Does My Baby Have Congenital Zika Virus Infection?

E Ruth, S O’Rourke, P Gavin

Rainbow Paediatric Infectious Diseases

Temple Street Children’s University Hospital

Introduction

ZIKV virus (ZIKV), a previously obscure and relatively minor infection outside of Africa has rapidly become a global health issue. ZIKV is now recognised as the first infectious agent in 50 years (since rubella) to cause birth defects and has generated such alarm as to be designated a public health emergency of international concern by the WHO1, 2. Irish parents concerned about the possibility of prenatal ZIKV infection are now requesting testing. We report one such illustrative case.

Clinical case

A nine-month old boy was referred because of concerns that prenatal ZIKV infection was the cause of complex congenital malformations that included dysmorphism, bilateral frontal lobe lissencephaly, sensorineural hearing loss, ptosis, dysplastic kidneys, pulmonary hypoplasia, and global developmental delay. Head circumference was normal. In February 2015, during the first trimester of pregnancy, the infant’s mother, a brazilian woman living in Ireland, had travelled with her husband to Brazil. Cases of ZIKV infection were first reported in Brazil at this time2,3. Both were bitten by mosquitoes but denied any history of illness. While there, the mother received IM Rho(D) immune globulin in a local hospital after a small PV bleed. The mother asked whether prenatal ZIKV infection (mosquito or transfusion-related) could have caused the infants congenital abnormalities. The infant’s father asked whether he might have been or continue to be a source of ZIKV infection for his partner. Serology on the baby was ZIKV IgG positive. As experience of ZIKV infection is somewhat limited, we reviewed the literature.

Epidemiology

ZIKV is an RNA flavivirus closely related to dengue and West Nile1,4 . It was first discovered, in 1947, in a monkey in the Zika forest of Uganda. ZIKV remained quiet over the next 70 years with only 14 human cases reported3,4. Seroprevalence studies, however, indicate that endemic ZIKV infection is common in Africa and South East Asia3- 5. In 2007, the situation changed when unprecedented ZIKV epidemics affecting tens of thousands occured in the Pacific Islands, reaching Brazil in early 2015 and spreading rapidly through the Americas2,3,5. From 2015, 67 countries have reported Zika virus transmission6. In contrast to endemic ZIKV infection in Africa and Asia, Pacific Island and South American ZIKV epidemics have been associated with increased numbers of cases of congenital microcephaly and Guillian-Barré syndrome1,6. To date, 22 countries have reported congenital microcephaly and other central nervous system abnormalities potentailly associated with ZIKV6. It is postulated that a new strain of ZIKV with increased virulence, fitness and epidemic potential evolved from south-east Asian lineage ZIKV3,4.

Clinical Presentation of Zika Virus Infection

Symptomatic ZIKV infection is non-specific, characterised by acute low grade fever, itchy maculopapular rash, non-purulent conjunctivitis and arthralgia, and is usually self-limiting, lasting 2 to 7 days1,3. Absence of symptoms in the mother or father was not particularly reassuring, as only 20% of ZIKV infections are symptomatic1,4.

Zika Virus Transmission

ZIKV is an arbovirus (arthropod-borne) transmitted to humans by Aedes species of mosquito, principally Aedes aegypti and the less effective vector Aedes albopticus1, 4. Aedes mosquitoes are also vectors for chikungunya, dengue, and West Nile viruses. Aedes mosquitoes are aggressive daytime biters and typically breed in domestic water containers. Public health campaigns to prevent transmission include treatment of standing water (swimming pools, hot tubs) and removal of standing water containers from around the home. Global distribution of Aedes mosquitoes includes subsaharan Africa, Asia, most of South America (A. aepypti) and as far as the great lakes in North America and southern Europe (A. albopictus). Anthroponotic (human-to-vector-to-human) transmission occurs during outbreaks but non-vector (in utero, perinatal, sexual and possibly transfusion-related) transmission are now described1,3,6.

ZIKV infection has been linked to sexual transmission in contacts of travellers returned from regions with epidemic ZIKV1,3. While ZIKV RNA has been detected in semen over 60 days after infection, 18 months after his return from Brazil we felt the father was unlikely to be a continued source of ZIKV infection7. Rho(D) immune globulin constituted another potential risk for maternal infection, as transfusion-related cases of dengue and West Nile are reported. Retrospective testing of blood donations In French Polynesia and Puerto Rico showing a high prevalence for ZIKV RNA among donors led to recommendations to discontinue local blood collections and to import blood from unaffected areas of the continental United States8.  At this stage, we concluded that the infant may have been exposed to asymptomatic maternal ZIKV infection (mosquito, sexual or transfusion-related) in Brazil during the first trimester.

Evidence for Zika Virus Infection as a Cause of Birth Defects

We then reviewed evidence linking ZIKV infection and congenital brain malformation. Although no flavivirus was previously shown to cause birth defects in humans, early reports of increased numbers of infants with unexplained microcephaly and birth defects followed  ZIKV outbreaks in Brazil (2015) and retrospectively French Polynesia (2013-14)1,6. Accumulated evidence satisfies formal criteria for human teratogenicity and causation, such that there is now scientific conscensus that ZIKV causes congenital microcephaly, other brain anomalies and Guillian-Barre syndrome9.  Specifically, strong epidemiologic evidence includes reports of microcephaly (a rare defect) in infants born to women with only brief periods of travel to countries with active ZIKV transmission (a rare environmental exposure), and multiple studies showing a temporal relationship between ZIKV infection and neurological disorders9. Risk of serious brain anomaly is considered highest following infection in the first trimester1. Detection of ZIKV in foetal and neonatal brain tissue from cases of congenital brain malformation provide additional evidence of biologic plausibility10.

Clinical Features of Congenital Zika Virus Infection

We then asked if the clinical picture fit that reported in infants with congenital ZIKV infection. Reports of congenital ZIKV most frequently describe infants with moderate to profound microcephaly1. Prominent redundant scalp skin caused by interruption of brain growth but not of scalp skin followed by partial collapse of the skull after an insult is considered characteristic and most uncomon in other causes of microcephaly. The full spectrum of fetal effects of congenital ZIKV is evolving but already includes: severe cerebral lesions without microcephaly; lissencephaly; brain atrophy; ventriculomegaly; intracranial calcification; brainstem dysfunction without visible malformations; eye (cataracts, intraocular calcifications and macular pigment mottling) and limb defects (arthrogryposis and club foot)1,6,11. While not typical, the clinical picture of unexplained congenital lissencephaly and possible prenatal exposure to epidemic ZIKV led to a test for ZIKV IgG being performed on the infant.

Diagnosis

ZIKV infection can be diagnosed by serologic and molecular methods12. The choice of test depends on the likely timing of infection. Acute infection is confirmed by demonstrating ZIKV RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) in specimens collected within 7 (serum) or 14 days (urine) of illness onset. Thereafter and up to 12 weeks from illness onset, recent ZIKV infection is diagnosed by demonstrating ZIKV IgM and neutralizing (IgG) antibody. Neutralising antibody persists for many years and is thought to confer prolonged, possibly lifelong immunity. Unfortunately, ZIKV serology may be falsely positive in residents of areas where flaviviruses are endemic.  Specifically, it may be difficult to distinguish recent ZIKV infection in persons previously infected with or vaccinated against related flaviviruses such as dengue or yellow fever.

Repeat ZIKV testing of a second serum specimen from the infant was inconclusive (IgG equivocal). However, maternal infection was ruled out by demonstrating negative ZIKV serology and RNA RT-PCR in maternal booking and post-natal blood specimens, thereby effectively excluding congenital ZIKV infection in the infant. The infant’s positive ZIKV serology most likely reflects nonspecific reactivity of the assay and does not support ZIKV infection as a cause of his complex congenital abnormalities.

Conclusions and Future Prospects

The present case is notable for a number of reasons. Firstly, as the ZIKV epidemic spreads in the Americas and Caribbean and reaches southern Europe and the numbers of people travelling to and from epidemic areas increases, similar cases are likely to present in Ireland. Imported cases of ZIKV in travellers returning from affected areas and of congenital brain malformation are already reported in Europe6,13. Furthermore, as in Florida where ZIKV infection has occurred in individulas with no history of travel, local acquisition of ZIKV infection is likely in southern Europe where Aedes albopictus mosquitoes, a favourable climate and a non-immune population exist14. In 2014, an outbreak of locally acquired chikungunya occured in Montpellier following transmission by Aedes albopictus mosquitoes15. The index case was a traveller returning from Cameroon.

Secondly, ZIKV must now be included among the potential causes of congenital infection in infants born to symptomatic or asymptomatic women if they (or potentially their sexual partner) has travelled to or from an expanding list of countries where ZIKV infection is possible. This list now includes popular holiday resorts in North America, the Caribbean and southern Europe.

And finally, it demonstrates the complexity and difficulties encountered in diagnosis of a new congenital infection syndrome during an evolving epidemic where the full clinical spectrum is not defined and again emphasises the importance of a thorough travel and exposure history. Physicians with questions about whom to test for suspected ZIKV infection, choice of test and interpretation of results should consult with infectious diseases experts for assistance

Conflict of Interest:

 The authors confirm no conflict of interest in this paper

Correspondence:

Dr Patrick Gavin,, Rainbow Paediatric Infectious Diseases Temple Street Childrens University Hospital

References

  1. Petersen LR, Jamieson DJ, Powers AM and Honein MA. Zika virus. N Engl J Med 2016; 374:1552-1563
  2. World Health Organisation. Zika Response Interim Report. May 2016
  3. Gatherer, D and Kohl A. Zika Virus: a previously slow pandemic spreads rapidly through the Americas. J Gen Virol. 2016. 97, 269–273.
  4. Musso D and Gubler DJ. Zika virus. 2016. Clin Microbiol Rev 29:487–524
  5. Hayes EB. Zika virus outside Africa. Emerg Infect Dis. 2009 Vol. 15, No. 9 1347-50
  6. 6. World Health Organisation. Situation Report. Zika virus. Microcephaly, Guillian-Barré 13 October 2016.
  7. Atkinson B, Hearn P, Afrough B, Lumley S, Carter D, Aarons EJ, Simpson AJ, Brooks TJ, Hewson R. 11 February 2016. Detection of Zika virus in semen. Emerg Infect Dis
  8. Kuehnert MJ, Basavaraju SV, Moseley RR, Pate LL, Galel SA, Williamson PC, Busch MP, Alsina JO, Climent-Peris C, Marks PW, Epstein JS, Nakhasi HL, Peyton Hobson J, Leiby DA, Akolkar PN, Petersen LR, Rivera-Garcia B. Screening of blood donations for Zika virus infection — Puerto Rico, April 3–June 11, 2016. Morb Mort Week Rep 2016;65.
  9. Rasmussen SA, Jamieson DJ, Honein MA and Petersen LR. Special Report- Zika virus and birth defects — Reviewing the evidence for causality. N Engl J Med 2016; 374:1981-1987
  10. Mlakar J, Korva M, Tul N, Popović M, Poljšak-Prijatelj M, Mraz J, Kolenc M, Resman Rus K, Vesnaver Vipotnik T, Fabjan Vodušek V, Vizjak A, Pižem J, Petrovec M and Avšič Županc T. Zika virus associated with microcephaly. N Engl J Med 2016; 374:951-958
  11. Broutet N, Krauer F, Riesen M, Khalakdina A, Almiron M, Aldighieri S, Espinal M, Low N and Dye C. Zika virus as a cause of neurologic disorders. N Engl J Med 2016; 374:1506-1509
  12. Rabe IB, Staples JE, Villanueva J, Hummel KB, Johnson JA, Rose L, Hills S, Wasley A, Fischer M, Powers AM. Interim guidance for interpretation of Zika virus antibody test results. Morb Mort Week Rep / June 3, 2016 / Vol. 65 / No. 21 S43-46
  13. Zammarchi L, Tappe D, Fortuna C, Remoli ME, Günther S, Venturi G, Bartoloni A, Schmidt-Chanasit J. Zika virus infection in a traveller returning to Europe from Brazil, March 2015. Euro Surveill. 2015;20 (23)
  14. European Centre for Disease Prevention and Control. Preparing for Zika in the EU. Stockholm, ECDC, 2016
  15. Delisle E, Rousseau C, Broche B, Leparc-Goffart I, L’Ambert G, Cochet A, Prat C, Foulongne V, Ferré JB, Catelinois O, Flusin O, Tchernonog E, Moussion IE, Wiegandt A, Septfons A, Mendy A, Moyano MB, Laporte L, Maurel J, Jourdain F, Reynes J, Paty MC, Golliot F. Chikungunya outbreak in Montpellier, France, September to October 2014. Euro Surveill. 2015;20(17)