Zika Update: What We’ve Learned So Far - PowerPoint Presentation

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Zika Update: What We’ve Learned So FarACOG District XII Annual District MeetingOrlando, FL: August 11, 2017

Neil S. Silverman, M.D.

Clinical Professor, Obstetrics and GynecologyDivision of Maternal-Fetal MedicineDavid Geffen School of Medicine at UCLAMember, ACOG Zika Expert Work Group

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Aedes aegypti

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Zika

– Disease and Risks

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Zika virus is an arbovirus transmitted to humans primarily through the bite of infected Aedes sp. mosquitoNearly all Zika outbreaks due to aegypti &

albopictusThese are the same mosquitoes that transmit dengue and chikungunya Dengue and Zika are flaviviruses (YF) ; chikungunya: alphavirusWest Nile also arbovirus/

flavivirus, but spread by Culex sp.The mosquito vectors typically breed in domestic water-holding containersAegypti -- high “vectorial capacity”: feeds primarily on humans, multiple humans in a single meal, lives close to humans , also daytime and nighttime feeders

Background

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About 20% of people infected with Zika virus become symptomaticAmong those with clinical illness Symptoms mild, typically develop within 1 week from exposure, lasting several days to a weekCharacteristic clinical findings: acute onset of fever, maculopapular rash, arthralgia, or conjunctivitis. Severe disease requiring hospitalization is uncommon and fatalities are rare.

Guillain-Barré syndrome also has been reported at increased rates in patients following Zika infectionClinical Disease

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Brasil P et al. N Engl J Med 2016. DOI: 10.1056/NEJMoa1602412

Clinical Features of

Zika

Virus

Infection in Pregnant Women.

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Brazil Zika OutbreakMay 2015: First infection in Brazil October 2015: increase in microcephaly

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Microcephaly is a very specific diagnosis, and typically unusual as an isolated finding: initially seen in newbornsOn ultrasound, defined as HC < 3 SD for GA (SMFM, 2016)*HC < 2 SD

for GA should trigger more detailed eval and f/uMicrocephaly became an early trigger to search for Zika association, but spectrum of disease became apparent

Microcephaly can occur as a result of a fetal brain disruption sequence: this appears to be pathology of Zika infection * ref: Chervenak

FA, et al, AJOG 1984

Microcephaly: the tip of the iceberg?

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Zika AssociatedPregnancy Outcomes

Fetal loss/miscarriage, stillbirth

Fetal growth abnormalities

Fetal brain anomalies

Microcephaly

Ventriculomegaly

Intracranial

calcifications

Eye abnormalities

Neurologic

Hypertonia

Arthrogryposis

Seizures

Miranda-

Filho

et al, AJPH April 2016, Vol 106 No. 4

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Long Term Pregnancy Outcomes: EvolvingUpdate on 13 infants born without microcephaly but ZKV-infected (Brazil)

Neuroimaging abnormal in all: all w/ ↓ brain volume, +/or ↑ vents11 referred for small head size but > 2SD, 2 for

devel. lag (5, 7 mos)10 w/dysphagia, 3 w/chorioretinitis, all hypertonic (MMWR 11/16)Recent Brazil cohort Zin AA, et al. JAMA Pediatrics 7/17/17

112 mother-infant pairs w/confirmed maternal

infx

64% of infants Zika (+), 21% of those with eye

abnl

10/24 with eye findings (42%) did not have microcephaly, while

8 (33%) had no CNS findings

Anticipate a spectrum of outcomes?

Developmental and/or intellectual delay

Motor abnormalities

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Brasil et al: Rio cohort1Prospective study cohort of134 symptomatic pregnant women with

confirmed ZKV infectionOverall, 49/117 (42%) liveborn ZKV-exposed infants had abnormal findings by 1st month of life [5% in ZKV(-): p< 0.001]

Adverse outcomes seen regardless of trimester of infx55% risk if maternal infx in 1

st

, 52% if in 2

nd

, 29% if in 3

rd

Updated report from US Zika Pregnancy Registry

2

Birth defects related to Zika in 6%, 21 in live births

No risk difference regarding

sx

; 11% risk if exposure in 1st

∆

Data from US territories: 5% of fetuses/newborns affected

(MMWR 6/18/17)

Outcomes from 2624 at-risk pregnancies, 1/16 through 4/17

Pregnancy Risk Estimates

1.

Brasil

et al, NEJM 12/16. 2.

Honein

M et al, JAMA 12/13/16

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Zika – Where is it

and where is it

not?

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As of July 2017: CDC.gov

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Zika in the US: as of Aug 9, 2017US States/DC (5413 cases): 200 in 2017Travel-associated Zika virus disease cases reported: 5140 (49 other routes)

Locally acquired vector-borne cases reported: 224In 2017: all travel cases so far , exc 1 local and 1 sexualUS Territories

Travel-associated cases reported: 147 (0 in 2017)Locally acquired cases reported: 37007 (including 553 so far in 2017)51 cases of Guillain-Barre syndrome CDC.gov

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Current Zika Statistics (as of 7/25/17)2086 pregnant travelers with laboratory evidence of Zika virus in US States and DC – vast majority imported/travel-related

1784 completed pregnancies91 reported liveborn infants and 8 fetal losses with Zika related birth defects

4341 pregnant cases in US territories (mostly Puerto Rico) --- 3051 completed, 128 affected liveborns

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Local Zika Transmission in FLA, TX

Pregnant women had been counseled to avoid travel to or sexual contact with those who traveled to Miami-Dade, FLA and Brownsville, TX

After 8/1/16 for Miami-Dade; 10/29/16 for TX

Travel restrictions lifted June 2, 2017 for Miami-Dade

–

still cautionary for south Texas

New local case (1

st

US for 2017) in S Texas (7/24)

1

st

sexual transmission case in FLA 8/1/17 (Pinellas)

Biggest risk in U.S. still remains travel exposure

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Through Aug 9, 2017

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Gulf Coast States: Zika’s Potential Economic Risks

Recent study reports on economic model to estimate Zika-related costs in 6 Gulf-area statesALA, FLA, GA, LA, MISSModeled for a 230-day outbreak, based on Brazil durationCost estimates based on both direct medical costs and productivity losses due to illness or adverse outcomes (including poor pregnancy outcomes)

Model included Medicaid and commercial costs, screening tests and, for pregnancy, ultrasound surveillanceModeled for Zika attack rates from 0.1% to 10%Even an attack rate of 1% (far lower than rates seen in French Polynesia/Micronesia outbreaks) resulted in total economic impact of $1.2 billion

Lee BY, et al. PLOS

Negl

Trop Dis, 4/27/17

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Zika

– Education and Testing

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How much fetal risk with confirmed maternal infection?Based on current data, range may be as high as 29%Rates are derived from methodologically diverse studiesDespite earlier reports, recent data suggest later GA at infection does not exclude potential adverse impact

Pregnant women should not travel to areas with active Zika transmissionWhat do we tell our pregnant patients?

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If in an area with transmission, protection and prevention strategies are important – and repellent for 3 weeks after return from these areasDEET, picaridin fine for use in pregnancyConsumer Reports (Sept 2017):

Deet at 15-30% concentrations works best, picardin 20% (spray, not lotion), oil of lemon eucalyptus 30% (Repel better than Coleman)Review article on repellents in Zika era:

Wylie B, et al. ObGyn 11/16The role of prevention

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While consequences of Zika infection are better understood, accurate diagnosis continues to be challengingVirus present in body fluids only transientlySerologic testing (IgM) can’t always reliably time infectionSerology prone to false-positive results and cross-reaction with other

flavivirusesWith declining prevalence of Zika infection, probability of false-positive tests increasesChanging epidemiology further limits diagnostic capabilities of existing tests

What informed the new testing guidelines?

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Early data: Zika RNA detected up to 7 days after symptomsZika Persistence Study (ZiPer: NEJM, 2017*) of persons with NAT-confirmed infection reported detection 8-15 days after sx in 36%, 16-30 days in 21%, > 60 days in 4%

Some series have shown extended viral persistence in pregnancyViral detection may exist longer in urine than in bloodZika IgM: typically detected with 1st 2 wks after symptomsPublished data limited but

ZiPer Study showed IgM (+) after sx after 0-7 days in 34%, 8-15 days in 100%, > 60 days in 80%Median of 4 months (8-210 days) to 1st negative IgM resultDetection of IgM antibodies might not indicate infection in current pregnancy

Persistence of NAT and Immune Responses

*Paz-Bailey G, et al. NEJM 2017: doi.org/10.1056/NEJMoa1613108

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Presumption has been that Zika infection confers immunity after the IgM responseBased on experience with other flaviviruses, previous Zika infection is likely to confer prolonged, likely lifelong immunityIf true, prior infection would prevent risks for a future pregnancyHowever, no commercially-available IgG testing exists

, and IgM duration limitedNew tests on the horizon .. NS1-basedZika Immunity

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As many areas in the Americas move into a 2nd or 3rd mosquito season after introduction of Zika virus, testing becomes more complexGiven the evolving epidemiology and the better-realized limitations of testing, updated testing algorithms for symptomatic and asymptomatic pregnant women emphasize a

shared decision-making modelPre-and post-test counseling, with results interpreted in context of limitations

New guidelines – what do the changes reflect?

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Screen pregnant women for Zika exposure risk and/or symptoms at every prenatal and hospital visitKnowledge of potential exposure before and during pregnancy is critical information for test interpretation

Symptomatic pregnant women with recent possible Zika exposure: testing still recommendedConcurrent NAT (blood/urine) and IgM as soon as possible, through 12 weeks post-exposure (can consider if > 12 wks

, but..)Pregnant women with exposure and u/s findings: still testAsymptomatic women with ongoing possible Zika exposure: testing still offered once/trimesterNAT testing of blood and urine, not IgM (diagnostic limits)

New guidelines: what’s the same (mostly)?

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Asymptomatic women with recent possible Zika exposure but not ongoing exposureTesting now not routinely recommended for this groupBUT: shared-decision making and

consideration of local/regional epidemiologic risks involved for this groupCDC acknowledges that data indicate that while perinatal Zika risk doesn’t differ by maternal symptoms, routine testing in a low-prevalence group increases risk of false-positives in absence of any prevention or therapies

If testing done, default to algorithm for symptomatic/no ongoing exposure: PCR and IgMCurrently: CA, FL, TX staying with prior guidelinesNew guidelines: what’s different (mostly)

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Confirmed Zika Cases in Mexico by State

January 1, 2016 – August 8, 2016

Baja California

Baja California Sur

Sonora

Chihuahua

Coahuila

Sinaloa

Durango

Nuevo León

Tamaulipas

Zacatecas

San Luis Potosi

Veracruz

Yucatán

Campeche

Quintana Roo

Oaxaca

Guerrero

Michoacán

Chiapas

Colima

Jalisco

Nayarit

Tabasco

Puebla

Morelos

México

Hidalgo

0 confirmed cases

1 – 25 confirmed cases

26 – 50 confirmed cases

51 – 100 confirmed cases

More than 100 confirmed cases

Ag. = Aguascalientes

Quer. = Querétaro

DF = Distrito Federal

Tl. = Tlaxcala

Ag.

Guanajuato

Quer.

DF

Tl.

Data provided by the Mexican Ministry of Health

http://www.epidemiologia.salud.gob.mx/doctos/avisos/2016/zika/DGE_ZIKA_CASOS_SEM028_2016.pdf

N = 1,490

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Confirmed Zika Cases in Mexico by State

January 1, 2016 – July 3, 2017

Baja California

Baja California Sur

Sonora

Chihuahua

Coahuila

Sinaloa

Durango

Nuevo León

Tamaulipas

Zacatecas

San Luis Potosi

Veracruz

Yucatán

Campeche

Quintana Roo

Oaxaca

Guerrero

Michoacán

Chiapas

Colima

Jalisco

Nayarit

Tabasco

Puebla

Morelos

México

Hidalgo

0 confirmed cases

1 – 25 confirmed cases

26 – 50 confirmed cases

51 – 100 confirmed cases

More than 100 confirmed cases

Ag. = Aguascalientes

Quer. = Querétaro

DF = Distrito Federal

Tl. = Tlaxcala

Ag.

Guanajuato

Quer.

DF

Tl.

Data provided by the Mexican Ministry of Health

https://www.gob.mx/cms/uploads/attachment/file/223168/Cuadro_Casos_ZIKA_y_Emb_SE26_2017.pdf

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Sexual transmission of Zika virus can occurMale/female, female/male, male/male all reportedPregnant women whose male partners at risk for Zika virus infection should consider using condoms or abstaining from sexual intercourse –

duration of pregnancy – Zika in semen up to 6 mos.Zika has recently been shown to cause testicular damage in mouse models (Govero

J, et al. Lancet Dec 15, 2016)ZKV persistence in testis/epididymis→ tissue injury resulting in diminished testosterone and inhibin B levels and oligospermia

Sexual Partner concerns/guidelines

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Zika “waiting periods” – counseling for OBGYNs

Timeframes to wait to get pregnant after travel to an area with a CDC travel notice (CDC 7/17)Women -- 8 weeks Men -- 6 monthsIf both partners traveled, wait 6 months + condomsEgg and sperm donors

(ASRM, 3/16)Wait period 6 months after infx, travel, or contactBlood donors (FDA, 2/16)4 week waiting period

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CDC Zika website: www.cdc.gov/zikaACOG’s Zika webpage: www.acog.org/zika

Floridawww.floridahealth.gov/diseases-and-conditions/zika-virusZika

Resources

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Neonatal coordination is Critical!

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Which newborns need Zika surveillance?

Zika testing for in 1st two days after birth for infants at risk: serum and urine for PCR, serum for IgMMothers with lab-confirmed infectionAbnormal clinical findings suggestive of congenital Zika and potential maternal epidemiologic link, regardless of maternal test results

All infants born to women with lab-confirmed Zika infection should get:Zika testing, comprehensive exam, head ultrasound, and standard hearing assessmentBased on newer data, they should also get formal eye exam (not just red reflex testing)

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Need for Neonatal Followup & DeficitsRecent report on 2549 completed pregnancies (1/16-4/17)5% of fetuses/newborns of women in Puerto Rico with confirmed Zika infection had likely Zika-associated birth defects

1Of liveborns without birth defects, only 52% had postnatal neuroimaging and 78% had hearing screensRecent US Pregnancy Registry Data worse (MMWR, 4/7/17)

2Among 895 liveborns with maternal infection: postnatal neuroimaging reported for 25%, Zika testing of at least 1 infant specimen 65%While 98% of pregnant women in P.R. in a recent survey took at least 1 measure to avoid Zika infection, use of repellents (45%) and condoms (40%) during pregnancy overall low 3

1. Shapiro-Mendoza CK, et al, MMWR 6/8/17. 2. Reynolds M et al, MMWR 4/7/17. 3. D’Angelo DV et al, MMWR 6/9/17

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Zika as an Endemic InfectionZika virus is considered endemic in some countries, and a large number of local residents are likely to be immune. However, US travelers to endemic areas may not be immune to Zika virus and infections have occurred among travelers to Asia and Africa

Updated 7/17

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Aug 4, 2016

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Plasmid-based vaccine: no live or attenuated virus

2500 study enrollees planned in high-risk areas to test both immunogenicity and efficacyNo pregnant women to be enrolled

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