Congenital Zika Virus Syndrome. Outline. Overview and Epidemiology of Zika Virus (ZIKV) ZIKV Genome and Structure. Whittney Barkhuff, MD

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1 Congenital Zika Virus Syndrome is zika virus.html Whittney Barkhuff, MD Outline Overview and epidemiology of Zika Virus Congenital Zika Virus Syndrome Current recommendations and guidelines Overview and Epidemiology of Zika Virus (ZIKV) Zika Virus (ZIKV) Mosquito vectored flavivirus (dengue, West Nile, yellow fever, Japanese encephalitis virus) First isolated in 1947 Observed to infect humans Global spread Introduction into naïve human populations Rapidly spreading outbreaks ZIKV Genome and Structure Positive sense single stranded RNA molecule, bases Genome encodes for a polyprotein with three structural proteins and 7 non structural proteins 1

2 Timeline of ZIKA * Robiero et al, 2014 Robiero et al, 2014 ZIKV Endemic regions Sequence analysis Continental Africa and Asia People exposed to ZIKV during childhood Immunity prior to puberty Introduction into dense, naïve populations has facilitated rapid viral evolution Infection of pregnant women who are immunologically naïve Significant genetic differences between historic samples from mosquitos and more modern isolates from human sources Studies in murine models and with human neurospheres suggest that current strain circulating in the Americas is more neuropathic and more teratogenic than the African isolate Mosquito Transmission Aedes aegypti Aedes albopictus Historically considered to be vectored by Aedes aegypti mosquitos Also Aedes albopictus (cold tolerant) cdc.gov cdc.gov 2

3 Other Routes of Transmission Countries and Territories with Active Zika Transmission Person to person spread Isolated from breast milk, urine, semen, sputum Sexual transmission Risk of sustained viral loads in males returning from ZIKVendemic regions More stable than other flaviviruses Zika Cases Reported in the U.S. Active Zika Virus Transmission in Florida ZIKV Infection Zika Associated Maculopapular Rash 20% people symptomatic Mild, self limited, non life threatening Headache Fever Malaise, arthralgias, conjunctivitis, pruritic maculopapular rash Nausea, vomiting, GI distress Viremia up to 10 days before onset of symptoms Plasma viral titers often clear within 2 days of presentation of clinical symptoms Ritter et al, 2016 Ritter et al,

4 Guillain Barre Syndrome Diagnosis 1/5000 cases of ZIKV during outbreak in French Polynesia May be closer to 1% Peak of Guillain Barre 5 9 weeks after ZIKV infection Definitive diagnosis by PCR based test Rapid serologic diagnostic test complicated by antibody crossreactivity with other cocirculating arboviruses (anti dengue and anti chikungynya) Published guidelines for testing of sera to rule out crossreactivity Ritter et al, 2016 Ritter et al, 2016 Microcephaly Congenital Zika Virus Syndrome Increase in the number of infants with microcephaly in Brazil first noted in September 2015, after the recognition of Zika virus transmission in the country earlier in the year By February 2016, more than 5,600 suspected cases of microcephaly in newborns had been reported Recognition of a similar increase in French Polynesia after an outbreak there in 2013 and 2014 Rapid regional mobilization of public health experts Epidemiological association and experimental research strongly support a causal relationship between intrauterine ZIKV infection and fetal primary microcephaly Franca et al, 2016 Congenital Zika Virus Syndrome Resembles other intrauterine viral infections associated with congenital malformations More severe abnormalities Typical presentation of intrapartum Zika infection: microcephaly, cutis gyrata, hypotonia, hyperreflexia, irritability Coarse areas of calcifications within subcortical cortical transition and basal ganglia Ventriculomegaly, lissencephaly Other systems may be affected Franca et al, 2016 Follow up of 11 infants with congenital ZIKV infections in Brazil Zika virus identified in the amniotic fluid, placenta, cord blood, and neonatal tissues (collected postmortem) for all patients Combined information from clinical evaluations and diagnostic laboratory and imaging findings with postmortem anatomical and pathological data to describe lesions caused by ZIKV congenital infection Document effect in different target tissues and organs during intrauterine development 4

5 Prenatal Imaging Findings * * Severe cerebral atrophy associated with fetal microcephaly (9/11 patients) Ventriculomegaly (10/11 patients), usually, severe, asymmetric Head circumference less than 2 SDs for gestational age in most infants Normal or enlarged head circumference with severe ventriculomegaly in 2/11 patients Hypoplasia of cerebellar vermis and cerebellum (9/11 patients) Athyrogryposis 3/11 patients, all died Polyhydramnios in 1/11 Oligohydramnios in 1/11 Normal doppler flow velocimetry indices in all patients Calcifications Fetal growth restriction Subcortical calcifications Reduced cerebral volume, callosal hypoplasia, vermian hypoplasia Abnormal cortical development (pachygyria) Basal ganglia and subcortical calcifications Agyric hemisphere Small clusters of calcification Small foci of calcification in brainstem Microcephaly Hypodevelopment of cerebral parenchyma Abnormal cortical development, ex vacuo ventriculomegaly, Ventriculomegaly, polymicrogyria Subcortical calcifications Lissencephaly Reduced cerebral volume, ventriculomegaly Chronic lymphocytic meningitis Shallow sulci, translucent white matter, enlarged lateral ventricle Coarse calcifications in brainstem Clinical features ` Eye involvement: Macular chorioretinal scar Strabismus Loss of photomotor reflexes Myoclonic seizures, hyporeflexia, cervical hypotonia, paralysis of the diaphragm, premature closure of anterior fontanelle Published Online Nov 3,

6 Congenital Zika Virus syndrome is a recognizable pattern of structural anomalies and functional disabilities secondary to central and, perhaps, peripheral nervous system damage 5 features rarely seen with other congenital infections or unique to congenital Zika Virus syndrome 1) Severe microcephaly with partially collapsed skull 2) Thin cerebral cortices with subcortical calcifications 3) Macular scarring with focal pigmentary retinal mottling 4) Congenital contractures 5) Marked early hypotonia and symptoms of extrapyramidal involvement Other teratogenic viruses TORCH Viruses Rubella Teratogenic viruses vertically transmitted from mother to infant Rubella, CMV, HSV, VZV Cross placenta and cause congenital defects Microcephaly Growth retardation Developmental delay Heart disease Hearing loss Blindness No effective therapeutic interventions to decrease risk of serious sequelae Some defects not apparent at birth Incidence of congenital rubella syndrome in rubella naïve populations appears to be less than with ZIKV Widespread necrosis of organs (eye, heart, brain, ear) Infection in 1 st trimester has highest rate (80%) of congenital rubella syndrome 6

7 Cytomegalovirus (CMV) TORCH Z Associated with severe neurologic impairment, microcephaly, intracranical calcifications, microgyria, eye defects, hearing loss Mostly asymptomatic in immunocompetent adults Primary infection during pregnancy leads to highest risk of defects A new TORCH infection Unique aspect: Mosquito vectored First flavivirus shown to definitively cause birth defects in humans Potential Treatments Established anti flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known antiviral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Current Recommendations and Guidelines Barrows et al, 2016 Screening Recommendations Newborn Screening Recommendations Must be done within 2 days of birth Screen infants whose mothers have laboratory evidence of ZIKV infection during pregnancy Also for infants with clinical findings suggestive of ZIKV infection and maternal history of possible exposure Contact department of health for most recent guidelines UNM infection control and prevention 7

8 Summary ZIKV is a newly recognized TORCH infection (TORCH Z) Asymptomatic or self limited disease in immunocompetent adults Wide range of neurologic abnormalities in developing fetus Transmission: Mosquito, vertical, sexual No current treatment or vaccine Maintain high suspicion for infants with severe neurologic abnormalities Unanswered Questions/Future Directions Spectrum of defects caused by prenatal Zika virus infection Transmission routes Risks of adverse outcomes among fetuses whose mothers were infected at different times during pregnancy Factors that might affect a woman s risk of adverse pregnancy or birth outcomes Optimal management (vaccine, drugs, etc) References Basu and Tumban. Zika Virus on a Spreading Spree; what we now know that was unknown in the 1950 s. Virology Journal 2016; 13:165. D Ortenzio E, Matheron S, de Lamballerie X, et al. Evidence of sexual transmission of Zika virus. N Engl J Med 2016;374: Franca GV et al. Congenital Zika virus syndrome in Brazil. The Lancet. 2016;388: Hayes EB. Zika virus outside Africa. Emerg Infect Dis. 2009;15(9); Klaise et al. Zika Fetal Neuropathogenesis; Etiology of a Viral Syndrome. PLOS Neg Trop Dis. 2016;10(8):2 20. Lancotti RS et al. Genetic and serologic properties of Zika virus associated with an epidemic, Emerg Infect Dis. 2008;14(1232 9). McCarthy M. Zika virus was transmitted by sexual contact in Texas, health officials report. BMJ 2016;352:i720. Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med 2016;374: Sarno M, Sacramento GA, Khouri R, et al. Zika virus infec tion and stillbirths: a case of hydrops fetalis, hydranencephaly and fetal demise. PLoS Negl Trop Dis 2016;10(2):e Suely de Oliviera Melo et al. Congenital Zika Virus Infection: Beyond Neonatal Microcephaly. JAMA Neurology. 2016;3720. Gettyimages.com Thank you! Questions? 8