Download Zika virus: What does a physician caring for

Paediatrics & Child Health, 2017, 48–51
doi: 10.1093/pch/pxx012
Practice Point
Practice Point
Zika virus: What does a physician caring for children in Canada
need to know?
Joan L. Robinson
Canadian Paediatric Society, Infectious Diseases and Immunization Committee, Ottawa, Ontario
Correspondence: Canadian Paediatric Society, 100-2305 St Laurent Blvd, Ottawa, Ontario K1G 4J8. E-mail [email protected],
website www.cps.ca
Abstract
Zika virus (ZIKV) was recently recognized to be teratogenic. The diagnosis of congenital ZIKV syndrome should be considered in children with unexplained microcephaly, intracranial calcifications, ventriculomegaly or major structural central
nervous system abnormalities. Management is evolving but suggestions are provided for children with findings compatible
with congenital infection and for those born to women with potential exposure during pregnancy.
Keywords: Congenital infection; Microcephaly; Teratogen; Zika virus
EPIDEMIOLOGY
Zika virus (ZIKV) is an RNA virus and member of the flavivirus family, which
includes West Nile, dengue, Japanese encephalitis, St. Louis encephalitis and
yellow fever viruses. ZIKV was first detected in monkeys in 1947 in the Zika
Forest, Uganda. A small number of human cases with nonspecific features were
documented in Africa and Asia over the subsequent 60 years (1). Then, in 2007,
ZIKV infected an estimated 73% of the population of Yap Island in the South
Pacific (2). Outbreaks were subsequently recognized in 2013 to 2014 in French
Polynesia, the Cook Islands, New Caledonia, and Easter Island (2). ZIKV was
detected in Brazil in 2015 (2) but may have been present there since 2013 (3).
During 2016, locally acquired cases have been documented in most countries in
South America and the Caribbean, Mexico, and the USA (in Florida and Texas
only, as of March 1, 2017) (see www.cdc.gov/zika/geo/index.html).
ZIKV is spread by the bite of Aedes aegypti mosquitoes and less commonly
Aedes albopictus, neither of which is known to be established in Canada (see
https://elifesciences.org/content/4/e08347 for maps of worldwide Aedes distribution). Because patients are commonly asymptomatic yet viremic, it is not
surprising that transmission via blood products occurs. ZIKV has been detected
in semen for ≥181 days (4) and in female genital secretions for up to 3 weeks
(5); male-to-female, female-to-male and male-to-male sexual transmission have
been documented (www.cdc.gov/zika/hc-providers/clinical-guidance/sexualtransmission.html).
CLINICAL FEATURES
The estimated incubation period is 3 to 12 days. Most infections (75% to 80%)
are asymptomatic. Common features of symptomatic infections are maculopapular rash (typically pruritic, starting proximally and spreading to the limbs,
with associated edema), low-grade fever, arthralgias (especially of small joints
in the hands and feet), myalgias, headache and nonpurulent conjunctivitis.
Recovery is usually complete within 3 to 14 days. Features overlap with disease
caused by dengue and chikungunya viruses, which are transmitted by the same
mosquitoes.
A small number of cases have had unusual features, including myelitis or
encephalitis (with detection of ZIKV in cerebrospinal fluid [CSF]) (6), hearing
loss, genitourinary symptoms, hematospermia, hypotension (2), thrombotic
thrombocytopenia (7) and death (6,8).
Guillain-Barré syndrome (GBS) has been associated with ZIKV infection, with an estimated incidence of 0.24/1000 total cases in French
Polynesia (9) and 1.73/1000 symptomatic cases in the USA and US territories as of November 16, 2016 (10). Onset is median only 7 days following initial ZIKV symptoms, with paresthesias and facial palsy possibly
being more common than usual (11). It is not clear whether any cases have
occurred in children.
CONGENITAL ZIKV SYNDROME (CZS)
ZIKV is neurotropic in mice when injected into the peritoneum (12), but was
not suspected to be teratogenic in humans until an unusual cluster of microcephaly was noted in Brazil in 2015. It appears that CZS cases commonly have
severe microcephaly, cerebral atrophy, abnormal cortical development, callosal
hypoplasia and diffuse subcortical calcifications (13,14). Microcephaly with
normal brain imaging was described in 0 of 11 (13) and 16 of 27 cases (14);
interpretation of these discordant results is not clear. Head circumference can
be normal with ventriculomegaly (13). Infants with severe microcephaly from
CZS have redundant scalp consistent with fetal brain disruption sequence.
Abnormal fetal tone can result in clubfoot or fetal akinesia deformation
sequence (arthrogryposis); the latter was described in 3 of 11 proven (13) and
7 of 104 possible cases (15). Microphthalmia, cataracts, and retinal abnormalities have been described in a small number of CZS cases (13,16). Sensorineural
hearing loss was documented in 5 of 70 cases (7%) (17). Intrauterine growth
retardation is common.
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A recent review article summarized the features of CZS that distinguish it from
other congenital infections as follows: “(1) severe microcephaly with partially collapsed skull; (2) thin cerebral cortices with subcortical calcifications; (3) macular
scarring and focal pigmentary retinal mottling; (4) congenital contractures; and
(5) marked early hypertonia and symptoms of extrapyramidal involvement (18).”
There are no consistent reports of congenital abnormalities outside of the central
nervous system (CNS). Congenital ZIKV infection without CNS involvement
undoubtedly occurs but has not been described to date (19); presumably such
cases would be labelled “congenital ZIKV infection,” rather than CZS.
Strong evidence that ZIKV causes CZS emerged from a case-controlled
study where ZIKV was detected in the amniotic fluid and/or brain/CSF of
fetuses and infants in 13 of 32 cases and 0 of 62 controls (14). It is surprising that 60 years elapsed between the first detection of ZIKV in humans and
the recognition that it is teratogenic. One possible explanation for the sudden
explosion of cases of CZS is that recent outbreaks are Asian-lineage ZIKV,
while the original cases were African-lineage ZIKV. The Asian lineage generates higher level viremia and therefore may more readily infect a population and
cross the placenta (20). Another theory is that “antibody-mediated enhancement” caused by ZIKV interacting with pre-existing dengue virus antibodies,
which are common in Brazilians, led to teratogenicity (21).
The incidence and risk of CZS with ZIKV infection during pregnancy are
unknown. Most, but not all mothers of infants with CZS recalled a rash during
pregnancy (13,19). Microcephaly occurred in an estimated 0.76% to 1.27%
of infants born to women with first trimester ZIKV in French Polynesia (22).
A study from Brazil estimated 1% to 13% risk, depending on the ZIKV infection
rate and the degree of overreporting of microcephaly (23). More alarming data
reported abnormal in-utero ultrasounds in 13 of 45 cases of ZIKV during pregnancy in Brazil (29%) (24). CZS has been described mainly with first trimester
infection but also with second and third trimester infection (13,19). There are
two reports of subependymal cysts and lenticulostriate vasculopathy (findings
suggestive of injury to the developing brain) on postnatal ultrasound following
maternal infection at 36 weeks gestation; one of the infants affected had ZIKV
detected in urine (25).
Perinatal transmission appears to be benign. It was documented in two
infants; one had a rash and the other was asymptomatic (26).
DIAGNOSIS
Diagnosis is by:
1. Serology (IgM or IgG or neutralizing antibody) or
2. Detection of ZIKV RNA by polymerase reaction (PCR) testing.
IgM becomes positive about 7 days following symptom onset, with IgG appearing about 3 days later (27). IgG presumably persists indefinitely. It is estimated
Figure 1. Investigating infants or children with features suggestive of congenital Zika syndrome.
Child born from 2016 on with unexplained microcephaly (present at birth or detected later), intracranial calcificaons,
ventriculomegaly or major structural CNS abnormalies AND maternal history of: i) travel to a ZIKV-endemic country
during pregnancy OR ii) sexual contact during pregnancy with a male who travelled to a ZIKV-endemic country in the
preceding 6 months.
Request:
• ZIKV serology and blood and urine for ZIKV PCR on mother and child1 as soon as possible (it is unclear up to what age they
may be posive) – document ming of potenal ZIKV exposure on requision to ensure correct serologic test is run
• That the placenta be saved
• U/S and MRI of the head on a non-urgent basis.
Discuss with a paediatric ID physician (may consider tesng child +/- mother for CMV, toxoplasmosis, rubella and LCMV +/- others,
depending on the history and findings).
All ZIKV tesng is
negave
Congenital ZIKV infecon is
excluded. Pursue other
tesng as directed by
paediatric ID physician.
ZIKV serology is posive or
indeterminate or ZIKV PCR
is posive from any
specimen
Discuss interpretaon of ZIKV serology and PCR results with a paediatric ID physician.
• If results are inconclusive, send placenta for pathology and ZIKV PCR (plus tesng for other potenal pathogens).
• Detecon of ZIKV by PCR from any specimen from the child is diagnosc of congenital ZIKV infecon (unless the child
travelled to a ZIKV-endemic country in the preceding 2 weeks).
• Detecon of ZIKV by PCR from the placenta or from any maternal specimen is highly suggesve of congenital ZIKV
infecon (unless the mother has post-partum travel to a ZIKV-endemic country in the preceding 2 weeks).
• ZIKV IgM from the child is highly suggesve of congenital ZIKV (unless the child has travelled to a ZIKV-endemic
country) but crossreacon with other viruses may occur. Confirmatory serology (a PRNT assay) may confirm that they
are ZIKV anbodies.
• A posive PRNT test can be from passive maternal anbodies but if it remains posive beyond 18 months of age and
the child has not travelled to a ZIKV-endemic country, the child has congenital ZIKV infecon.
• Follow-up advice regarding children with congenital ZIKV infecon can be found at:
h˜ps://www.cdc.gov/mmwr/volumes/65/wr/mm6533e2.htm?s_cid=mm6533e2_w. Consult a paediatric neurologist.
Request ophthalmic and audiologic assessments on all possible or proven cases of congenital infecon with any
pathogen (with repeat audiologic assessment annually unl age 6 years, even if inial tesng was normal).
Negative maternal ZIKV serology more than 4 weeks after exposure rules out ZIKV infection and congenital ZIKV infection. However, since one may wait weeks for results, sending specimens
for PCR and testing the child simultaneously is advised. Assuming that the child has not travelled to a ZIKV-endemic country, they should only have positive ZIKV serology if the mother tests
positive. Discuss with an ID physician or microbiologist if results are positive only from the child.
CMV cytomegalovirus; CNS central nervous system; CSF cerebrospinal fluid; ID infectious diseases; IgM Immune globulin; LCMV lymphocytic choriomeningitis virus; MRI magnetic resonance imaging;
PCR polymerase chain reaction; PRNT plaque reduction neutralization test; U/S ultrasound; ZIKV Zika virus.
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Figure 2. Management of infants born to women with potential exposure to ZIKV during pregnancy.
1
1
Travel to a ZIKV-endemic country during pregnancy or sexual contact during pregnancy with a male who travelled to a ZIKV-endemic country in the preceding 6 months.
CMV cytomegalovirus; ID infectious diseases; IgM immune globulin; MRI magnetic resonance imaging; PCR polymerase chain reaction; ZIKV Zika virus.
that IgM persists 3 months (27). Both IgM and IgG can crossreact with other
flaviviruses and therefore must be confirmed to be ZIKV antibodies by a plaque
reduction neutralization test (PRNT). If PRNT titres for both dengue and
ZIKV are identified, the result will be assessed as “indeterminate.” Current testing in Canada consists only of IgM with PRNT done when IgM is positive or
when IgM is negative but the requisition clarifies that exposure is remote.
PCR testing on blood is usually only positive during the first 4 days of symptoms (27). However, viremia persisted for ≥71 days in one pregnant woman
(28) and ≥67 days in CZS (29), possibly because fetuses have prolonged viremia from immature immune systems; ZIKV crosses the placenta, yielding persistent maternal viremia. PCR on urine is usually positive on days 2 through 9
following symptom onset (27). See Figures 1 and 2 for guidance on testing in
different scenarios or with positive laboratory results.
Delayed onset of hearing loss is well described in infants with congenital rubella
or cytomegalovirus who are asymptomatic at birth; there may also be late sequelae
with congenital ZIKV infection. Therefore, all women with potential ZIKV exposure during pregnancy should be identified. When the exposure is noted only after
delivery, ZIKV serology should be requested on the mother or infant. The algorithm in Figure 2 is followed when results are positive or indeterminate.
Testing is generally not advised for asymptomatic or symptomatic children
with exposure to ZIKV after birth, unless they require hospitalization. However,
when considering testing a febrile traveller for arboviruses, add ZIKV if appropriate. Travel history should be ascertained from all children with GBS.
PREVENTION
There is no treatment for ZIKV infections. Several vaccines are in development
and may be licensed as early as 2018. Travellers to areas with ZIKV should use
personal protective measures (i.e., bed nets, appropriate clothing and mosquito
repellents) to prevent mosquito bites day and night, both inside and outside
(See www.cps.ca/documents/position/preventing-mosquito-and-tick-bites and
www.phac-aspc.gc.ca/publicat/ccdr-rmtc/12vol38/acs-dcc-3/index-eng.
php). Those who are or may become pregnant and their sexual partners should
avoid travel to affected areas, where practical (https://travel.gc.ca/travelling/
advisories).
Although ZIKV RNA has been detected in breast milk, the virus is not thought
to be infectious. However, some experts advise caution with breastfeeding during
acute ZIKV infection. There was a case of transmission from a dying elderly man
Paediatrics & Child Health, 2017, Vol. 22, No. 1
with very high grade viremia to his son (10), but nonsexual person-to-person
transmission appears to be rare. However, routine infection control precautions
always apply. Pending more data on transmission, pregnant women should
employ meticulous hand hygiene when they have direct contact with infants
with congenital ZIKV infection. For more detail (particularly about adults), see
www.phac-aspc.gc.ca/publicat/ccdr-rmtc/16vol42/dr-rm42-5/ar-01-eng.php?
id=zika_virus_16_phac_catmat.
Acknowledgements
This practice point was reviewed by the Fetus and Newborn and Community
Paediatrics Committees of the Canadian Paediatric Society, as well as by the
CPS Developmental Paediatrics Section executive. It has also been reviewed by
investigators for the Canadian Paediatric Surveillance Program (CPSP) Severe
Microcephaly Study.
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CPS INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE
Members: Natalie A Bridger MD; Shalini Desai MD; Ruth Grimes MD (Board Representative); Timothy Mailman MD; Joan L Robinson MD (Chair); Marina Salvadori
MD (past member); Otto G Vanderkooi MD
Liaisons: Upton D Allen MBBS, Canadian Pediatric AIDS Research Group; Tobey Audcent MD, Committee to Advise on Tropical Medicine and Travel (CATMAT), Public
Health Agency of Canada; Carrie Byington MD, Committee on Infectious Diseases, American Academy of Pediatrics; Nicole Le Saux MD, Immunization Monitoring Program,
ACTive (IMPACT); Fahamia Koudra MD, College of Family Physicians of Canada; Rhonda Kropp BScN MPH, Public Health Agency of Canada; Jane McDonald MD,
Association of Medical Microbiology and Infectious Disease Canada; Dorothy L Moore MD, National Advisory Committee on Immunization (NACI)
Consultant: Noni E MacDonald MD
Principal author: Joan L Robinson MD