Zika Virus Prevention and Treatment Recommendations

An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT)

Table of contents

Key Points

  • There has been a substantial reduction in the risk of Zika virus (ZIKV) infection among Canadian travellers. Accordingly, CATMAT no longer routinely recommends that pregnant travellers avoid travel to areas where Zika is known or suspected to occur, or that special precautions to prevent sexual transmission while abroad or upon return are necessary.
    • Some travellers, for example based on their values and preferences, might choose to follow recommendations for prevention of sexual or vertical (mother to fetus) transmission of ZIKV because Zika continues to present a low risk in many tropical and subtropical areas.
  • Given the low risk of ZIKV infection, CATMAT recommends against routine testing of asymptomatic pregnant women. The poor positive predictive value, especially for screening serology tests, means a positive test has a high likelihood of being a false positive, which may have significant adverse consequences. The low population prevalence of infection means a negative test result is of negligible clinical utility.
  • In a situation where testing is completed and ZIKV is confirmed CATMAT recommends:
    • women should wait at least 2 months after their return from a risk area or onset of symptoms (whichever occurs later) before trying to conceive/having unprotected sex.
    • men should wait at least 3 months after their return from a risk area or onset of symptoms (whichever occurs later) before trying to conceive with their partner or engaging in unprotected sex.
  • In the case of a confirmed or symptomatic case with compatible symptoms of ZIKV infection in the male partner, CATMAT recommends that pregnant couples abstain from unprotected sex for the duration of the pregnancy.
  • Travellers and health care providers should remain vigilant for emergent information related to ZIKV outbreaks. Should a significantly increased risk of ZIKV transmission be identified in a specific travel destination, pre- and post-travel advice should be modified accordingly. This would include consideration of avoiding travel to the outbreak area during pregnancy. The Government of Canada provides up to date information on ZIKV risk via Travel Health Notices, which identify disease outbreaks, and Travel advice and advisories which provide country-specific health risk information.
  • Travel during pregnancy typically poses multiple health risks. The risk of ZIKV infection should be included in a broader discussion about infectious diseases and other potential complications when considering travel while pregnant.

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. The Agency acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Summary

Over the last two years, there has been a substantial decrease in reported rates of Zika virus (ZIKV) related disease in countries (primarily in the Americas) that suffered from the outbreak that started in 2015. As expected, there also has been a significant (>90%) decrease in reports of ZIKV infection among travellers visiting these countries. Current reports suggest only low level endemic or intermittent transmission in many areas of the tropical and subtropical world. This indicates a substantial reduction in the risk of ZIKV infection among Canadian travellers. Accordingly, CATMAT no longer routinely recommends that: pregnant travellers avoid travel to areas where Zika is known or suspected to occur, or that special precautions to prevent sexual transmission while abroad or upon return are necessary. Rather, CATMAT suggests that precautions for preventing ZIKV transmission be considered within the general context of the infectious and non-infectious risks travel may pose to a pregnant woman.

Introduction

Zika virus (ZIKV) infection is caused by a flavivirus transmitted through the bite of an infected Aedes mosquito, mainly Aedes aegypti. Although infections in humans have been known to occur for some time, ZIKV emerged on the global stage when it caused major outbreaks in many tropical and subtropical areas of the world, especially in the Americas Footnote 1,Footnote 2. During these outbreaks, a previously unrecognized pattern of Zika-related adverse outcomes emerged. Pre-eminent among these were complications of pregnancy including major congenital anomalies. First identified through spatial and temporal clustering of ZIKV activity with an increased incidence of congenital microcephaly Footnote 3 - Footnote 5 is now known that these can be manifest as a constellation of fetal developmental problems that are collectively referred to as a congenital Zika syndrome (CZS)Footnote 6 - Footnote 10The risk of CZS is substantial if infected while pregnant. For example, of 972 completed pregnancies enrolled in the US Zika Pregnancy Registry, 5% showed evidence of CZS (95% CI = 4%-7%). The greatest impact was observed when infection occurred during the first trimester (15% with CZS) Footnote 11. Similar results have been described for: affected US Territories, with a CZS rate of 5% among completed affected pregnancies Footnote 12 and for French territories in the Americas where 7% (39/555) of fetuses and infants were identified as having suffered defects possibly associated with ZIKV infection. In this last study, effects were more common if infection occurred during the first trimester, but were also seen if infection occurred in the second (3.6%) or third (5.3%) trimesters Footnote 7. Recently, data have been described for Zika associated harms before and after birth in a population of children born to infected mothers in US territories and freely associated states Footnote 13. From a population of 1,450 children with follow-up care, 6% suffered from a Zika-associated birth defect(s), 9% had a neurodevelopmental abnormality(ies) possibly associated with congenital infection, and 1% had both.

Although disease is usually relatively benign in adults, ZIKV infection can cause neurologic sequelae such as Guillain-Barré syndrome (GBS) Footnote 4, Footnote 8, Footnote 14. A case control study done in French Polynesia estimated a 0.24 in 1,000 risk for developing GBS in persons infected with ZIKV. This is comparable to the GBS risk of 0.25 to 0.65/1,000 observed following Campylobacter jejuni infection. There are also reports of acute disseminated encephalomyelitis (ADEM) following ZIKV infection Footnote 9.

Complicating the picture for ZIKV epidemiology and prevention, the virus can be transmitted sexually, with most reported cases being from an infected male to a female, although female to male and male to male transmission have also been reported Footnote 15. The risk of such transmission remains difficult to quantify, though a significant proportion of symptomatic men shed viral RNA in their semen. For example, 22/36 (61%) of men in a US-based study had detectable viral RNA in their semen when tested within 30 days of illness onset Footnote 10. This dropped to < 10% at 3 - 4 months after illness, and approximately 1% at 5-6 months after illness. Importantly, recovery of infectious ZIKV was rarer, occurring in 3/78 (4%) samples with all positives being obtained within 30 days of illness onset Footnote 10, though the possibility of false negatives in this cohort cannot be ruled out. Complementing these observations, the median serial interval between onset of symptoms in couples where sexual transmission occurred was 12 days (interquartile range: 10-14.5 days) Footnote 15. Overall, these data suggest that the period during which sexual transmission (from a male) is likely to occur is much shorter than the period (often 6 months) for which sexual precautions had been previously recommended.

The purposes of this statement are to review current knowledge related to ZIKV infection and to provide guidelines for health care providers on prevention and management of ZIKV disease.

Methods

This statement was developed by a working group of the Committee to Advise on Tropical Medicine and Travel (CATMAT). Members of the working group were from CATMAT, the Public Health Agency of Canada (the Agency) and the Society of Obstetricians and Gynaecologists of Canada. Each member was a volunteer, and none declared a relevant conflict of interest. The working group was responsible for assessing available literature, synthesis and analysis of the evidence, drafting recommendations, and writing. Secretariat support was provided throughout the process by the Public Health Agency of Canada. The final statement was approved by the full CATMAT committee.

This guideline complements existing CATMAT statements including the Statement on Personal Protective Measures to Prevent Arthropod bites Footnote 16 and the Statement on Pregnancy and Travel Footnote 17.

This document is an update to the CATMAT Zika statement published in February 2018. The most important changes are related to: the overall reduction in ZIKV transmission in many areas previously affected by the outbreak, the consequent significant reduction in risk for travellers (see Table 1); and, the availability of a systematic review related to sexual transmission Footnote 15.

Epidemiology

ZIKV was first isolated from monkeys in Uganda in 1947. Soon after, in 1952, human infections were detected in Uganda and Tanzania Footnote 18,Footnote 19. However, human infections were rarely reported until 2007, when a large outbreak of ZIKV disease occurred on the island of Yap (Micronesia) Footnote 20. Between 2013 and 2015, additional outbreaks occurred on islands and archipelagos in the Pacific region Footnote 21 - Footnote 23. In 2014, local transmission in the Americas was reported on Easter Island Footnote 24. Subsequently, ZIKV caused a large outbreak in the Americas Footnote 25 as well as in other countries/regions. Since the outbreak peaked in 2016, the number of locally acquired reported cases in the majority of affected countries has decreased substantially Footnote 26,Footnote 27, as has the number of travel-associated cases reported in Canada and the United States Footnote 28,Footnote 29. For example, in the first 11 months of 2018, only 58 cases of travel-associated ZIKV infection had been reported in the continental United States Footnote 30, compared to almost 5,000 cases during the entirety of 2016 and 437 in 2017 Footnote 29. Similar decreases in travel-associated infections have been observed in Canada, with the number of cases reported dropping from 468 in 2016 to 74 in 2017, and then to 14 as of August 31, 2018 (personal communication, J. Sciberras, Public Health Agency of Canada, Nov. 19, 2018) and without a concomitant decrease in testing.

Transmission

The mosquitoes associated with ZIKV tend to be more active during the day but can bite at night, with peak activity often occurring in the morning and later in the afternoon. In vertebrate hosts, the incubation period is usually 3 - 14 days Footnote 31, with blood viremia (the period when ZIKV is present in the blood) usually lasting for about 2 weeks Footnote 32 - Footnote 35, but with the possibility of longer periods of viral detection in blood and other body fluids Footnote 36. Vertical transmission between mother and developing fetus presumably occurs during the viremic period Footnote 37,Footnote 38. Other described routes of transmission include blood product transfusion Footnote 39 and sexual transmission after symptomatic infection Footnote 40 - Footnote 43. There is a report of sexual transmission from a symptomatic infected woman to a sexual partner Footnote 15,Footnote 44 and another report of sexual transmission from an asymptomatically infected male to their partner Footnote 15,Footnote 45.

Viral RNA has been detected in various biological fluids for prolonged periods, but isolation of infectious virus has only been documented at substantially lower rates and for shorter time intervals. Viral RNA has been detected in urine up to 6 weeks after illness onset; however, the median time until the loss of viral genome detection was determined to be 8 days Footnote 35. For individuals with detectable viral RNA in their serum the median time for loss of detection was 14 days, a small percentage of patients were reverse transcriptase polymerase chain reaction (RT-PCR) positive for more than a month Footnote 34. In particular, pregnant women carrying congenitally-infected fetuses may be symptomatically viremic for a prolonged period, thus, Zika should be considered in pregnant women with compatible exposure history and extended duration of fever, despite the typically short viremic phase of flaviviruses, in general Footnote 46,Footnote 47.

Based on a cohort of symptomatic men followed in the US, a significant proportion (61%) had detectable viral RNA in their semen in the first month after illness onset Footnote 10. This decreases to 1% or less by 6 months after symptom onset. Duration of shedding increased modestly with increasing age, and with certain symptoms. Interestingly, persistence of RNA in semen was most strongly and inversely associated with frequency of ejaculation. For example, men who reported ejaculating 4 times per week were estimated to clear RNA 3 weeks earlier than men who reported ejaculating once per week. This raises the possibility of a modifiable risk factor for prolonged shedding. In this same study, infectious virus was isolated from 3/19 (16%) samples obtained within 30 days after illness onset but in none of the 59 samples that were obtained later. The 3 men in which infectious virus was isolated had relatively high (>7.0 log10) ZIKV RNA copies per milliliter of semen in their first sample which declined in subsequent samples to 5.8 (log10 copies/ml of semen), 3.1 (log10 copies/ml of semen), and undetectable, respectively. These follow-up samples were obtained at 38, 59 and 76 days following illness onset and infectious ZIKV was not detected in the two men who still had detectable ZIKV RNA Footnote 10. Nevertheless, it remains theoretically possible that some of the PCR positive but culture negative cases were contagious. To date the longest period after symptom onset at which replication-competent virus has been detected in semen was 69 days; this was reported in a single case report of a vasectomized man Footnote 48. ZIKV RNA has also been detected at lower concentrations in men who have undergone vasectomy, but at rates similar to men who have not had this procedure. Although not studied extensively, the persistent shedding of ZIKA RNA in semen is considered to be similar amongst infected symptomatic and asymptomatic men based on case reports of sexual transmission and on data from asymptomatic blood donors Footnote 45, Footnote 49, Footnote 50.

Neutralizing antibodies for ZIKV are detectable after infection, and by extrapolation from other flaviviruses that induce a humoral antibody response, post-infection immunity is presumed to be lifelong Footnote 51. Among couples where such data is available (n=15) the median time between onset of sexual partners' symptoms (serial interval) was 12 days (interquartile range: 10±14.5 days) while the maximum was 44 days Footnote 15. Based on RT-PCR data, the median duration of ZIKV positivity was 13.9 days (95% CI: 7.2-19.6) for any fluid in the female genital tract, with a maximum of 37 days. There were too few data available for analysis of viral culture specimens in female genital tract fluids Footnote 15.ZIKV RNA has been detected in breast milk; however, there have not been any unequivocally documented reports of transmission to infants through breastfeeding Footnote 41. At this time, the World Health Organization (WHO) considers that "the benefits of breastfeeding for the infant and mother outweigh any potential risk of Zika virus transmission through breast milk" Footnote 52. Until further evidence is available regarding transmission through breast milk, CATMAT suggests that potential benefits and harms of breastfeeding during acute ZIKV infection should be discussed with each patient and decisions be made on an individual basis.

Clinical Manifestations

Approximately 20-25% (possibly as high as 50%) Footnote 53 of persons infected with ZIKV will manifest symptoms, including fever, myalgia, pruritis, eye pain, and maculopapular rash Footnote 20, Footnote 54, Footnote 55.

Early clinical manifestations are similar to other arboviral infections including dengue and chikungunya Footnote 54,Footnote 56. Thus, the differential diagnosis of a febrile returned traveller will likely include these arboviral infections, other viral illnesses Footnote 57,Footnote 58, as well as malaria Footnote 59.

Post-infectious neurologic complications, such as GBS, have been reported from many countries that were affected by the outbreak Footnote 8, Footnote 33, Footnote 60, Footnote 61. They include French Polynesia where a case-control study estimated that the odds of positive ZIKV serology was substantially greater in GBS cases compared to matched controls (OR 59.7; 95% CI 10.4 to ∞) Footnote 62. In the same study, and based on a ZIKV population seroprevalence of 0.66, the risk of GBS following ZIKV infection was estimated at approximately 0.25/ 1000. Other neurological manifestations have also been reported in association with ZIKV infection, e.g., acute myelitis, meningoencephalitis, acute disseminated encephalomyelitis, and reverse sensory polyneuropathy Footnote 9, Footnote 51, Footnote 63, Footnote 64 suggesting that the neurological spectrum of sequelae associated with ZIKV is relatively broad.

Clinically relevant thrombocytopenia and subcutaneous hematomas have been reported in a small number of cases Footnote 65,Footnote 66. Deaths from other causes have also been reported Footnote 67,Footnote 68.

Over 30 countries Footnote 4 have reported CZS Footnote 69. Common manifestations include microcephaly, cerebral atrophy, abnormal cortical development, callosal hypoplasia, and diffuse subcortical calcifications Footnote 70,Footnote 71. Ocular abnormalities and other congenital malformations such as arthrogryposis and hydrops fetalis have also been described Footnote 72 - Footnote 74.

Reviews of the epidemiology of ZIKV, as well as the causal association of ZIKV and microcephaly have been published Footnote 75.

Risk to travellers

There are multiple lines of evidence to indicate that the risk of ZIKV infection for travellers has decreased significantly. First, the number of cases reported in the epidemic regions of the Americas has decreased Footnote 26,Footnote 27. For US territories specifically, more than 36,000 cases (presumed to be locally acquired) were reported in 2016, compared to 652 (98% decrease) cases reported in 2017 Footnote 29 and 116 cases reported so far (as of December 4) in 2018 (> 99% decrease) Footnote 15,Footnote 30. Second, the number of travel-related cases reported in Canada and the United States has decreased by approximately two orders of magnitude since 2016. In Canada, the overall decrease from 2016 to 2018 has been > 95% (468 cases in 2016 to 14 cases as of August 31, 2018). A similar decrease has also occurred in the continental United States Footnote 29 where 4,897 cases (travel-related) were reported in 2016, 437 in 2017 (91% reduction) and 34 cases reported so far (as of August 1) in 2018 (> 99% decrease); and, in the European Union where 2,121 cases were reported in 2016 and 198 cases (93% reduction) were reported in 2017 Footnote 76.

Set against the total travel volumes to countries affected by the outbreak, which exceeds 7 million annually for Canadians Footnote 77, the estimated risk of a traveller being confirmed with a ZIKV infection is currently very low, e.g., < 1 case/200,000 trips (14 cases in 2018, adjusted for surveillance period). While this is an underestimate of the true risk of infection, (the majority of infections are likely not reported), it nevertheless supports that ZIKV-infection among Canadian travellers has become a rare event. Accordingly, adverse outcomes associated with ZIKV-infection must be rare events in absolute terms, even with significant under-reporting. Indeed, from October 2015 - August 31 2018, a total of 4 sexually transmitted cases have been reported in Canada Footnote 28. During the same time period, 45 cases have been reported among pregnant women in Canada Footnote 28. From March to December 2017, CZS had been reported in ≤ 5 infants in Canada Footnote 78.

Areas of risk

Transmission of ZIKV can occur in most areas of the world where Aedes aegypti, the principal vector, occurs. This means that there is the potential for transmission through much of the tropical and subtropical world and beyond. As described above, the risk of transmission to travellers is considered low.

Previously, CATMAT recommendations were linked to the WHO country classification scheme for ZIKV to determine areas of risk or potential riskFootnote 79. In July 2019, the WHO implemented a new approach for categorizing countries according to the presence or absence of current and historical reported ZIKV transmissionFootnote 80. It should be noted that monitoring and reporting in some areas is suboptimal, and that this approach provides only an approximation of the areas of risk. Due to a general absence of laboratory and surveillance data from many countries/territories, it provides a conservative risk assessment (i.e. includes countries/territories where cases have been reported but also includes countries where there is a known historical risk but cases are not currently being reported).

Notwithstanding the above, travellers and health care providers should remain vigilant for emergent information related to ZIKV that might influence decision-making, for example evidence that indicates a significant outbreak is occurring in a travel destination. If this is the case, pre- and post-travel advice should be modified accordingly, including potentially recommending avoiding travel to the outbreak area during pregnancy. The Government of Canada provides up to date information on ZIKV risk via Travel Health Notices, which identify disease outbreaks, and Travel advice and advisories which provide country-specific health risk information.

Prevention - Decision to travel to areas of risk

All travellers

Health care providers should discuss with travellers what is known and what is not known about ZIKV to help their patients make an informed choice about travel and precautions. Factors to consider include:

  • The low absolute risk for ZIKV infection and consequent impact on travellers. Travel health providers should keep themselves informed of any evolving risks for transmission in destination regions, as with other endemic and potentially epidemic infectious risks.
  • The potential for ZIKV infection during pregnancy to have a severe impact on the fetus.
  • The possibility of serious sequelae such as post-infection neurologic complications (e.g., GBS, ADEM).
  • The potential for sexual transmission, which is particularly relevant to couples who are actively trying to conceive.
  • The potential for co-morbidities to predispose to more serious outcomes (there is little specific evidence in this regard, though it is reasonable to expect such impacts).
  • Patients' values and preferences (including risk perception and risk tolerance).
  • The potential impacts of following the recommendation on a couple's reproductive plans.

Pregnant women and women who are planning a pregnancy

CATMAT no longer routinely recommends that pregnant women and those planning a pregnancy avoid travel to areas where Zika is known or suspected to occur.

Depending on individual values and preferences, including risk tolerance, some pregnant women or those planning a pregnancy might nevertheless choose to minimize risk by not travelling to these areas.

For pregnant travellers, there are many health considerations in addition to Zika. For more information in this regard, see the CATMAT Statement on Pregnancy and Travel Footnote 17.

Prevention of mosquito-borne transmission

CATMAT recommends that all travellers to areas of risk should be advised to adhere to recommendations for the use of personal protective measures (PPM) against mosquito bites (see below). Because the mosquitoes that transmit ZIKV often bite during daylight hours, PPM should be used through all hours of the day and night. In addition to ZIKV, PPM provide protection against other vector-associated diseases such as malaria, dengue, and chikungunya. Recommendations for PPM can be found in CATMAT's Statement on Personal Protective Measures to Prevent Arthropod Bites Footnote 16.

Prevention of sexual transmission

ZIKV RNA has been detected in semen 6 or more months after symptomatic infection. However, infectious (culturable) virus appears to be much less persistent Footnote 10, and mostly documented only for periods shorter than a month. At this time, all reported cases of sexual transmission have occurred within 41 days after illness onset in the source male partner, and the large majority have occurred within 20 days Footnote 10. Sexual transmission should be prevented by abstinence from exposure to semen, and minimized by proper condom use.

Asymptomatic traveller

CATMAT no longer recommends routine use of measures to prevent sexual transmission from asymptomatic travellers while in or after returning from areas where Zika is known or suspected to occur. This applies to all travellers, including pregnant ones. The proportion of all travellers returning from tropical and subtropical areas who have been asymptomatically infected with ZIKV is considered to be negligible. Nevertheless, depending on individual values and preferences, including risk tolerance and the potential impact of an infection (e.g., during a pregnancy), travellers might still choose to minimize risk by using condoms and/or restricting sexual activity, and this should be discussed with each patient.

Symptomatic traveller

Compatible symptoms

CATMAT recommends that those with symptoms compatible with ZIKV infection, and no alternate diagnosis to explain their symptoms should discuss the likelihood of ZIKV infection (which will be low in most cases) with their health care provider when making the decision on whether to apply measures to prevent sexual transmission. Diagnostic testing can be considered after discussion of the risks of both false negative and false positive results.

Confirmed case

CATMAT recommends that those who have confirmed ZIKV infection should follow recommendations for preventing sexual transmission. Based on current information on the incubation period and duration of viremia, and the unclear duration of viral persistence in tissues, travellers who choose to apply these recommendations should do so as follows:

  • Women should wait at least 2 months after their return from an affected area or onset of symptoms (whichever occurs later) before trying to conceive/having unprotected sex.
  • Men should wait at least 3 months after their return from an affected area or onset of symptoms (whichever occurs later) before trying to conceive with their partner or engaging in unprotected sex. In some circumstances, for example based on risk tolerance, men might wish to delay trying to conceive for up to 6 months, which represents the outer theoretical limit of the potentially contagious period.

In the case of a confirmed or symptomatic case with compatible symptoms of ZIKV infection in the male partner, CATMAT recommends that pregnant couples should abstain from unprotected sex for the duration of the pregnancy.

Role of laboratory testing in transmission prevention or monitoring of pregnant women

Laboratory testing for ZIKV infection is fully described below. In theory, based on information from other similar viral infections, the absence of ZIKV-specific antibodies 2 weeks or more after the last possible exposure implies that the individual has never been infected, and is not contagious to sexual partners or to the fetus. Nevertheless, there are major limitations in the usefulness of ZIKV screening tests; neither serology nor molecular testing can ever be 100% sensitive. The absence of ZIKV RNA in a semen sample might indicate absence of contagiousness at that time, but intermittent shedding is possible and there are no data to support the use of this approach to defining a risk-free sexual contact. Of more concern, the current very low prevalence of ZIKV infection means that an increase in the false positive rate is to be expected, especially for serology when preliminary testing is carried out. As well, screening enzyme-linked immunosorbent assay (ELISA)s may detect cross reacting antibodies to related flaviviruses such as dengue viruses. Furthermore, in the context of previous travel, the presence of antibody (in the absence of detectable viral RNA) may indicate a remote / previous infection. These false positive results could result in significant anxiety, unnecessary delays in conception, and potentially inappropriate decisions regarding termination of pregnancy. Currently, testing in Canada is focused on symptomatic individuals coming from potentially endemic areas, and pregnant women. It has been observed that testing of asymptomatic individuals (men or non-pregnant women) has a very low yield of true positives. In addition to the poor specificity of a positive test (especially serologic screening tests), the very low population prevalence of infection means that a negative result is of negligible predictive utility. Therefore, routine testing of asymptomatic travellers and their partners is not recommended.

Laboratory Diagnosis

Molecular testing using RT-PCR and screening serology procedures are conducted by some provincial laboratories in Canada. The National Microbiology Laboratory (NML) provides RT-PCR, IgM and IgG ELISA serological testing support to provinces and territories, along with confirmatory plaque reduction neutralization test (PRNT) diagnostics. Sensitivity and specificity of molecular tests are presumed to be high during the initial few days of illness, since ZIKV appears to circulate in the blood for several days after onset of symptoms Footnote 81. ZIKV RNA may be present in urine for a week or more after symptom onset Footnote 81, Footnote 82. Information about NML's guidelines and testing recommendations are available on the For health professionals: Zika virus webpageFootnote 83.

At the NML, screening serology is currently performed using a US CDC based in-house IgM ELISA and a commercial IgG ELISA. Serum samples identified as being positive by one or both of the ELISAs are then tested by a confirmatory ZIKV PRNT to determine if viral specific antibodies are present Footnote 25. IgM antibodies appear approximately 5 to 6 days after onset of symptoms, and may wane as early as 3 months after exposure Footnote 84. IgG antibodies are usually detected a few days later, with maximal sensitivity about 2 months after infection Footnote 33. For the acutely unwell patient with less than 10 days of symptoms, both RT-PCR and serology should be requested to maximize sensitivity. For the convalescent patient with symptom onset over 10 days ago, only serology should be requested. Serum samples collected from exposed individuals several months after returning from ZIKV endemic areas may no longer be positive for IgM antibodies, however, IgG antibodies may persist for years. Appropriate diagnostic specimens for RT-PCR testing include plasma/serum, urine, cerebrospinal fluid (CSF), amniotic fluid and placental tissue. Serology is usually only performed on serum; however, viral antibodies may be detected in CSF in some cases of neurological disease.

As stated previously ZIKV is a member of the Flaviviridae family, and serologic tests, including the IgM ELISA, may be cross-reactive with other flaviviruses such as dengue, West Nile, and Yellow Fever (including vaccine recipients) Footnote 1. Confirmation of ZIKV exposures therefore depends upon the amplification of viral RNA by RT-PCR, or by confirmatory PRNT serologic testing. Confirmatory testing generally requires neutralizing IgG production, which may appear later than IgM. The specificity of the IgM or IgG ELISAs is limited particularly during secondary flavivirus infections. Patients whose serum samples are IgM positive and have ZIKV-specific antibodies confirmed through PRNT are confirmed cases of viral infection. As previously noted individuals whose serum samples are IgG positive but negative for IgM and have PRNT documented ZIKV specific antibodies were most likely exposed several months before their serum sample(s) was collected. Despite repeat testing, serological results may remain equivocal particularly in cases where the individual was previously infected with a related flavivirus. For secondary exposures an IgM positive result usually infers that a recent flavivirus infection is likely, but it may be unclear if this infection was due to Zika virus or a related virus such as dengue. This is because individuals previously infected with or vaccinated against non-Zika flaviviruses may also exhibit cross reactivity in PRNT tests making them difficult to interpret. It is also recommended for equivocal cases that acute and convalescent sera be collected 2 - 3 weeks apart to increase the likelihood of documenting a seroconversion or a diagnostic increase (four-fold or greater) in ZIKV specific neutralizing antibodies. As discussed above, a negative serology at least 2 weeks after the last possible exposure is presumed to indicate the absence of recent infection, although the precise sensitivity of currently available tests has not been determined. If a negative serological test result is being considered in order to support the discontinuation of transmission precautions, a careful risk assessment is required and collection of a second serum sample should also be considered at a later date to definitively rule out a ZIKV exposure.

In regions where the ZIKV outbreak has been extensive, positive serology (IgM, IgG and PRNT) may increasingly represent remote, rather than recent infection. As mentioned above, the declining incidence of transmission in most areas of the world will increase the false positive rates particularly for relatively non-specific tests such as IgM. Therefore, confirmation of recent infection, especially during pregnancy and for those with exposure in the past, now rests primarily on PCR.

PCR for ZIKV can be performed on amniotic fluid (when amniocentesis is technically feasible) to confirm infection of the fetus. At this time, the risk of adverse outcomes of pregnancy if the fetus is infected with ZIKV is at least 8% of adverse outcomes Footnote 12, so the risk of the procedure must be weighed against the clinical utility of this test result. A negative PCR result likely means that the fetus is not currently infected, but would not eliminate the possibility of previous infection. It is not known when ZIKV RNA would be expected to appear in amniotic fluid after infection, or how long it is likely to be detectable. There is some evidence that viral RNA may persist in amniotic fluid for months Footnote 85.

For postnatal diagnosis of congenital infection, PCR for ZIKV can be performed on placental tissue, umbilical cord blood or infant blood, and CSF for confirmation of congenital infection. It is possible, however, that infants or fetuses infected weeks prior to specimen sampling will no longer have detectable viral RNA.

Screening and Management

Evaluation of non-pregnant travellers returning from countries with demonstrated or potential autochthonous Zika transmission

Testing for ZIKV infection using (PCR) should be considered in the diagnosis of any ill traveller with compatible epidemiologic and clinical history, when symptom onset is within 3 days after arrival in, to 14 days after departing from an area of risk as identified by the WHO. Testing for other similar viral infections and for malaria should also be done as appropriate.

Given the low incidence of infection in most regions, most testing should be limited to molecular techniques, performed within 2 weeks of the onset of symptoms. It may often be appropriate to perform molecular tests for other similar arboviral infections on the same specimen Footnote 84.

Serologic testing could be considered for male returned travellers whose clinically compatible illness has resolved, and are at least 2 weeks post exposure, in order to assess for potential contagiousness to sexual partners. However, the higher probability of false positive results must be considered and discussed with the patient, prior to testing.

Serological testing of male individuals with a history of travel to an area with Zika virus transmission but no ongoing major outbreak, and no history of related symptoms is not recommended, given the very low risk of infection and high risk of false positive serology.

A negative test result for a symptomatic or asymptomatic patient, whether from an initial or follow-up serology (e.g., if the first test is equivocal), indicates that a recent ZIKV infection is very unlikely. However, the risk of false positive results, the time required for confirmatory serologic testing, and the relatively short period during which transmission prevention measures might be required all combine to limit the usefulness of such testing Footnote 84. The decision to test should be made in consultation with a health care provider, and should be set against the broader context of the likelihood of infection and patient values and preferences. Testing would only be appropriate when transmission prevention measures are planned during the testing period, which may take several weeks.

The potential for viremia or transmission following a second exposure is unknown. Given that neurologic disorders like GBS have occurred following ZIKV infection, returning travellers should be counselled to report any neurologic symptoms to their doctor. In the event of the diagnosis of GBS or other unusual neurologic syndrome, a travel history for the patient and any male sexual partners should be elicited. If ZIKV infection is thought to be potentially associated with the illness, a specialist should be consulted.

Evaluation in the context of pregnancy

Evaluation of pregnant women with a travel history to an area of risk

Health care providers should take a travel history from their pregnant patients including relevant information related to the travel history of their partner(s). Any patient who indicates that they or their partner have recently travelled to areas of transmission should be further evaluated.

Screening of asymptomatic pregnant women with possible exposure during pregnancy or during the peri-conception period should be discussed on a case-by-case basis between the woman and her health care provider. The declining incidence of Zika transmission in most areas of the world means that infection rates in this population will be very low, and the risk of false positive laboratory results, particularly for serology, correspondingly elevated. False positive diagnoses would have important implications for adverse events related to unwarranted additional testing and anxiety, as well as resource utilization. The decision whether to screen should take into account intensity of the potential exposure, the use of prevention measures, the likelihood of remote infection, and the transmission trends at the location of potential exposure. In most cases, screening is NOT recommended. Screening would be done as for the symptomatic pregnancy patient, see below. The decision to test should include consideration of how the results of the screening tests would be used to inform subsequent decisions. The likelihood of false negative, and especially false positive results in the absence of a recent infection always require careful discussion with the patient. Diagnosis and identification of poor fetal outcomes will allow for appropriate counselling.

Pregnant women and their partners may be justifiably concerned about the risk of ZIKV infection to their fetus and may want to receive counselling to decide the best course of action, including the question of termination. The risk of vertical infection (with clinical sequelae) in the setting of symptomatic or asymptomatic maternal infection appears highest in the first trimester Footnote 5. However severe sequelae have been reported after infection at all stages of pregnancy Footnote 86. This uncertainty makes pregnancy counselling a difficult prospect. Regardless, discussion and informed decision making regarding options for management of ZIKV infection in pregnancy (much like any other congenital infection or congenital anomaly) requires thorough consultation with a Maternal Fetal Medicine Specialist or another specialist familiar with reproductive infectious diseases.

Evaluation of pregnant women with symptoms compatible with ZIKV infection

Testing should be offered to pregnant women with acute signs and symptoms compatible with ZIKV. Given the reports of longer periods of viremia in some pregnant women, for the patient with symptoms during the preceding 12 weeks, both RT-PCR (on blood and urine) and serology should be requested to maximize sensitivity and specificity. For the convalescent patient with symptom onset over 12 weeks ago, only serology should be requested, although the sensitivity as well as the specificity of testing at this stage is unknown. Repeated ultrasound monitoring is indicated, unless the woman is found to be negative on laboratory testing. A woman whose fetus is suspected of having a congenital anomaly should also be offered testing if she or her partner has travelled to any location where ZIKV transmission may be occurring Footnote 87,Footnote 88 even at a low level.

Although measurements of head circumference and biparietal diameter may occur as early as 15 weeks, there is no defined gestational age by which microcephaly and other intracranial abnormalities can be ruled out. Serial monitoring by ultrasound with close attention to measurement trends over time is recommended. It is possible that changes in intracranial anatomy may not be elucidated until well into the third trimester, or later.

Counselling recommendations are as in the section on the asymptomatic woman, above.

Evaluation of the fetus among pregnant women diagnosed with ZIKV infection

Serial ultrasounds (every 3 - 4 weeks) are recommended in pregnant women with confirmed or suspected (if testing results are pending or equivocal) ZIKV infection in pregnancy. Should CNS calcifications or fetal microcephaly be noted at ultrasonography of an asymptomatic pregnant returned traveller, then specific ZIKV testing of the fetus (e.g., amniocentesis), in addition to other investigations to elucidate alternate aetiologies, should be considered to help define the likely cause of the anomaly.

Evaluation of the infant born to a woman diagnosed with ZIKV infection or with suspected congenital ZIKV infection or CZS

Infants born to women with confirmed or suspected ZIKV infection in pregnancy, or those with unexplained microcephaly, intracranial calcifications, ventriculomegaly or major structural central nervous system abnormalities or other symptoms of congenital ZIKV infection in whom the mother had potential exposure to the virus, should be tested. This testing should include serology, PCR of serum (umbilical cord or infant sample), and PCR of placenta; if CSF is sampled, this can also be sent for PCR and serology. Management is evolving and infants with suspected or confirmed CZS should also undergo further work-up including: routine lab tests (CBC and liver enzymes), head ultrasound, ophthalmologic examination, and hearing evaluation as outlined in current guidelines by the Canadian Paediatric Society (CPS) Footnote 89. Care should be taken to ensure a thorough work up for other important and treatable causes of congenital infections, such as cytomegalovirus and Toxoplasma. Infants with confirmed CZS should have neurodevelopmental monitoring throughout infancy to assess the potential for long-term sequelae.

Infants born to women with symptoms of active ZIKV infection around the time of delivery are at risk for perinatal transmission of the disease. In the limited number of reported cases to date, perinatally infected infants have exhibited either no or mild symptoms and laboratory findings (rash, thrombocytopenia) Footnote 37. Regardless, such infants should be monitored closely given the unclear spectrum of potential illness in this emerging infection. Testing with serology and serum PCR during acute illness is recommended. Long term follow-up with a pediatric infectious disease specialist is suggested.

Treatment

Currently there is no specific therapy for the treatment of ZIKV infection. Treatment is supportive with antipyretics (acetaminophen in pregnancy), hydration and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out to reduce the risk of hemorrhage Footnote 90. Symptomatic disease typically lasts for up to 7 days. Urgent medical care is recommended for any symptoms associated with GBS, and treating health care providers should be made aware of recent travel to area with ZIKV circulation and/or symptoms of ZIKV infection.

If ZIKV infection is confirmed in the setting of pregnancy, referral to a Maternal Fetal Medicine Specialist or specialist familiar with Reproductive Infectious Diseases should be made. If microcephaly, intracranial calcifications or other abnormalities are identified, appropriate counselling by a Neonatologist and Pediatric Infectious Diseases Specialist on potential neurodevelopmental outcome should be offered to parents.

Summary of Recommendations for ZIKV

Table 1a - Recommendations for prevention of ZIKV
Action

Group

Areas estimated to have a likelihood of travel-related infection and associated impacts including CZSFootnote 1

Decision to travel to areas of risk

Pregnant women and women and couples who are planning a pregnancy

Risk of ZIKV is considered low. CATMAT no longer routinely recommends avoiding or postponing travel to any affected areas, however travellers and health care providers should remain vigilant of Zika virus activity in the area of travel.

Discussion should occur around decision to travel, based on individual values and preferences, including risk of ZIKV infection. Some pregnant women or those planning a pregnancy may choose to minimize risk by:

  • not travelling to these areas or
  • postponing travel until after pregnancy or
  • postponing pregnancy until after travel.

Some countries in these ZIKV affected areas have a significant risk of malaria infection, e.g., Sub-Saharan Africa. As malaria infection during pregnancy is associated with substantial risk of maternal and fetal harm, pregnant travellers should avoid travel to these areas (for more information, see CATMAT's Statement on pregnancy and travel).

All other travellers

Low risk for ZIKV infection and consequent impact on travellers. Health care providers should discuss current knowledge about ZIKV, associated risks, and values and preferences with patients.

Prevention of mosquito borne transmission

All travellers

CATMAT recommends adherence to recommendations for the use of personal protective measures (PPM) against mosquito bites through all hours of the day and night.

Prevention of sexual transmission

All asymptomatic travellers (including pregnant women and women and couples who are planning a pregnancy)

Risk of ZIKV is considered low. CATMAT no longer recommends routine use of measures to prevent sexual transmission from asymptomatic travellers while in or after returning ZIKV affected areas.

Discussion should occur around individual values and preferences as travellers may still choose to minimize risk by using condoms and/or restricting sexual activity by following the recommendations below.

 

All symptomatic travellers (including pregnant women and women and couples who are planning a pregnancy)

If symptoms compatible with ZIKV infection are present and no alternate explanation for symptoms is established, CATMAT recommends that discussion should occur around likelihood of ZIKV infection to inform decision to apply recommendations to prevent sexual transmission.

If ZIKV infection is confirmed, CATMAT recommends:

  • women wait at least 2 months after their return from these areas or onset of symptoms (whichever occurs later) before trying to conceive and/or having unprotected sex;
  • male partners wait at least 3 months after their return from these areas or onset of symptoms (whichever occurs later) before trying to conceive and/or having unprotected sex.

In the case of a confirmed or clinically compatible ZIKV infection in the male partner, couples planning a pregnancy might wish to delay conception for up to 6 months, depending on personal risk tolerance. The 6 months represents the outer theoretical limit of the potentially contagious period for a male partner.

In the case of a confirmed or symptomatic case with compatible symptoms of ZIKV infection in the male partner, CATMAT recommends that pregnant couples abstain from unprotected sex for the duration of the pregnancy.

Footnote 1

As designated by the WHOFootnote 80

Return to footnote 1 referrer

Table 1b - Recommendations for screening and management of ZIKV
Risk group

Recommendations

All travellers

Testing should be considered for any ill traveller with compatible epidemiologic and clinical history (for areas designated by the WHO), when symptom onset is within 3 days after arrival in, to 14 days after departing from an area of risk.

Serology and viral RNA testing in Canada is only recommended for symptomatic individuals or those that fulfill other routine testing criteria (see below).

In the acutely unwell patient with less than 10 days of symptoms, both RT-PCR and serology should be requested to maximize sensitivity.

In the convalescent patient with symptom onset over 10 days prior to presentation, only serology should be requested.

Male partners

Serologic testing may be considered for male returned travellers (for areas designated by the WHO) whose clinically compatible illness has resolved, and are at least 2 weeks post exposure, in order to help assess for potential contagiousness to sexual partners.

Serological testing of male individuals with a history of travel to an area (designated by the WHO with Zika virus transmission) but no history of related symptoms will have significant rates of false negative and false positive results, and is not recommended.

For those awaiting test results, and those who test positive, avoidance of pregnancy for 3 months after the last possible exposure is expected to reduce any risk to negligible levels.

Negative serology

A negative result for a symptomatic or asymptomatic traveller (male or female), whether from an initial or follow-up serology (e.g., if the first test is equivocal), indicates that a recent ZIKV infection is very unlikely.

All pregnant women

All pregnant patients with a travel history during the peri-conception period or pregnancy to an area of risk (as designated by the WHO) should receive an evaluation to assess whether increased levels of transmission have been reported around the time of possible exposure.

Asymptomatic pregnant women

Asymptomatic pregnant women with a travel history to an area of risk (as designated by the WHO) should seek evaluation to determine whether increased levels of transmission were reported around the time of travel. If so, they should discuss the role of testing with their health care provider; in most cases, testing is NOT recommended. If recommended, testing would consist of serology at least 2 weeks after the last potential exposure and fetal ultrasounds, at a frequency to be determined in consultation with the woman's obstetrician.

Symptomatic pregnant women

Acutely unwell patient within ≤12 weeks of symptom onset (for areas designated by the WHO), both RT-PCR and serology should be requested to maximize sensitivity.

Convalescent patient with symptom onset over 12 weeks (for areas designated by the WHO), only serology should be requested. RT-PCR should be added if the patient continues to suffer from fever, regardless of symptom duration.

Serial ultrasound monitoring is indicated, unless the woman found to be negative on laboratory testing, including negative serology at least 2 weeks after the last possible exposure.

Fetus of pregnant women with confirmed or suspected ZIKV infection

Pregnant women with confirmed or suspected ZIKV infection in pregnancy should receive serial ultrasounds (every 3 - 4 weeks).

Infant born to a woman with confirmed or suspected ZIKV infection or with suspected CZS

Infants born to women with confirmed or suspected ZIKV infection in pregnancy, or those with microcephaly, intracranial calcifications or other symptoms of CZS in whom the mother had potential exposure to the virus, should be tested.

This testing should include serology, PCR of serum (umbilical cord or infant sample), and PCR of placenta; if CSF is sampled, this can also be sent for PCR and serology.

Infants with suspected or confirmed congenital ZIKV infection/ syndrome

Infants with suspected or confirmed congenital ZIKV infection/syndrome should also undergo further work-up including routine lab tests (CBC and liver enzymes), head ultrasound, ophthalmologic examination, and hearing evaluation.

Those with confirmed CZS should have neurodevelopmental monitoring throughout infancy to assess the potential for long-term sequelae Footnote 89.

Table 1c - Recommendations for treatment of ZIKV

Risk group

Recommendations

Pregnant cases

Acetaminophen, hydration, and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out. Urgent medical care is recommended for any symptoms associated with GBS or other neurologic syndromes. Referral to a maternal fetal medicine specialist or infectious diseases specialist should be made. If fetal abnormalities are identified, appropriate counselling should be offered.

All other cases

Antipyretics, hydration, and rest. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue can be ruled out. Urgent medical care is recommended for any symptoms associated with GBS or other neurologic syndromes.

Additional resources and useful links:

Government of Canada - For health professionals: Zika Virus

Government of Canada - Travel health notice: Zika virus infection: Global Update

Pan American Health Organization - Zika Virus Infection

World Health Organization - Zika virus classification tables

Committee to Advise on Tropical Medicine and Travel - Travel Medicine Resources for Canadian Practitioners

Acknowledgements

This statement was developed by the Zika Working Group: Libman M (chair), Boggild A, Bui Y, Drebot M, McCarthy A, Schofield S, Tataryn J, van Schalkwyk J, Wood H, Yudin M and approved by CATMAT.

CATMAT would like to acknowledge the technical and administrative support from the Office of Border and Travel Health at the Public Health Agency of Canada for the development of this statement.

CATMAT members: McCarthy A (Chair), Acharya A, Boggild A,, Bui Y, Crockett M, Greenaway C, Libman M, and Vaughan S.

Liaison members: Audcent T (Canadian Paediatric Society) and Pernica J (Association of Medical Microbiology and Infectious Disease Canada).

Ex officio members: Marion D (Canadian Forces Health Services Centre, Department of National Defence), McDonald P (Bureau of Medical Sciences, Health Canada), Rossi C (Medical Intelligence, Department of National Defence) and Schofield S (Pest Management Entomology, Department of National Defence).

Conflict of interest

None declared.

References

1

Hayes EB. Zika virus outside Africa. Emerg Infect Dis 2009;15(9):1347-1350.

Return to first footnote 1 referrer

2

Kraemer MU, Sinka ME, Duda KA, Mylne AQ, Shearer FM, Barker CM, et al. The global distribution of the arbovirus vectors Aedes aegypti and Ae. albopictus. eLife 2015;4(e08347):1-18.

Return to footnote 2 referrer

3

Triunfol M. A new mosquito-borne threat to pregnant women in Brazil. Lancet Infect Dis 2016;16(2):156-157.

Return to footnote 3 referrer

4

World Health Organization. Surveillance for Zika virus infection, microcephaly and Guillain-Barré syndrome Interim guidance 7 April 2016. 2016; Available at: http://apps.who.int/iris/bitstream/10665/204897/1/WHO_ZIKV_SUR_16.2_eng.pdf?ua=1. Accessed April 12, 2016.

Return to first footnote 4 referrer

5

Cauchemez S, Besnard M, Bompard P, Dub T, Guillemette-Artur P, Eyrolle-Guignot D, et al. Association between Zika virus and microcephaly in French Polynesia, 2013-15: a retrospective study. Lancet 2016;ePub.

Return to footnote 5 referrer

6

Schuler-Faccini L. Possible Association Between Zika Virus Infection and Microcephaly-Brazil, 2015. Morb Mortal Wkly Rep 2016;65(3):59-62.

Return to footnote 6 referrer

7

Hoen B, Schaub B, Funk AL, Ardillon V, Boullard M, Cabie A, et al. Pregnancy Outcomes after ZIKV Infection in French Territories in the Americas. N Engl J Med 2018 Mar 15;378(11):985-994.

Return to footnote 7 referrer

8

European Centre for Disease Prevention and Control. Rapid risk assessment: Zika virus epidemic in the Americas: potential association with microcephaly and Guillain-Barré syndrome, 10 December 2015. 2015; Available at: http://ecdc.europa.eu/en/publications/Publications/zika-virus-americas-association-with-microcephaly-rapid-risk-assessment.pdf. Accessed Feb. 2, 2016.

Return to first footnote 8 referrer

9

Brito Ferreira ML. Neurologic Manifestations of Arboviruses in the Epidemic in Pernambuco, Brazil. American Academy of Neurology 68th Annual Meeting 2016.

Return to first footnote 9 referrer

10

Mead PS, Duggal NK, Hook SA, Delorey M, Fischer M, Olzenak McGuire D, et al. Zika Virus Shedding in Semen of Symptomatic Infected Men. N Engl J Med 2018 Apr 12;378(15):1377-1385.

Return to first footnote 10 referrer

11

Reynolds MR, Jones AM, Petersen EE, Lee EH, Rice ME, Bingham A, et al. Vital Signs: Update on Zika Virus-Associated Birth Defects and Evaluation of All U.S. Infants with Congenital Zika Virus Exposure - U.S. Zika Pregnancy Registry, 2016. MMWR Morb Mortal Wkly Rep 2017 Apr 7;66(13):366-373.

Return to footnote 11 referrer

12

Shapiro-Mendoza CK, Rice ME, Galang RR, Fulton AC, VanMaldeghem K, Prado MV, et al. Pregnancy Outcomes After Maternal Zika Virus Infection During Pregnancy - U.S. Territories, January 1, 2016-April 25, 2017. MMWR Morb Mortal Wkly Rep 2017 Jun 16;66(23):615-621.

Return to first footnote 12 referrer

13

Rice ME, Galang RR, Roth NM, et. al. Vital Signs: Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital zika virus infection - U.S. Territories and Freely Associated States. MMWR Morb Mortal Wkly Rep 2018 August 7, 2018;67:858-867.

Return to footnote 13 referrer

14

Boggild AK, Geduld J, Libman M, Yansouni CP, McCarthy AE, Hajek J, et al. Surveillance report of Zika virus among Canadian travellers returning from the Americas. CMAJ 2017 Mar 6;189(9):E334-E340.

Return to footnote 14 referrer

15

Counotte MJ, Kim CR, Wang J, Bernstien k, Deal CD, Broutet NJN, et al. Sexual transmission of Zika virus and other flaviviruses: A living systematic review. PLoS Med 2018;15(7).

Return to footnote 15 referrer

16

Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on Personal Protective Measures to Prevent Arthropod Bites. Can Commun Dis Rep 2012;38(ACS-3):1-18.

Return to first footnote 16 referrer

17

Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on Pregnancy and Travel. Can Commun Dis Rep 2010;36(ACS-2):1-44.

Return to first footnote 17 referrer

18

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):13-48.

Return to footnote 18 referrer

19

Dick GWA. Zika virus (II). Pathogenicity and physical properties. Trans R Soc Trop Med Hyg 1952;46(5):521-534.

Return to footnote 19 referrer

20

Duffy MR, Chen TH, Hancock WT, Powers AM, Kool JL, Lanciotti RS, et al. Zika virus outbreak on Yap Island, Federated States of Micronesia. New Engl J Med 2009;360(24):2536-2543.

Return to first footnote 20 referrer

21

Cao-Lormeau VM, Roche C, Teissier A, Robin E, Berry AL, Mallet HP, et al. Zika virus, French Polynesia, South Pacific, 2013. Emerg Infect Dis 2014;20(6):1085-1086.

Return to footnote 21 referrer

22

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.

Return to footnote 22 referrer

23

World Health Organization. Zika virus infection - Cape Verde. 2015; Available at: http://www.who.int/csr/don/21-december-2015-zika-cape-verde/en/. Accessed Feb. 2, 2016.

Return to footnote 23 referrer

24

Tognarelli J, Ulloa S, Villagra E, Lagos J, Aguayo C, Fasce R, et al. A report on the outbreak of Zika virus on Easter Island, South Pacific, 2014. Arch Virol 2015;ePub.

Return to footnote 24 referrer

25

Pan American Health Organization. Countries and territories with autochthonous transmission in the Americas reported in 2015-2016. 2016; Available at: http://www.paho.org/hq/index.php?option=com_content&view=article&id=11603%3Acountries-territories-zika-autochthonous-transmission-americas&catid=8424%3Acontents&Itemid=41696&lang=en. Accessed November 10, 2016.

Return to first footnote 25 referrer

26

Pan American Health Organization. Regional zika epidemiological update (Americas) Aug 25, 2017. 2017; Available at: https://www.paho.org/hq/index.php?option=com_content&view=article&id=11599:regional-zika-epidemiological-update-americas&Itemid=41691&lang=en. Accessed August 27, 2018.

Return to first footnote 26 referrer

27

Caribbean Public Health Agency (CARPHA). CARPHA concludes risk of getting zika in the Caribbean low at this time. 2018; Available at: http://carpha.org/articles/ID/180/CARPHA-Concludes-Risk-of-Getting-Zika-in-the-Caribbean-Low-at-this-Time. Accessed August 27, 2018.

Return to first footnote 27 referrer

28

Government of Canada. Surveillance of Zika. 2018; Available at: https://www.canada.ca/en/public-health/services/diseases/zika-virus/health-professionals.html. Accessed October 12, 2018.

Return to first footnote 28 referrer

29

Centers for Disease Control and Prevention (CDC). Zika Cases in the United States. 2018; Available at: https://www.cdc.gov/zika/reporting/case-counts.html. Accessed October 12, 2018.

Return to first footnote 29 referrer

30

Centers for Disease Control and Prevention (CDC). 2018 Case Counts in the US. Provisional data as of December 4, 2018. 2018; Available at: https://www.cdc.gov/zika/reporting/2018-case-counts.html. Accessed December 12, 2018.

Return to first footnote 30 referrer

31

Krow-Lucal ER, Biggerstaff BJ, Staples JE. Estimated Incubation Period for Zika Virus Disease. Emerg Infect Dis 2017 May;23(5):841-845.

Return to footnote 31 referrer

32

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):1501-1505.

Return to footnote 32 referrer

33

European Centre for Disease Prevention and Control. Zika virus infection: Factsheet for health professionals. 2015; Available at: http://ecdc.europa.eu/en/healthtopics/zika_virus_infection/factsheet-health-professionals/Pages/factsheet_health_professionals.aspx. Accessed Jan. 22, 2016.

Return to first footnote 33 referrer

34

Lessler JT, Ott CT, Carcelen AC, Konikoff JM, Williamson J, Bi Q, Kucirka LM, Cummings DA, Reichd NG,Chaissona LH. Times to key events in the course of Zika infection and their implications: a systematic review and pooled analysis. Bull World Health Organ 2016.

Return to footnote 34 referrer

35

Paz-Bailey G, Rosenberg ES, Doyle K, Munoz-Jordan J, Santiago GA, Klein L, et al. Persistence of Zika Virus in Body Fluids - Preliminary Report. N Engl J Med 2017 Feb 14.

Return to first footnote 35 referrer

36

Murray KO, Gorchakov R, Carlson AR, Berry R, Lai L, Natrajan M, et al. Prolonged Detection of Zika Virus in Vaginal Secretions and Whole Blood. Emerg Infect Dis 2017 Jan;23(1):99-101.

Return to footnote 36 referrer

37

Besnard M, Lastère S, Teissier A, Cao-Lormeau VM, Musso D. Evidence of perinatal transmission of zika virus, French Polynesia, December 2013 and February 2014. Euro Surveill 2014;19(13):20751.

Return to first footnote 37 referrer

38

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(1):6-7.

Return to footnote 38 referrer

39

Musso D, Nhan T, Robin E, Roche C, Bierlaire D, Zisou K, et al. Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Euro Surveil 2014;19(14):20761.

Return to footnote 39 referrer

40

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):359-361.

Return to footnote 40 referrer

41

Foy BD, Kobylinski KC, Chilson Foy JL, Blitvich BJ, Travassos da Rosa A, Haddow AD, et al. Probable non-vector-borne transmission of Zika virus, Colorado, USA. Emerg Infect Dis 2011;17(5):880-882.

Return to footnote 41 referrer

42

Dallas County Health and Human Services. DCHHS Reports First Zika Virus Case in Dallas County Acquired Through Sexual Transmission. 2016; Available at: http://www.dallascounty.org/department/hhs/press/documents/PR2-2-16DCHHSReportsFirstCaseofZikaVirusThroughSexualTransmission.pdf. Accessed Feb. 2, 2016.

Return to footnote 42 referrer

43

Hills SL, Russell K, Hennessey M, Williams C, Oster AM, Fischer M, et al. Transmission of Zika Virus Through Sexual Contact with Travelers to Areas of Ongoing Transmission - Continental United States, 2016. Morb Mortal Wkly Rep 2016;65(8):215-216.

Return to footnote 43 referrer

44

Davidson A, Slavinski S, Komoto K, Rakeman J, Weiss D. Suspected Female-to-Male Sexual Transmission of Zika Virus - New York City, 2016. MMWR Morb Mortal Wkly Rep 2016 Jul 22;65(28):716-717.

Return to footnote 44 referrer

45

Freour T, Mirallie S, Hubert B, Splingart C, Barriere P, Maquart M, et al. Sexual transmission of Zika virus in an entirely asymptomatic couple returning from a Zika epidemic area, France, April 2016. Euro Surveill 2016 Jun 9;21(23):10.2807/1560-7917.ES.2016.21.23.30254.

Return to first footnote 45 referrer

46

Schwartz KL, Chan T, Rai N, Murphy KE, Whittle W, Drebot MA, et al. Zika virus infection in a pregnant Canadian traveler with congenital fetal malformations noted by ultrasonography at 14-weeks gestation. Trop Dis Travel Med Vaccines 2018 Apr 4;4:2-018-0062-8. eCollection 2018.

Return to footnote 46 referrer

47

Suy A, Sulleiro E, Rodo C, Vazquez E, Bocanegra C, Molina I, et al. Prolonged Zika Virus Viremia during Pregnancy. N Engl J Med 2016 Dec 29;375(26):2611-2613.

Return to footnote 47 referrer

48

Arsuaga M, Bujalance SG, Diaz-Menendez M, Vazquez A, Arribas JR. Probable sexual transmission of Zika virus from a vasectomised man. Lancet Infect Dis 2016 Oct;16(10):1107-3099(16)30320-6. Epub 2016 Sep 19.

Return to footnote 48 referrer

49

Brooks RB, Carlos MP, Myers RA, White MG, Bobo-Lenoci T, Aplan D, et al. Likely Sexual Transmission of Zika Virus from a Man with No Symptoms of Infection - Maryland, 2016. MMWR Morb Mortal Wkly Rep 2016 Sep 2;65(34):915-916.

Return to footnote 49 referrer

50

Musso D, Richard V, Teissier A, Stone M, Lanteri MC, Latoni G, et al. Detection of Zika virus RNA in semen of asymptomatic blood donors. Clin Microbiol Infect 2017 Dec;23(12):1001.e1-1001.e3.

Return to footnote 50 referrer

51

Baud D, Gubler DJ, Schaub B, Lanteri MC, Musso D. An update on Zika virus infection. Lancet 2017 Jun 21.

Return to first footnote 51 referrer

52

World Health Organization. Breastfeeding in the context of Zika virus Interim Guidance 25 February 2016. 2016; Available at: http://apps.who.int/iris/bitstream/10665/204473/1/WHO_ZIKV_MOC_16.5_eng.pdf?ua=1. Accessed March 4, 2016.

Return to footnote 52 referrer

53

Gallian P, Cabié A, Richard P, Paturel L, Charrel RN, Pastorino B, et al. Zika virus in asymptomatic blood donors in Martinique. Blood 2017 American Society of Hematology;129(2):263-266.

Return to footnote 53 referrer

54

Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Herida M. Current Zika virus epidemiology and recent epidemics. Med Mal Infect 2014;44(7):302-307.

Return to first footnote 54 referrer

55

Hamer DH, Barbre KA, Chen LH, Grobusch MP, Schlagenhauf P, Goorhuis A, et al. Travel-Associated Zika Virus Disease Acquired in the Americas Through February 2016: A GeoSentinel Analysis. Ann Intern Med 2017 Jan 17;166(2):99-108.

Return to footnote 55 referrer

56

Villamil-Gómez WE, González-Camargo O, Rodriguez-Ayubi J, Zapata-Serpa D, Rodriguez-Morales AJ. Dengue, chikungunya and Zika co-infection in a patient from Colombia. J Infect Public Health 2015;ePub.

Return to footnote 56 referrer

57

Committee to Advise on Tropical Medicine and Travel (CATMAT). Fever in the returning international traveller initial assessment guidelines. Can Commun Dis Rep 2011;37(ACS-2):1-24.

Return to footnote 57 referrer

58

Shinohara K, Kutsuna S, Takasaki T, Moi ML, Ikeda M, Kotaki A, et al. Zika fever imported from Thailand to Japan, and diagnosed by PCR in the urines. J Travel Med 2016;23(1):1-3.

Return to footnote 58 referrer

59

Committee to Advise on Tropical Medicine and Travel (CATMAT). Canadian Recommendations for the Prevention and Treatment of Malaria. 2014;140006.

Return to footnote 59 referrer

60

Oehler E, Watrin L, Larre P, Leparc-Goffart I, Lastãre S, Valour F, et al. Zika virus infection complicated by guillain-barré syndrome - case report, French Polynesia, December 2013. Euro Surveill 2014;19(9):20720.

Return to footnote 60 referrer

61

World Health Organization. Zika virus, Microcephaly and Guillain-Barré Syndrome Situation Report 26 February 2016. 2016; Available at: http://apps.who.int/iris/bitstream/10665/204491/1/zikasitrep_26Feb2016_eng.pdf?ua=1. Accessed March 4, 2016.

Return to footnote 61 referrer

62

Cao-Lormeau V, Blake A, Mons S, Lastere S, Roche C, Vanhomwegen J, et al. Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 2016;ePub.

Return to footnote 62 referrer

63

Mécharles S, Herrmann C, Poullain P, Tran T, Deschamps N, Mathon G, et al. Acute myelitis due to Zika virus infection. Lancet 2016;ePub.

Return to footnote 63 referrer

64

Carteaux G, Maquart M, Bedet A, Contou D, Brugières P, Fourati S, et al. Zika Virus Associated with Meningoencephalitis. N Engl J Med 2016;ePub.

Return to footnote 64 referrer

65

Karimi O, Goorhuis A, Schinkel J, Codrington J, Vreden SGS, Vermaat JS, et al. Thrombocytopenia and subcutaneous bleedings in a patient with Zika virus infection. Lancet 2016;387:939-940.

Return to footnote 65 referrer

66

Zammarchi L, Stella G, Mantella A, Bartolozzi D, Tappe D, Günther S, et al. Zika virus infections imported to Italy: clinical, immunological and virological findings, and public health implications. J Clin Virol 2015;63:32-35.

Return to footnote 66 referrer

67

Baud D, Van Mieghem T, Musso D, Truttmann AC, Panchaud A, Vouga M. Clinical management of pregnant women exposed to Zika virus. Lancet Infect Dis 2016;16(5):523.

Return to footnote 67 referrer

68

Arzuza-Ortega L, Pérez-Tatis G, López-García H. Fatal Zika virus infection in girl with sickle cell disease, Colombia. Emerging Infect Dis 2016;22(5).

Return to footnote 68 referrer

69

World Health Organization. Zika Virus Microcephaly Guillian-Barré Syndrome 10 March 2017. 2017.

Return to footnote 69 referrer

70

Melo AS, Aguiar RS, Amorim MM, Arruda MB, Melo FO, Ribeiro ST, et al. Congenital Zika Virus Infection: Beyond Neonatal Microcephaly. JAMA Neurol 2016 Oct 3.

Return to footnote 70 referrer

71

de Araujo TV, Rodrigues LC, de Alencar Ximenes RA, de Barros Miranda-Filho D, Montarroyos UR, de Melo AP, 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 Sep 15.

Return to footnote 71 referrer

72

Ventura CV, Maia M, Bravo-Filho V, Góis AL, Belfort R. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet 2016;387(10015):228.

Return to footnote 72 referrer

73

Costa F, Sarno M, Khouri R, de Paulo Freitas B, Siqueira I, Ribeiro GS, et al. Emergence of Congenital Zika Syndrome: Viewpoint From the Front Lines. Ann Intern Med 2016;ePub.

Return to footnote 73 referrer

74

Sarno M, Sacramento GA, Khouri R, do Rosário MS, Costa F, Archanjo G, et al. Zika Virus Infection and Stillbirths: A Case of Hydrops Fetalis, Hydranencephaly and Fetal Demise. PLOS Negl Trop Dis 2016;10(2):e0004517.

Return to footnote 74 referrer

75

Rasmussen SA, Jamieson DJ, Honein MA, Petersen LR. Zika Virus and Birth Defects - Reviewing the Evidence for Causality. N Engl J Med 2016;ePub.

Return to footnote 75 referrer

76

European Centre for Disease Prevention and Control. Disease data from ECDC Surveillance Atlas - Zika virus disease. 2017:Available at: https://ecdc.europa.eu/en/zika-virus-infection/surveillance-and-disease-data/disease-data. Accessed July 16, 2018.

Return to footnote 76 referrer

77

Statistics Canada. International Travel Survey. Custom extract. 2015.

Return to footnote 77 referrer

78

Canadian Paediatric Surveillance Program, Canadian Paediatric Society. CPSP 2017 Results. 2018.

Return to footnote 78 referrer

79

World Health Organization. Zika virus classification tables. 2018; Available at: http://www.who.int/emergencies/zika-virus/classification-tables/en/. Accessed October 12, 2018.

Return to footnote 79 referrer

80

World Health Organization. Zika virus transmission tables. 2019 (July 2, 2019): https://www.who.int/emergencies/diseases/zika/countries-with-zika-and-vectors-table.pdf.

Return to first footnote 80 referrer

81

European Centre for Disease Prevention and Control. Rapid risk assessment: Zika virus infection outbreak, French Polynesia, 14 February 2014. 2014; Available at: http://ecdc.europa.eu/en/publications/Publications/Zika-virus-French-Polynesia-rapid-risk-assessment.pdf. Accessed Feb. 2, 2016.

Return to first footnote 81 referrer

82

Centers for Disease Control and Prevention (CDC). Revised diagnostic testing for Zika, chikungunya, and dengue viruses in US Public Health Laboratories. 2016; Available at: http://www.cdc.gov/zika/pdfs/denvchikvzikv-testing-algorithm.pdf. Accessed March 3, 2016.

Return to footnote 82 referrer

83

Dimitrova K, Makowski K, Cunningham I, Holloway K, Giles E, Andonova M, et al. Zika virus in Canada. Can Commun Dis Rep 2016;42:101-104.

Return to first footnote 83 referrer

84

Drebot M, for the National Microbiology Laboratory. Laboratory diagnosis. 2018 May 11.

Return to first footnote 84 referrer

85

Calvet G, Aguiar RS, Melo AS, Sampaio SA, de Filippis I, Fabri A, et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis 2016;ePub.

Return to footnote 85 referrer

86

Brasil P, Pereira J,Jose P., Raja Gabaglia C, Damasceno L, Wakimoto M, Ribeiro Nogueira RM, et al. Zika Virus Infection in Pregnant Women in Rio de Janeiro — Preliminary Report. N Engl J Med 2016;ePub.

Return to footnote 86 referrer

87

World Health Organization. Zika virus situation reports. 2016; Available at: http://www.who.int/emergencies/zika-virus/situation-report/en/. Accessed October 4, 2016.

Return to footnote 87 referrer

88

Centers for Disease Control and Prevention (CDC). Advice for people living in or traveling to South Florida. 2016; Available at: http://www.cdc.gov/zika/intheus/florida-update.html. Accessed October 4, 2016.

Return to footnote 88 referrer

89

Robinson JL. Zika virus: What does a physician caring for children in Canada need to know? Paediatr Child Health 2017 Mar;22(1):48-55.

Return to first footnote 89 referrer

90

Centers for Disease Control and Prevention (CDC). Clinical Evaluation & Disease. 2016; Available at: http://www.cdc.gov/zika/hc-providers/clinicalevaluation.html. Accessed Feb. 5, 2016.

Return to footnote 90 referrer

Report a problem or mistake on this page
Please select all that apply:

Thank you for your help!

You will not receive a reply. For enquiries, contact us.

Date modified: