaks of ZIKV in the Americas and Southern Pacific have been secondary to the Asian genotype.

Epidemiology

ZIKV was first identified in 1947 in a sentinel monkey in Uganda. At the time, it was assumed that the infection would not cause disease in humans. Serological surveys in tropical communities across the world suggested human infection was possible. Sporadic human infections presenting with mild febrile illness were identified over the next 50 years in the African continent.

In a 2007 outbreak, three-quarters of the total population of 6700 in the State of Yap in the western Pacific Ocean became infected with ZIKV. In a subsequent outbreak in 2013 in French Polynesia, 32,000 individuals became infected. This outbreak included identification of the first cases of Guillain–Barre Syndrome (GBS) secondary to ZIKV.

The eastward progress of the infection towards South America was confirmed by an outbreak of a mild febrile illness with self-limiting rash in Brazil in March 2015.

Between March and December 2015, an estimated 1.3 million suspected cases of ZIKV were reported in Brazil.³ During this period, more than 4000 cases of microcephaly were reported to Brazil’s Ministry of Health. The rate of microcephaly increased from one case per 10,000 live births prior to the outbreak to ten per 10,000 live births by December 2015.^4,5

The spread of infection was confirmed in 38 countries and territories in the Americas by March 2016.^3,5 During the same period only sporadic cases of ZIKV were reported in South East Asia. The global spread of ZIKV seems to have ceased since February 2017.⁶

ZIKV transmission

ZIKV can be transmitted through mosquito bites, mother to foetus, blood products and sex.

Mosquito transmission

Mosquito-borne transmission of ZIKV remains the most common route of transmission of infection. ZIKV is carried and spread by Aedes aegypti and Aedes albopictus mosquitoes. The Aedes mosquitoes can be found in almost all tropical and subtropical areas throughout the globe. In North America, the A. aegypti mosquito can be found primarily in Florida but they have also been detected as far north as Washington DC. In Europe, the A. albopictus is present in Southern Europe including the entire Mediterranean coasts and as far as northern Italy.

A. aegypti and A. albopictus mosquitoes have equally low intrinsic capacity to transmit ZIKV. They often bite multiple humans in each feed during the day and night. Their daytime feeding activity makes them a successful vector of the infection to humans.

By feeding on a person infected with ZIKV, the mosquitoes become infected. They spread infection by biting non-infected individuals. The human–mosquito–human transmission cycle accounts for the majority of ZIKV infections globally. It should be noted that A. aegypti is also the main vector for dengue and chikungunya viruses. As the result, many areas with high burden of ZIKV also experience high prevalence of dengue and chikungunya infections.

Mother-to-child transmission

Transmission of ZIKV from mothers to their children was first reported in French Polynesia in 2014.⁷ Two women presented with rash and fever secondary to ZIKV infection in the 38th week of pregnancy. ZIKV was detected in their serum, saliva, urine and breast milk. Both infants had evidence of ZKV in their serum and urine by the third day of age. Subsequent increase in the number of cases of microcephaly in newborn infants of mothers with ZIKV infection during pregnancy highlighted the virus’s ability to cross through placenta.

Sexual transmission

Sexual transmission of ZIKV was first reported in 2011 in an observation in 2008 where a scientist who had visited Senegal and subsequently his wife became infected with ZIKV. The observation that the wife had not left the US since early 2007 led to the proposal of sexual transmission of ZIKV. At the time no human case of ZIKV was ever reported in the Americas. The case is considered to be the first report of sexual transmission of an arbovirus.⁸ More recently, the case of a Parisian woman becoming infected with ZIKV after having sex with a man who acquired the infection in Brazil weeks earlier further supports the evidence of sexual transmission of ZIKV.⁹

Sexual transmission of ZIKV between male partners has also been reported.¹⁰ Sexual transmission is not believed to play a major role in the global spread of the virus globally.

Transfusion of blood products

Transmission of ZIKV through infected blood products has been reported.^11,12 In a study on 1505 blood donors in French Polynesia, 42 tested positive for the infection.¹³ It is therefore reasonable for blood bank centres to screen donated blood for ZIKV infection. Lack of standardised and validated commercially available diagnostic assays poses a challenge to achieve this aim at present.

Transplant of infected organs

ZIKV infection after transplant of kidney and liver of infected donors has been reported in a small case series.¹⁴

Other routes of transmission

Experimental transmission of flaviviruses through skin has been reported previously.¹⁵

The case of the 38-year-old man who became infected with ZIKV after looking after an elderly relative with the infection raised the possibility of non-sexual human-to-human transmission of ZIKV.¹⁶

Detection of ZIKV has been reported in human breast milk.¹⁷ The case of a five-month-old child who acquired ZIKV through breast milk of his mother during her acute infection highlights the possibility of the transmission of infection though this route.¹⁸

Pathophysiology

It is believed that ZIKV’s life cycle inside the host cell is similar to that of other flaviviruses. ZIKV can infect a number of hosts: mosquitoes, mice, primates and humans.

ZIKV is an enveloped, single-stranded RNA virus with a single genome of approximately 11 kb in length. The virus entry into the target cell requires a cellular receptor that is yet to be identified. The viral RNA remains inside the cytoplasm where it replicates and produces an antisense RNA. New viral RNA is produced from the antisense RNA. Through migration to the cell’s endoplasmic reticulum, the single viral RNA gene produces viral polyprotein. Viral and cellular proteases break down the polyprotein into three structural and seven non-structural viral proteins. The reassembly of the proteins around the newly replicated viral RNA forms new viral particles that then bud off the host cell’s membrane to infect new host cells.

Longitudinal studies have reported that ZIKV can be detected in whole blood specimens for 81 days compared with that of 14 days for serum specimens.^19–21 The duration of ZIKV viraemia may be even longer during pregnancy and as far as 107 days after the onset of symptoms.²²

Replicating and infectious ZIKV has been detected in urine and saliva of patients during the acute phase of the infection that raises the possibility of transmission via those samples.²³ ZIKV is generally detected in the urine up to six weeks after the start of clinical presentations.²⁰

ZIKV has been detected in the urine of a patient 91 days after the onset of symptoms.²⁴ The virus has been detected in conjunctival fluid at high viral load (9.3 log₁₀ copies/ml) and as far as 30 days after the onset of symptoms.²⁵

Clinical presentations

Prior to the 2007 outbreak in Yap, there were only 14 cases of human infection with ZIKV reported in the literature. The 2007 ZIKV outbreak in Yap provided information on the clinical features of the infection.²⁶

ZIKV infection mostly causes a mild self-limiting non-specific illness similar to other viral infections. Because of the geographical overlap with high prevalent areas of dengue, and chikungunya, the clinical manifestations may be considered secondary to any of the three viral infections until a diagnosis is confirmed.

It has been estimated that only 25% of individuals infected with ZIKV become symptomatic. It is therefore likely that most cases of infection remain undiagnosed.

Longitudinal studies suggest that the clinical symptoms develop after an incubation period of between three and 14 days after exposure to ZIKV.^27,28

Maculopapular rash is the most common presentation affecting 90% of patients with symptoms. The rash can involve face, trunk, upper and lower limbs, including palms and soles.

Low-grade fever (less than 38.5°C), arthralgia of small joints of the hands and feet, non-purulent conjunctivitis, myalgia, headache and retro-orbital pain were the other presenting complaints of infected patients.²⁶

The symptoms of ZIKV infection are mild and resolve after seven days in most cases.²⁹

The clinical presentations of acute ZIKV may vary during pregnancy. Rash and fever may not be as common features as reported in non-pregnant adults.^30,31 A prospective observational cohort study on pregnant women with rash within the previous five days in Brazil provided good information on ZIKV infection during pregnancy.³¹ The investigators screened all study women for TORCH, dengue, parvovirus, syphilis, HIV, chikungunya and ZIKV infections. Women with any of the infections except for ZIKV were excluded from the analysis. Among the 182 pregnant women with acute ZIKV infection, conjunctival injection and headache were the most common symptoms. Only 25% of pregnant women in that study reported fever.³¹

Diagnosis

Through its emergency use authorisation scheme, FDA has approved of a number of diagnostic assays for ZKV. The current data on the performance of these assays are limited. As the result, the Centre for Disease Control and Prevention (CDC) has issued a testing algorithm for diagnosis of ZIKV infection.³² The algorithm sets strict indications for testing patients for ZIKV, of which neither preconception screening, nor screening of asymptomatic non-pregnant individuals, is included.

According to the testing algorithm, ZIKV can be identified by reverse transcription polymerase chain reaction (RT-PCR) or serology testing against ZIKV antigens. Because of the cross reactivity with other flaviviruses, use of enzyme linked immunosorbent assay (ELISA) for detection of neutralising antibodies against ZIKV is of limited value. Use of ELISA for virus-specific immunoglobulin M is considered of acceptable performance for the diagnosis of acute ZIKV infection. Plaque reduction neutralisation tests (PRNTs) detect antibodies against each flavivirus species with higher specificity and have been used for diagnosis of ZIKV. Because of significant overlap between the areas of high prevalence of dengue and ZIKV, joint use of dengue and ZIKV PRNTs or PCRs is recommended where indicated.

The algorithm provides criteria for identification of patients with acute ZIKV infection, ZIKV infection with unknown duration, flavivirus infection and not infected with ZIKV. It postulates that acute ZIKV infection should be diagnosed when a patient tests positive in urine and serum by RT-PCR. Patients testing positive on RT-PCR of serum or urine with a positive anti-ZIKV IgM antibody are also considered acutely infected.

Diagnosis of infection with ZIKV of unknown duration can be established by having a positive RT-PCR in serum. Patients who test positive for ZIKV PRNT and negative for dengue virus PRNT are also considered to have been infected with ZIKV. The algorithm identifies a significant diagnostic limitation where only infection with flavivirus without identification of timing or type can be confirmed. This condition applies to individuals with positive serological evidence (PRNT > 10) of ZIKV and dengue virus at the same time. The condition would apply to individuals with prior exposure to flaviviral antigens; those living in high prevalence of flaviviruses, and those previously immunised against flaviviral infections (yellow fever, Japanese encephalitis, and tick-borne encephalitis).

Complications

Most adults infected with ZIKV recover from the infection without sequelae. Infection with ZIKV has nevertheless been associated with two distinct clinical complications: congenital malformations and neurological complications.

Teratogenicity and congenital malformations

Association between ZIKV infection during pregnancy and congenital malformations was first reported in Brazil in 2015. Compared with the average annual of 200 cases between 2010 and 2014, the authorities noticed a 20-fold increase in the number of infants born with microcephaly in 2015.⁴ Between October 2015 and April 2016, the number of cases of newborn infants with microcephaly reported in Brazil reached 7015 cases.⁵ The continuous increase in the number of newborn infants with microcephaly led to confirmation of the causality between maternal ZIKV and congenital microcephaly.^5,33

A retrospective study subsequently identified cases of newborns with neural defects during the ZIKV outbreak in French Polynesia.³⁴ Subsequent studies estimated the risk of microcephaly associated with ZIKV as 95 cases per 10,000 women infected during the first trimester of pregnancy.³⁵

ZIKV infection in pregnancy can cause severe foetal microcephaly, decreased brain tissue, retinal scarring and pigmentation, and hypertonicity. These presentations are known as ‘congenital Zika syndrome’.³⁶

The clinical and neuroimaging features of microcephaly secondary to ZIKV have been reported to be different from those secondary to TORCH infections.³⁷ Diffuse cortical thinning, apoptosis of post-migratory neurons in the neocortex and early mineralisation with high ZIKV viral load have been reported on histopathology investigations of infants born with CNS abnormalities.^38,39 Acute maternal ZIKV infection may cause foetal brain abnormality in the absence of maternal rash and microcephaly.³⁶

The proposed mechanism for mother-to-foetus ZIKV infection postulates that the virus may be able to cross the placenta by using a tyrosine kinase receptor (AXL) to infect the human umbilical vein endothelial cells that provide a mode of entry into the foetal circulation.⁴⁰ Although acute ZIKV infection during the first or early stages of the second trimester of pregnancy is associated with severe microcephaly,³⁵ there is evidence that infection during any stage of pregnancy can result in congenital malformations.^31,41

Transmission of ZIKV from mother to child is not limited to the prenatal period. Infants can acquire infection during birth when their mothers become infected within two weeks of delivery.⁷ Infants exposed to ZIKV but without microcephaly at birth may have a high risk of developing microcephaly from five months of age.⁴²

ZIKV was originally believed to remain detectable in the blood of pregnant women for up to seven days after the onset of symptoms. Recent reports of its detection in the blood of pregnant women ten weeks after the onset of the symptoms emphasised the duration of possible risk of infection to the foetus may be significantly longer.^38,43

The possibility of ZIKV transmission through breastfeeding has caused some controversy. The virus has been isolated from breast milk of women who became infected with ZIKV between the 35th and 37th week of pregnancy.^44,45 No case of mother-to-child transmission of ZIKV through breastfeeding has been reported so far. The current recommendations support breastfeeding of newborns by mothers infected with ZIKV.⁴⁶

The evidence on causality between ZIKV and congenital malformations has been debated. Those not convinced highlight that no case of foetal abnormality was reported during the ZIKV outbreak in Yap in 2008.²⁶ An analysis of 1850 pregnant women in Colombia who became infected with ZIKV during pregnancy (90% during the third trimester) also reported no cases of microcephaly.⁴⁷ Furthermore, no evidence exists to confirm that any other flavivirus causes congenital malformation.⁴⁸ There is also no evidence of ZIKV causing teratogenicity in animal models. Evidence supporting causality between ZIKV infection and congenital malformation has been provided by the report of microcephaly in the French Polynesia outbreak and case reports on detection of the virus in foetal amniotic fluid, placenta and brain tissue.^35,38 The proportion of infants with gross CNS abnormalities was significantly higher among 125 mothers with ZIKV infection compared to 61 uninfected mothers in the prospective observational study in Brazil, where microcephaly was present in four infants born to mothers with ZIKV only.³¹ Foetal mortality rate was 7% in each group in that study. Further evidence supporting the possible correlation between ZIKV infection and microcephaly was provided by the detection of Zika-specific IgM in the CSF of 30 of 31 neonates with microcephaly born to mothers with ZIKV infection.⁴⁹

Because of concerns on the impact of maternal ZIKV infection on foetal growth, the current guidelines recommend all pregnant women travelling to areas where ZIKV infection is endemic should undergo serology screening for the infection and serial ultrasound investigations of the foetal microcephaly and intracranial calcifications.⁵⁰

Neurological complications

Case reports suggested association between GBS and infection with flaviviruses – Japanese Encephalitis,⁵¹ dengue⁵² and West Nile.⁵³ It has been reported that ZIKV is neurotropic.⁵⁴

Significant increase in the number of cases of GBS was first reported during the ZIKV outbreak in French Polynesia.^56,57

Data from seven countries with ZIKV outbreaks report an increase of between 2.0 and 9.8 times in the incidence of GBS compared to pre-ZIKV outbreak intervals.⁵⁸ It has been estimated that the incidence of GBS secondary to ZIKV to be 0.24 per 1000 infected persons.⁵⁶

The most common clinical presentations of GBS secondary to ZIKV include limb weakness, inability to walk, ascending paralysis and paresthesia. Cranial neuropathy is also a common presentation with bilateral facial nerve palsy reported in over half of the cases.^56,59 Signs of autonomic dysfunction such as excessive sweating, cardiac dysrhythmia, BP instability or ileus can also develop.

The symptoms commence between three and ten days after fever, rash and other general symptoms of ZIKV infection. GBS is characterised by rapid progression and usually without relapse. Progression of weakness can take up to six weeks although the majority of patients will reach their nadir within two weeks of the onset of symptoms. During this period a proportion of patients may develop respiratory failure and require assisted ventilation in an intensive treatment unit. GBS has been successfully managed by intravenous immunoglobulin therapy or plasma exchange.⁶⁰

Brighton criteria for GBS diagnosis provide evidence of certainty of the diagnosis. Accordingly, evidence of demyelination on nerve conduction studies (NCSs) and presence of albuminocytologic dissociation in CSF (elevation of albumin without an elevation of white cell count) compose the first level of evidence for GBS diagnosis. Presence of either CSF white cell count of less than 50 cells/mm³ or NCSs consistent with GBS compose the second level of evidence for GBS diagnosis. Level three diagnosis relies on presence of clinical features of GBS without CSF or NCS evidence. The strength of data from case series should be assessed according to the certainty of Brighton criteria for GBS diagnosis.

NCSs of GBS patients secondary to ZIKV infection show a predominately acute inflammatory demyelinating polyneuropathy feature. Acute motor axonal neuropathy has been reported among the patients in French Polynesia too.^56,59

The mechanism of ZIKV infection causing GBS is not well understood. A possible resemblance of ZIKV antigens with those of nerve cells leading to immune dysregulation and the development of GBS has been proposed as a mechanism. The virus’s neurotropism has been proposed as supportive evidence in this respect.

The evidence of CNS infection in patients with GBS, however, is not convincing; only 10% of 42 patients with GBS had evidence of ZIKV in their CSF.⁵⁹ Also, unlike other infections where GBS develops in the post-infectious phase, GBS may develop during acute and post-infectious phases of ZIKV infection.

A report from a single centre in Brazil suggested encephalitis, transverse myelitis and chronic inflammatory demyelinating polyneuropathy as other CNS complications of ZIKV infection.⁶¹ These data remain to be confirmed.

With early standard treatment and care, the prognosis of GBS secondary to ZIKV remains good. The difficulty of early diagnosis and possible burden of those cases on any health system may challenge maintaining this prognosis. Cases of febrile rash followed by acute flaccid paralysis should therefore raise suspicions of this complication.^61,62

Cardiac complications

Several arboviral infections (dengue, West Nile, chikungunya) may cause myocarditis and pericarditis. The case of a 45-year-old man diagnosed with acute ZIKV after return from French West Indies highlighted the possibility of cardiac complications with ZIKV. During his acute illness, a mild elevation of troponin I and creatine phosphokinase with ST-segment elevation in anteroseptal cardiac region was recorded. Patient’s chest pain, elevated enzymes and ECG findings resolved promptly after treatment with bisoprolol and ramipril. A cardiac MRI scan after ten days did not identify major abnormal findings.⁶³ Further prospective study on 22 patients admitted to ITU for ZIKV-related GBS reported that 14 developed mild elevation in troponin, ECG abnormalities (ST-segment elevation, T wave inversion, low voltage QRS complexes) and moderate biventricular ejection fraction on echocardiography.⁶⁴ A study on rhesus monkeys infected with ZIKV reported detection of viral RNA in myocardiocytes at day five after infection. Viral RNA, however, was not detected in the myocardial cells at day 10. Of note, the investigators did not find histopathological evidence of myocarditis or pericarditis in infected animals.⁶⁵ ZIKV-related myocarditis therefore remains a possibility that may be managed successfully with early myocardial supportive treatment.

Prevention

Prevention of mosquito bite transmission of ZIKV

Owing to the extent of transmission of infection through mosquito bites, prevention of mosquito bites is the most important prevention measurements against ZIKV infection. The information on the affected areas is regularly updated online.⁶⁶

Aedes mosquitoes can bite during the day and twilight. Personal protection against mosquito bites including wearing long sleeves and long pants, using insect repellents and staying indoors where possible are important steps. Individuals infected with ZIKV may prevent further spread of the infection by following the same precautions.

Prevention of sexual transmission of ZIKV

Estimating the role of sexual transmission of ZIKV in areas where it is endemic is difficult. Sexual transmission becomes a significant mode of transmission of the virus in non-endemic areas where Aedes mosquitoes normally do not live.

Observations on sexual transmission of ZIKV show that the virus can be detected in semen,⁹ vaginal and cervical secretions.^67,68 Female-to-male and male-to-male sexual ZIKV transmissions have also been reported.^10,69 There is even a report of ZIKV transmission through oral sex.⁹

ZIKV can remain in semen well beyond its clearance in the blood. It is generally believed that semen becomes clear of the virus after three months.^20,70 Cases have been reported where ZIKV was present in semen for a longer period – between 41 and 188 days after onset of illness.^24,71–75 The significance of these findings was highlighted further when ZIKV was cultured in semen 69 days after the day of illness, confirming the viability of infection after such a long interval.⁷⁶ ZIKV viral load in semen may be 10⁵ times higher than that in blood or urine.⁷⁷ The significance of these findings is the risk to which women, particularly those who plan to conceive, may be exposed.

Sexual transmission has been mostly identified from asymptomatic infected men to their female partners.^8,74,78 Because of the role of sexual transmission of ZIKV, international advice by WHO and CDC has been issued.

The recommendations consider travelling to or living in areas where mosquito transmission of ZIKV has occurred as a potential risk of exposure to the virus. According to WHO guidelines, individuals living outside areas of ZIKV mosquito transmission where one or both partners have been exposed to ZIKV should abstain from sex or have sex with condoms for at least six months after the last day of possible exposure.⁷⁹

CDC recommendation on this issue is somewhat different: men should wait for six months after onset of symptoms (if symptomatic) or since the last day of possible exposure to ZIKV (if asymptomatic) before having unprotected sex. Women should wait for eight weeks after onset of symptoms or from the last possible day of exposure to the virus (if asymptomatic).⁸⁰

For pregnant women, CDC guidelines recommend that men who have been potentially exposed to the virus either by living in or travelling to ZIKV mosquito transmission areas or by having sex with men or women with such a history must abstain from sex with their pregnant partner for the duration of pregnancy.⁸¹ Sexual abstinence or use of condoms is recommended for individuals living in areas of ZIKV mosquito transmission.⁸²

Vaccines and treatment

At present, there is no effective treatment or vaccine against ZIKV available. Broad spectrum antiviral agents such as ribavirin and some of the directly acting anti-hepatitis C virus agents have been proposed as possible candidates against ZiKV.⁸³ Knowledge and experience in development of vaccines against other flavivirus infections has expedited the research in development of vaccine against ZIKV. As the result, five types of ZIKV a vaccines are being currently investigated for their safety and effectiveness.⁸⁴ Until further information, prevention of ZIKV transmission remains the most effective modality against ZIKV infection.

Conclusion

The emergence of ZIKV with its successful rapid transmission and devastating complications on human health poses a significant global health challenge. With the large number of countries affected by ZIKV and ease of international travel, it is likely that physicians working in non-endemic areas will have to manage patients with ZIKV and its complications for the foreseeable future.

Having a low threshold of clinical suspicion particularly among obstetricians, neurologists, general and intensive care physicians is essential in this respect. When clinically suspected, the best method of laboratory diagnosis should be discussed with the regional reference laboratories. Confirmed cases must be reported to public health officials for further epidemiological assessment and support including those for sexual partners of infected patients.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

References

Suwanmanee

Luplertlop

Dengue and Zika viruses: lessons learned from the similarities between these Aedes mosquito-vectored arboviruses. J Microbiol 2017; 55: 81–89.

Lanciotti

Kosoy

Laven

et al . Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg Infect Dis 2008; 14: 1232–1239.

Hennessey

Fischer

Staples

JE.

Zika virus spreads to new areas – region of the Americas, May 2015–January 2016. MMWR 2016; 65: 55–58.

European Centre for Disease Prevention and Control. Rapid risk assessment: Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome. Stockholm, http://ecdc.europa.eu/en/publications/Publications/zika-virus-americas-association-with-microcephaly-rapid-risk-assessment.pdf (2015, accessed 29 November 2017).

World Health Organization. Situation report. Zika virus microcephaly and Guillain-Barré syndrome, http://apps.who.int/iris/bitstream/10665/251462/1/zikasitrep17Nov16-eng.pdf (2016, accessed 29 November 2017).

World Health Organisation. Situation report, Zika virus microcephaly and Guillain-Barré syndrome, http://apps.who.int/iris/bitstream/handle/10665/254714/zikasitrep10Mar17-eng.pdf;jsessionid=187CDB5079E293501FA3B10A92068DB8?sequence=1 (2017, accessed 1 April 2018).

Besnard

Lastere

Teissier

et al . Evidence of perinatal transmission of Zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill 2014; 19: 20751.

Foy

Kobylinski

Chilson Foy

et al . Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis 2011; 17: 880–882.

D’Ortenzio

Matheron

de Lamballerie et al . Evidence of sexual transmission of Zika virus. N Engl J Med 2016; 374: 2195–2198.

10.

Deckard

Chung

Brooks

et al . Male-to-male sexual transmission of Zika virus – Texas, January 2016. MMWR 2016; 65: 372–374.

11.

Motta

IJF

Spencer

Cordeiro da Silva

et al . Evidence for transmission of Zika virus by platelet transfusion. N Engl J Med 2016; 375: 1101–1103.

12.

Barjas-Castro

Angerami

Cunha

et al . Probable transfusion-transmitted Zika virus in Brazil. Transfusion 2016; 56: 1684–1688.

13.

Musso

Nhan

Robin

et al . Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveill 2014; 19: 20761.

14.

Nogueira

Estofolete

Terzian

et al . Zika virus infection and solid organ transplantation: a new challenge. Am J Transplant 2017; 17: 791–795.

15.

Chen

Wilson

ME.

Transmission of dengue virus without a mosquito vector: nosocomial mucocutaneous transmission and other routes of transmission. Clin Infect Dis 2004; 39: e56–e60.

16.

Swaminathan

Schlaberg

Lewis

et al . Fatal Zika virus infection with secondary nonsexual transmission. N Engl J Med 2016; 375: 1907.

17.

Colt

Garcia-Casal

Peña-Rosas

et al . Transmission of Zika virus through breast milk and other breastfeeding-related bodily-fluids: a systematic review. PLoS Negl Trop Dis 2017; 11: e0005528.

18.

Blohm

Lednicky

Marquez

et al . Evidence for mother-to-child transmission of Zika virus through breast milk. Clin Infect Dis 2018; 66: 1120–1121.

19.

Mansuy

Mengelle

Pasquier

et al . Zika virus infection and prolonged viremia in whole-blood specimens. Emerg Infect Dis 2017; 23: 863–865.

20.

Paz-Bailey

Rosenberg

Doyle

et al . Persistence of Zika virus in body fluids – preliminary report. N Engl J Med. Epub ahead of print 14 February 2017. DOI: 10.1056/NEJMoa1613108.

21.

Murray

Gorchakov

Carlson

et al . Prolonged detection of Zika virus in vaginal secretions and whole blood. Emerg Infect Dis 2017; 23: 99–101.

22.

Suy

Sulleiro

Rodó

et al . Prolonged Zika virus viremia during pregnancy. N Engl J Med 2016; 375: 2611.

23.

Bonaldo

Ribeiro

Lima

et al . Isolation of infective Zika virus from urine and saliva of patients in Brazil. PLoS Negl Trop Dis 2016; 10: e0004816.

24.

Nicastri

Castilletti

Liuzzi

et al . Persistent detection of Zika virus RNA in semen for six months after symptom onset in a traveller returning from Haiti to Italy, February 2016. Euro Surveill 2016; 21. DOI: 10.2807/1560-7917.ES.2016.21.32.30314

25.

Tan

JJL

Balne

Leo

et al . Persistence of Zika virus in conjunctival fluid of convalescence patients. Sci Rep 2017; 7: 11194.

26.

Duffy

Chen

Hancock

et al . Zika virus outbreak on Yap island, Federated States of Micronesia. N Engl J Med 2009; 360: 2536–2543.

27.

Hall-Mendelin

Pyke

Moore

et al . Assessment of local mosquito species incriminates Aedes aegypti as the potential vector of Zika virus in Australia. PLoS Negl Trop Dis 2016; 10: e0004959.

28.

Koenig

Almadhyan

Burns

MJ.

Identify-isolate-inform: a tool for initial detection and management of Zika virus patients in the emergency department. West J Emerg Med 2016; 17: 238–244.

29.

Petersen

Wilson

Touch

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: 11–15.

30.

Schuler-Faccini

Ribeiro

Feitosa

et al . Possible association between Zika virus infection and microcephaly – Brazil, 2015. MMWR 2016; 65: 59–62.

31.

Brasil

Pereira

Jr Raja Gabaglia

et al . Zika virus infection in pregnant women in Rio de Janeiro – preliminary report. N Engl J Med 2016; 375: 2321–2334.

32.

Centres for Disease Control and Prevention . Zika virus diagnostic testing. CDC 24/7: saving lives, protecting people, https://www.cdc.gov/zika/hc-providers/types-of-tests.html (2016, accessed 21 November 2017).

33.

Kleber de Oliveira

Coretz-Escalante

De Oliverira

et al . 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 2016; 65: 242–247.

34.

European Centre for Disease Prevention and Control. Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome. Solna: ECDC, https://ecdc.europa.eu/en/publications-data/rapid-risk-assessment-zika-virus-epidemic-americas-potential-association (2015, accessed 21 November 2016).

35.

Cauchemez

Besnard

Bompard

et al . Association between Zika virus and microcephaly in French Polynesia, 2013–15: a retrospective study. Lancet 2016; 387: 2125–2132.

36.

França

Schuler-Faccini

Oliveira

et al . Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation. Lancet 2016; 388: 891–897.

37.

de Fatima Vasco Aragao

van der Linden

Brainer-Lima

et al . 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.

38.

Driggers

Korhonen

et al . Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med 2016; 374: 2142–2151.

39.

Tang

Hammack

Ogden

et al . Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 2016; 18: 587–590.

40.

Richard

Shim

B-S

Kwon

Y-C

et al . AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses. Proc Natl Acad Sci USA 2017; 114: 2024–2029.

41.

de Araújo

TVB

Rodrigues

de Alencar Ximenes

et al . Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study. Lancet Infect Dis 2016; 16: 1356–1363.

42.

van der Linden

Pessoa

Dobyns

et al . Description of 13 infants born during October 2015–January 2016 with congenital Zika virus infection without microcephaly at birth – Brazil. MMWR 2016; 65: 1343–1348.

43.

Calvet

Aguiar

Melo

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: 653–660.

44.

Dupont-Rouzeyrol

ABiron

O’Connor

et al . Infectious Zika viral particles in breastmilk. Lancet 2016; 387: 1051.

45.

Sotelo

et al . Persistence of Zika virus in breast milk after infection in late stage of pregnancy. Emerg Infect Dis 2017; 23: 856–857.

46.

Centre for Disease Control and Prevention. Zika virus, Zika in infants and children. CDC 24/7: saving lives, protecting people, https://www.cdc.gov/pregnancy/zika/testing-follow-up/zika-in-infants-children.html (accessed 29th November 2017).

47.

Pacheco

Beltran

Nelson

et al. Zika virus disease in Colombia – Preliminary report. N Engl J Med. Epub ahead of print 15 June 2016. DOI: 10.1056/NEJMoa1604037.

48.

Rasmussen

Jamieson

Honein

et al . Zika virus and birth defects – reviewing the evidence for causality. N Engl J Med 2016; 374: 1981–1987.

49.

Cordeiro

Pena

Brito

et al . Positive IgM for Zika virus in the cerebrospinal fluid of 30 neonates with microcephaly in Brazil. Lancet 2016; 387: 1811–1812.

50.

Petersen

Polen

Meaney-Delman

et al . Update: interim guidance for health care providers caring for women of reproductive age with possible Zika virus exposure – United States, 2016. MMWR 2016; 65: 315–322.

51.

Xiang

Zhang

Tan

et al . Guillain-Barré syndrome associated with Japanese encephalitis virus infection in China. Viral Immunol 2014; 27: 418–420.

52.

Chen

Lee

CT.

Guillain-Barré syndrome following dengue fever. Ann Emerg Med 2007; 50: 94–95.

53.

Sejvar

Bode

Marfin

et al . West Nile virus-associated flaccid paralysis. Emerg Infect Dis 2005; 11: 1021.

54.

Tang H, Hammack C, Ogden SC, et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell. 2016; 18(5): 587.

55.

Mlakar

Korva

Tul

et al . Zika virus associated with microcephaly. N Engl J Med 2016; 374: 951.

56.

Cao-Lormeau

Blake

Mons

et al . Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 2016; 387: 1531–1539.

57.

Oehler

Watrin

Larre

et al . Zika virus infection complicated by Guillain-Barre syndrome – case report, French Polynesia, December 2013. Euro Surveill 2014; 19: 207020.

58.

Dos Santos

Rodriguez

Almiron

et al . Zika virus and the Guillain-Barré syndrome? Case series from seven countries. N Engl J Med 2016; 375: 1598–1601.

59.

Parra

Lizarazo

Jiménez-Arango

et al . Guillain-Barré syndrome associated with Zika virus infection in Colombia. N Engl J Med 2016; 375: 1513–1523.

60.

Willison

Jacobs

van Doorn

PA.

Guillain-Barré syndrome. Lancet 2016; 388: 717–727.

61.

da Silva

IRF

Frontera

Bispo de Filippis

et al . Neurologic complications associated with Zika virus in Brazilian adults. JAMA Neurol 2017; 74: 1190–1198.

62.

Del Carpio Orantes

Juárez Rangel

García-Méndez

Incidence of Guillain-Barré syndrome at a secondary centre during the 2016 Zika outbreak. Neurologia. Epub ahead of print 25 September 2017. DOI: 10.1016/j.nrl.2017.07.019.

63.

Aletti

Lecoules

Kanczuga

et al . Transient myocarditis associated with acute Zika virus infection. Clin Infect Dis 2017; 64: 678–679.

64.

Resiere

Ferge

Fabr

et al . Cardiovascular complications in patients with Zika virus induced Guillain-Barre syndrome. J Clin Virol 2018; 98: 8–9.

65.

Dong

Huang

et al . Characterisation of a 2016 clinical isolate of Zika virus in non human primates. EBioMedicine 2016; 12: 170–177.

66.

Centres for Disease Control and Prevention. World map of areas with risk of Zika, https://wwwnc.cdc.gov/travel/page/world-map-areas-with-zika (2017, accessed 20 December 2017).

67.

Prisant

Bujan

Benichou

et al . Zika virus in the female genital tract. Lancet Infect Dis 2016; 16: 1000–1001.

68.

Nicastri

Castilletti

Balestra

et al . Zika virus infection in the central nervous system and female genital tract. Emerg Infect Dis 2016; 22: 2228–2230.

69.

Davidson

Slavinski

Komoto

et al . Suspected female-to-male sexual transmission of Zika Virus – New York City, 2016. MMWR 2016; 65: 716–717.

70.

de Laval

Matheus

Labrousse

et al . Kinetics of Zika viral load in semen. N Engl J Med 2017; 377: 697–699.

71.

Barzon

Pacenti

Berto

et al . Isolation of infectious Zika virus from saliva and prolonged viral RNA shedding in a traveller returning from the Dominican Republic to Italy, January 2016. Euro Surveill 2016; 21: 30159.

72.

Atkinson

Hearn

Afrough

et al . Detection of Zika virus in Semen. Emerg Infect Dis 2016; 22: 940.

73.

Gaskell

Houlihan

Nastouli

et al . Persistent Zika virus detection in Semen in a traveler returning to the United Kingdom from Brazil, 2016. Emerg Infect Dis 2017; 23: 137

74.

Venturi

Zammarchi

Fortuna

et al . An autochthonous case of Zika due to possible sexual transmission, Florence, Italy, 2014. Euro Surveill 2016; 21: 30148.

75.

Turmel

Abgueguen

Hubert

et al . Late sexual transmission of Zika virus related to persistence in the semen. Lancet 2016; 387: 2501.

76.

Arsuaga

Bujalance

Díaz-Menéndez

et al . Probable sexual transmission of Zika virus from a vasectomised man. Lancet Infect Dis 2016; 16: 1107.

77.

Mansuy

Dutertre

Mengelle

et al . Zika virus: high infectious viral load in semen, a new sexually transmitted pathogen? Lancet Infect Dis 2016; 16: 405.

78.

Hills

Russell

Hennessey

et al . Transmission of Zika virus through sexual contact with travellers to areas of ongoing transmission – continental United States, 2016. MMWR 2016; 65: 215–216.

79.

World Health Organization. Prevention of potential sexual transmission of Zika virus: interim guidance, http://apps.who.int/iris/bitstream/10665/204421/1/WHO_ZIKV_MOC_16.1_eng.pdf?ua=1 (2016, accessed 29 December 2017).

80.

Petersen

Meaney-Delman

Neblett-Fanfair

et al . Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika Virus exposure – United States, September 2016. MMWR 2016; 65: 1077.

81.

Brooks

Friedman

Kachur

et al . Update: interim guidance for prevention of sexual transmission of Zika Virus – United States, July 2016. MMWR 2016; 65: 745.

82.

Müller

Harms

Schubert

et al . Inactivation and environmental stability of Zika virus. Emerg Infect Dis 2016; 22: 1685.

83.

Mumtaz

van Kampen

Reusken

et al . Zika virus: where is the treatment? Curr Treat Options Infect Dis 2016; 8: 208–211.

84.

Koppolu

Shantha Raju

Zika virus outbreak: a review of neurological complications, diagnosis, and treatment options. J Neurovirol. Epub ahead of print 13 February 2018. DOI: 10.1007/s13365-018-0614-8.