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DynaMed Plus

DynaMed Plus is the next-generation clinical reference tool physicians can rely on for fast, easy access to point-of-care decision support. Written by a team of specialized physicians and researchers, content is updated several times daily to include information on the latest evidence-based research, providing practice-changing answers to clinical questions with optimized speed. 

Zika virus infection

  • Updated 2017 Feb 17 12:00:00 AM: reported mortality extremely low in 2015-2017 Zika virus outbreak in Americas (Pan American Health Organization Zika Update 2017 Mar 23 ) view update
  • local transmission reported in United States, with 278 confirmed cases reported in Florida as of March 20, 2017 (Florida Department of Health 2017 Mar 20) view update
  • FDA alert to physicians who care for pregnant women that Laboratory Corporation of America (LabCorp) has reported false positive results for commercially available ZIKV Detect IgM Capture ELISA (InBios International, Inc.) (FDA MedWatch 2016 Dec 23) view update

 

 

General Information

Description

  • mosquito-borne flavivirus infection transmitted by Aedes species, primarily A. aegypti and A. africanus(1, 2, 4)
  • symptoms associated with infection are typically self-limited and commonly include(1, 2)
    • rash, typically maculopapular
    • fever
    • myalgias and arthralgias
    • conjunctivitis
  • Zika virus outbreak is ongoing in the Americas, with highest rates of infection in Brazil and Colombia(1, 2)
  • Zika virus is teratogenic
    • congenital infection is associated with microcephaly and other brain defects, ocular lesions and fetal loss
    • risk of congenital anomalies appears highest when maternal infection is acquired during the 1st trimester of pregnancy

Also called

  • Zika

Epidemiology

Geographic distribution

  • regions and countries with active transmission
    Countries and Territories with Active Zika Virus Transmission:
    RegionCountry or Territory
    South AmericaArgentina
    Bolivia
    Brazil
    Colombia
    Ecuador
    French Guiana
    Guyana
    Paraguay
    Peru
    Suriname
    Venezuela
    Central AmericaBelize
    Costa Rica
    El Salvador
    Guatemala
    Honduras
    Mexico
    Nicaragua
    Panama
    The CaribbeanAnguilla
    Antigua
    Aruba
    The Bahamas
    Barbados
    Barbuda
    Bonaire
    British Virgin Islands
    Cayman Islands
    Cuba
    Curacao
    Dominica
    Dominican Republic
    Grenada
    Guadeloupe
    Haiti
    Jamaica
    Montserrat
    Martinique
    Puerto Rico
    Saba
    Saint Barthelemy
    Saint Lucia
    Saint Martin
    Saint Vincent and the Grenadines
    Sint Eustatius
    Sint Maarten
    Trinidad and Tobago
    Turks and Caicos
    United States Virgin Islands
    Oceania/Pacific IslandsAmerican Samoa
    Fiji
    Kosrae, Federated States of Micronesia
    Marshall Islands
    New Caledonia
    Papua New Guinea
    Palau
    Samoa
    Solomon Islands
    Tonga
    AsiaIndonesia
    Malaysia
    Maldives
    Singapore
    Thailand
    Vietnam
    AfricaAngola
    Cape Verde
    Guinea-Bissau
    References - CDC 2017 Mar 15, WHO Zika situation report 2017 Mar 10
  • previous sporadic outbreaks reported in Africa and Southeast Asia(6)
  • real-time outbreak map can be found at healthmap.org

Incidence/Prevalence

Worldwide

  • history of Zika virus detection and its geographic spread(5)
    • virus first isolated in 1947 from a macaque in Zika forest of Uganda
    • first human case reported in Nigeria in 1952
    • East African Zika virus likely spread to Southeast Asia around 1945
    • period of stable endemicity in Africa and Southeast Asia persisted in 20th century
  • multiple epidemics reported to date
    • first large-scale outbreak and eastward spread in 2007 on Yap Island, Micronesia
      • total of 49 confirmed and 59 probable cases of Zika virus disease identified between April and July in 2007
      • common symptoms included fever, rash, arthralgia, and conjunctivitis
      • no hemorrhage or death documented
      • estimated 5,005 (73%) of 6,892 residents ≥ 3 years old had Zika virus infection during outbreak, and about 82% of whom had subclinical infections
      • Reference - N Engl J Med 2009 Jun 11;360(24):2536 full-text
    • second major outbreak reported in French Polynesia in 2013-2014
    • present outbreak in Americas began in Brazil in 2015

United States and United States territories

Other regions

Risk factors

  • residence in or travel to affected areas(1, 2, 3)
  • mosquito exposure(1, 2, 3)
  • unprotected sexual contact with someone who has traveled recently to areas with active transmission(8)

Associated conditions

  • coinfection with other viral illnesses transmitted by same mosquito vector may occur
  • coinfection with dengue and chikungunya
    • coinfection with dengue and chikungunya not uncommon in Nicaragua
      • based on 2 cohort studies
      • 346 patients with suspected arboviral illness between September 2015 and April 2016 in Nicaragua had acute-phase serum samples tested for Zika virus, dengue, and chikungunya
        • viruses were detected by multiplex real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay with lack of validation
        • 263 patients had ≥ 1 viruses
          • 192 had monoinfection
          • 71 had coinfection with 2 or 3 viruses
        • Reference - Clin Infect Dis 2016 Dec 15;63(12):1584
    • 2.6% coinfection rate with dengue reported among 77 patients who presented with dengue-like illness in May 2015 in Pernambuco, Brazil (Medicine (Baltimore) 2016 Mar;95(12):e3201 full-text)

Etiology and Pathogenesis

Pathogen

  • Zika virus
    • single-stranded RNA virus of the Flaviviridae family, genus Flavivirus
    • 2 lineages exist based on phylogenetic analysis of viral envelope gene sequences
      • African lineage, largely restricted to African countries including Uganda, Kenya, Central African Republic, Senegal, and Nigeria
      • Asian lineage
        • circulating in Southeast Asian countries since mid-1900s, in French Polynesia in 2013, and in Americas in 2015
        • strains in the Americas appear most closely related to French Polynesia strains, with 99.7% nucleotide homology and 99.9% amino acid homology
        • strains circulating in Salvador, Bahia State, Brazil appear to form a distinct lineage from those circulating in other locations in Brazil or Americas (Emerg Infect Dis 2016 Oct;22(10):1788 full-text)
    • References - (2), Lancet 2016 Jan 16;387(10015):227

Transmission

  • transmitted primarily via bite of infected Aedes mosquito(2, 3)
    • main reservoirs are likely humans and nonhuman primates
    • anthroponotic (human-to-vector-to-human) transmission occurs during outbreaks
    • incubation period likely about 3 to 12 days but not precisely determined
  • other modes of transmission include(1, 2, 4)
  • potential modes of transmission include
    • transfusion of blood or blood products
      • 1 case of possible spread of virus through blood transfusion has been reported(2)
      • 1 case of probable Zika virus transmission through platelet products reported in 55-year-old man who received transfusion during liver transplantation surgery (Transfusion 2016 Jul;56(7):1684)
      • 2 cases of possible Zika virus transmission through platelet transfusion from a single person who donated platelets 2 days before developing acute Zika virus illness (N Engl J Med 2016 Sep 15;375(11):1101 full-text)
      • detection of Zika viral RNA in 3% of 1,505 blood donors who were asymptomatic at time of donation between November 2013 and February 2014 during outbreak in French Polynesia (Euro Surveill 2014 Apr 10;19(14) full-text, correction can be found in Euro Surveill 2014;19(15):pii/20771)
    • breast feeding(7)
      • viral RNA has been detected in breast milk of infected women
      • no cases of transmission reported but this route of transmission not yet well evaluated
      • detection of infective Zika virus and viral RNA in breast milk collected 4 days postpartum from 27-year-old woman who developed fever and maculopapular rash during perinatal period (Lancet 2016 Mar 12;387(10023):1051)
    • 1 case of transmission from an elderly patient with an unusually high viral load to a family contact who reported kissing and hugging the patient, but no known direct contact with bodily fluids (MMWR Morb Mortal Wkly Rep 2016 Sep 16;65(36):981 full-text)
  • sources from which virus has been detected but not transmission not shown
  • estimated reproduction number (R0) of Zika virus infection

Pathogenesis

  • pathogenesis not well studied, but early data indicate that
    • virus infects and replicates in skin cells including dermal fibroblasts, epidermal keratinocytes, and immature dendritic cells
    • infected epidermal keratinocytes rapidly undergo apoptotic cell death
    • viral replication induces innate immune response and production of type I interferons in infected cells
    • virus disseminates likely via blood and infected persons typically remain viremic for a few days
    • References - (2), J Virol 2015 Sep;89(17):8880
  • virus has demonstrated neurotropism in vitro and in animal models (J Neuroinfect Dis 2016 Jun;7(2) full-text)

History and Physical

History

Chief concern (CC)

  • about 20%-25% of infected persons develop symptoms(1, 2)
  • when present, common symptoms include(1, 2, 4, 5, 9)
    • rash, typically maculopapular
    • arthralgias and myalgias
    • conjunctivitis
    • headache
    • acute-onset fever (often low-grade and short-lived)
  • frequency of symptoms in the first 4 days of illness based on review of 119 confirmed cases in Rio de Janeiro reported between January and July 2015
    • macular or papular rash in 97% (median duration 5.5 days)
    • itching in 79%
    • prostration in 73%
    • headache in 66%
    • arthralgia in 63%
    • myalgia in 61%
    • nonpurulent conjunctivitis in 56%
    • retro-orbital pain in 45%
    • enlarged lymph nodes in 41%
    • chills in 37%
    • fever in 36%
    • anorexia in 35%
    • photophobia in 34%
    • oropharyngeal pain in 32%
    • edema in 29%
    • taste alteration in 27%
    • nausea in 24%
    • petechiae or bleeding in 21%
    • nasal congestion in 20%
    • sweating in 19%
    • diarrhea in 19%
    • abdominal pain in 17%
    • cough in 16%
    • coryza in 15%
    • Reference - PLoS Negl Trop Dis 2016 Apr;10(4):e0004636
  • similar frequency of symptoms and disease severity reported in a cases series of 158 children with probable confirmed travel-related Zika virus infection (MMWR Morb Mortal Wkly Rep 2016 Oct 7;65(39):1082)
  • similar frequency of symptoms reported among 72 pregnant women with confirmed acute Zika virus infection (N Engl J Med 2016 Dec 15;375(24):2321 full-text) see Zika virus in pregnancy and congenital Zika syndrome for additional detail

Social history (SH)

  • ask all patients about travel to areas with active transmission(2)
  • note specific location and dates of travel (incubation period range 3-12 days)(2)
  • ask about risk factors for transmission including(8)
    • mosquito exposure
    • unprotected sexual contact with someone who has traveled recently to areas with active transmission

Physical

General physical

  • check for elevated temperature(1, 2)

Skin

  • most symptomatic patients will present with maculopapular rash(1, 2)

HEENT

  • examine conjunctiva for redness, a common feature(1, 2)

Diagnosis

Making the diagnosis

  • consider the diagnosis of Zika virus infection in patients with(1, 2, 3, 4)
    • ≥ 1 of the following symptoms
      • macular or papular rash
      • arthralgias
      • conjunctivitis
      • fever (may be low-grade)
    • risk factors such as history of travel to or residence in an area with active transmission within 2 weeks of illness onset
  • complete blood count, routine chemistries often normal but mild leukopenia, thrombocytopenia and hepatic transaminitis reported(9)
  • suspected cases should be reported to local health departments in United States for coordination of testing, care and to prevent spread(2)
  • most testing is performed by Centers for Disease Control and Prevention (CDC) and some state health departments in United States though commercial assays are available in some institutions
  • patients with suspected Zika virus infection should also be evaluated for dengue and chikungunya virus infection as symptoms and geographic distribution of these 3 illnesses overlap(4)
  • specific considerations during pregnancy
    • for asymptomatic pregnant women in areas without active transmission
      • ask about possible Zika virus exposure at each prenatal care visit including
        • history of travel to or residence in an area with active Zika virus transmission
        • unprotected sexual contact with a partner who has traveled to or resides in an area with active Zika virus transmission
      • offer testing to any asymptomatic pregnant women with possible exposure
        • use RT-PCR for testing on all appropriate specimens available (serum or urine preferred) for women presenting < 2 weeks after potential exposures
          • positive result confirms infection
          • negative result does not exclude infection and serologic testing with Zika virus IgM should be performed 2-12 weeks after the potential exposure
      • perform Zika virus IgM testing for women presenting 2-12 weeks after the potential exposure; if antibody test is positive or equivocal, perform RT-PCR on all appropriate specimens available (serum or urine preferred)
    • for asymptomatic pregnant women in areas with ongoing risk for exposure
      • screen for infection using Zika virus IgM antibody testing at routine care visits during the 1st and 2nd trimesters
      • perform immediate RT-PCR testing for positive or equivocal antibody test results
    • for symptomatic pregnant women who seek care < 2 weeks after symptom onset
      • perform serum and urine real-time RT-PCR testing for Zika virus
      • if RT-PCR results are negative, test for Zika virus and dengue virus immunoglobulin (IgM) testing
      • if Zika virus and dengue virus IgM test results are positive or equivocal, perform plaque reduction neutralization test (PRNT)
    • for symptomatic women who seek care 2-12 weeks after symptom onset
      • perform Zika virus IgM testing
      • if serologic test results are positive or equivocal, perform real-time RT-PCR on all appropriate specimens available (serum or urine preferred)
      • if RT-PCR results are negative AND Zika virus and dengue virus IgM test results are positive or equivocal, perform PRNT assay
    • if Zika virus infection is suspected or confirmed, consider serial ultrasounds every 3-4 weeks to assess fetal growth and anatomy
    • decision on amniocentesis should be individualized
    • see testing algorithm provided by CDC for additional detail
  • In the United States, all suspected cases of Zika virus infection should be reported to local health departments for coordination of testing, care, and to prevent spread.
  • see also CDC interim guidance on management in pregnancy and testing algorithm provided by CDC for additional detail

Differential diagnosis

  • important to rule out or assess for concurrent(1, 2)
    • dengue and chikungunya fever
    • both dengue and chikungunya are transmitted by the same mosquito vector
      Comparison of Frequency of Reported Symptoms:
      Symptoms Dengue Chikungunya Zika
      FeverMore commonCommonCommon
      Myalgia/arthralgiaCommonMore commonLess common
      Edema of extremitiesRareRareCommon
      Maculopapular rashCommonCommonMore common
      Retro-orbital painCommonLess commonCommon
      ConjunctivitisRareLess commonCommon
      LymphadenopathiesCommonCommonLess common
      HepatomegalyRareCommonRare
      Leukopenia/thrombocytopeniaCommonCommonRare
      HemorrhageCommonRareRare
      References - Med Mal Infect 2014 Jul;44(7):302, Clin Infect Dis 2009 Sep 15;49(6):942.
  • other considerations include(1, 2)
    • malaria
    • leptospirosis
    • rickettsial infections
    • influenza
    • infectious mononucleosis
    • acute HIV infection
    • meningococcal disease
    • measles
    • rubella
    • parvovirus B19 infection
    • enteroviral infections
    • scarlet fever (see Group A Streptococcus)
    • other alphavirus infections, which vary with geography
      • Ross River virus disease (Australia and Oceania)
      • Mayaro virus
      • Barmah Forest virus (Australia)
      • O'nyong-nyong (Africa)
      • Sindbis virus (Africa, Asia, Scandinavia, Russia)
      • Semliki Forest virus (Africa)
      • Reference - Clin Infect Dis 2007 Jul 1;45(1):e1 full-text
    • Usutu virus (Emerg Infect Dis 2016 Nov;22(11):2000)
  • see also Fever in the returning traveler

Testing overview

Recommendations

  • Centers for Disease Control and Prevention (CDC) 2016 guidance for laboratories testing for Zika virus infection
    • specimen type
      • serum is required for all diagnostic testing
      • additional sample types including urine, whole blood, and cerebrospinal fluid may be tested if indicated
    • recommended Zika virus testing
      • for symptomatic persons who seek care < 2 weeks after symptom onset
        • perform serum and urine real-time reverse transcription polymerase chain reaction (RT-PCR) testing for Zika virus
        • if RT-PCR results are negative, test for Zika virus IgM testing
        • if Zika virus and dengue virus IgM test results are positive or equivocal, perform plaque reduction neutralization test
        • see testing algorithm PDF provided by CDC for additional detail
      • for symptomatic persons who seek care ≥ 2 weeks after symptom onset
        • perform Zika virus IgM testing
        • if serologic test results are positive or equivocal, perform plaque reduction neutralization test
        • may consider RT-PCR testing on urine and whole blood samples
        • see testing algorithm PDF provided by CDC for additional detail
    • in Puerto Rico, plaque reduction neutralization test not currently routinely recommended for Zika virus testing of any specimens
    • see below for specific recommendations during pregnancy
    • Reference - CDC 2016 Nov 16
  • CDC interim guidance for Zika virus antibody testing and interpretation of test results
    • perform serum IgM antibody testing for Zika and dengue if real-time RT-PCR testing result is negative
    • if IgM antibody testing result negative
      • for serum samples collected < 7 days after illness onset
        • combination of negative IgM result and negative RT-PCR result suggestive of no recent infection
        • negative IgM result, in absence of RT-PCR testing, does not rule out infection
      • for samples collected from 7 days to 12 weeks, a negative IgM result to both Zika and dengue viruses rules out recent infection with either virus
    • if IgM antibody testing for either Zika or dengue shows positive, equivocal, or inconclusive results, perform plaque reduction neutralization test (PRNTs) against Zika, dengue, or other endemic flaviviruses
      • positive Zika PRNT result (titer ≥ 10) with negative PRNTs against other flaviviruses (titer < 10) confirms recent Zika virus infection
      • PRNT titer ≥ 10 for both Zika and dengue virus (or another flavivirus) supportive of recent flavivirus infection
      • interpretation of a negative Zika PRNT is similar to that of a negative IgM antibody testing result (see above)
    • Reference - MMWR Morb Mortal Wkly Rep 2016 Jun 3;65(21):543 full-text

Blood tests

Serology

  • serum virus-specific immunoglobulin M (IgM) and neutralizing antibodies(2, 4, 9)
    • greater sensitivity at end of first week of illness
    • cross-reacts with other flavivirus (such as dengue or yellow fever)
    • Centers for Disease Control and Prevention (CDC) IgM Antibody Capture Enzyme-Linked Immunosorbent Assay (Zika MAC-ELISA)
    • novel European Zika-specific IgM and IgG enzyme-linked immunosorbent assay (ELISA) assays reported to differentiate Zika virus-positive samples from samples with different flavivirus infections including tick-borne encephalitis virus, dengue, yellow fever, and hepatitis C virus (Euro Surveill 2016 Apr 21;21(16) full-text)
  • commercial assays are also available at some institutions
    • FDA alert to physicians who care for pregnant women that Laboratory Corporation of America (LabCorp) has reported false positive results for commercially available ZIKV Detect IgM Capture ELISA (InBios International, Inc.)
      • physicians should wait for confirmatory test results before patient management decisions are made; commercially available IgM tests remain useful in ruling out Zika exposure
      • confirmatory tests by CDC or qualified laboratories may take a week to a month to complete; laboratories should be alerted of patient's pregnancy status for prioritization
      • Reference - FDA MedWatch 2016 Dec 23
  • plaque reduction neutralization assays
    • can be used to distinguish among cross-reacting flavivirus antibodies(2, 9)
    • currently not routinely recommended for testing of any specimens in Puerto Rico (CDC 2016 Nov 16)

Viral identification

Reverse transcriptase-polymerase chain reaction (RT-PCR)

  • distinguishes Zika from other flaviviruses such as dengue(2, 9)
  • typically performed on serum or urine(2, 9)
  • whole blood can be tested by some RT-PCR tests that have Food and Drug Administration (FDA) Emergency Use Authorization (EUA) in specific populations, including
    • symptomatic persons presenting up to 14 days after symptom onset
    • asymptomatic pregnant women presenting within 14 days of last possible Zika virus exposure
    • infants with suspected congenital Zika virus infection
    • Reference - CDC 2016 Nov 16
  • experience with the test on other specimen types, such as amniotic fluid, is limited(2, 9)
  • sensitivity of RT-PCR varies within 14 days after symptom onset
  • plasma RT-PCR appears more sensitive than urine RT-PCR on urine samples within first 5 days of symptomatic Zika virus infection
    • based on cohort study
    • 61 patients had RT-PCR testing on urine and plasma specimens within first 5 days of illness onset
    • positive RT-PCR results in 46 plasma samples and 37 urine samples
    • similar viral loads detected in plasma and urine samples among 28 patients who had positive RT-PCR results on both sample types
    • Reference - Euro Surveill 2016 Jul 28;21(30) full-text
  • detection of viral RNA up to 58 days in whole blood samples, 26 days in urine samples, and 3 days in serum samples after illness onset in 6 patients with Zika virus infection (Euro Surveill 2016 Jun 30;21(26) full-text)
  • single-reaction multiplex real-time RT-PCR reported to detect Zika, chikungunya, and dengue viruses from serum samples (Emerg Infect Dis 2016 Jul;22(7):1295 full-text)

Treatment

Treatment overview

  • no specific antiviral treatment for Zika virus is available(2, 4)
  • supportive care is recommended, focused on rest, hydration, pain control, and fever control(2, 4)
    • acetaminophen is generally preferred
    • aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided until dengue, which carries risk of hemorrhage, can be ruled out
  • most patients recover in about 5-7 days(1, 2, 4)
  • severe disease and need for hospitalization is uncommon(2, 4)
  • infected patients should be advised to avoid mosquito exposure during first week of illness to reduce risk of local transmission(2, 4)

Recommendations

Guidelines for evaluation and management of pregnant women

  • Centers for Disease Control and Prevention (CDC) interim guidelines for pregnant women and women of reproductive age during a Zika virus outbreak - United States, 2016
    • assess any pregnant women for possible Zika virus exposure at each prenatal care visit
    • possible Zika virus exposure include
      • travel to or residence in an area with active Zika virus transmission
      • unprotected sexual contact with a partner who has traveled to or resides in an area with active Zika virus transmission
    • screening and testing for symptomatic pregnant women
      • test any pregnant women with possible Zika virus exposure who has
        • ≥ 1 of the following symptoms
          • fever
          • maculopapular rash
          • arthralgias
          • conjunctivitis
      • perform dengue virus immunoglobulin (IgM) testing in any symptomatic pregnant women
      • recommended Zika virus testing by time of evaluation
        • for women who seek care < 2 weeks after symptom onset
          • perform serum and urine real-time RT-PCR testing for Zika virus
          • if RT-PCR results are negative, test for Zika virus IgM testing
          • if Zika virus and dengue virus IgM test results are positive or equivocal, perform plaque reduction neutralization test
          • see testing algorithm PDF provided by CDC for additional detail
        • for women who seek care 2-12 weeks after symptom onset
          • perform Zika virus IgM testing
          • if serologic test results are positive or equivocal, perform real-time RT-PCR on all appropriate specimens available (serum and urine preferred)
          • if RT-PCR results are negative AND Zika virus and dengue virus IgM test results are positive or equivocal, perform plaque reduction neutralization test
          • see testing algorithm PDF provided by CDC for additional detail
      • in Puerto Rico, plaque reduction neutralization test not currently routinely recommended for testing of any specimens
    • screening and testing for asymptomatic pregnant women
      • for those who reside in areas without active transmission and who seek care < 2 weeks after last possible exposure
        • offer real-time RT-PCR testing on all appropriate specimens available (serum and urine preferred)
        • if RT-PCR result is negative, perform Zika virus IgM testing 2-12 weeks after the exposure
        • if Zika virus IgM test results are positive or equivocal, perform plaque reduction neutralization test
      • for those who reside in areas without active transmission and who seek care 2-12 weeks after last possible exposure
        • offer Zika virus IgM testing
        • if serologic test results are positive or equivocal, perform real-time RT-PCR on all appropriate specimens available (serum and urine preferred)
        • if RT-PCR results are negative, perform plaque reduction neutralization test
      • for those with ongoing risk for exposure to Zika virus (such as living in or frequently traveling to an area with active transmission)
        • offer Zika virus IgM testing as part of routine obstetric care during the first and second trimesters
        • if serologic test results are positive or equivocal, perform serum and urine real-time RT-PCR
        • if RT-PCR results are negative, perform plaque reduction neutralization test
        • decision on testing should be made by local health authorities in areas with active transmission
      • in Puerto Rico, plaque reduction neutralization test not currently routinely recommended for testing of any specimens
      • see testing algorithm PDF provided by CDC for additional detail
    • screening and testing for symptomatic and asymptomatic pregnant women who seek care > 12 weeks after illness onset or possible exposure
      • Zika virus IgM testing may be used
      • if presence of fetal abnormalities, perform real-time RT-PCR testing on maternal serum and urine samples
      • negative IgM or RT-PCR results do not rule out recent Zika virus infection
      • consider serial fetal ultrasounds to monitor fetal growth and anatomy
    • fetal testing for women with established or suspected diagnosis of Zika virus infection or other flavivirus infection
      • perform serial ultrasounds every 3-4 weeks to monitor fetal growth and anatomy
      • discuss risk and benefits of fetal testing; decision on amniotic fluid analysis via RT-PCR should be made on a case by case basis
      • all women with positive testing or fetal ultrasound findings of microcephaly or intracranial calcifications should be referred to a maternal fetal medicine specialist
      • consider pathologic testing for Zika virus infection such as RT-PCR and immunohistochemical staining on fetal tissue, including placenta and umbilical cord, in cases of fetal loss or stillbirth
    • treatment of women with Zika virus infections
      • supportive care is the recommended treatment for pregnant women with Zika virus infection, including
        • rest
        • fluids
        • fever control
          • acetaminophen is preferred
          • aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) should generally be avoided in pregnancy and specifically avoided when dengue is a consideration as dengue diagnosis carries risk of hemorrhage
    • for infants born to mother who had Zika virus infection during pregnancy or fetuses diagnosed with Zika virus in pregnancy
      • obtain histopathology of the placenta and umbilical cord
      • test frozen placental tissue and cord tissue for Zika virus RNA
      • see below for additional guidance for infected infants
  • References - CDC 2016 Nov 16, MMWR Morb Mortal Wkly Rep 2016 Jul 25;65(29):739 full-text, MMWR Morb Mortal Wkly Rep 2016 Apr 1;65(12):315 full-text
  • American Congress of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine practice advisory providing interim guidance for care of obstetric patients and women of reproductive age during a Zika virus outbreak are consistent with CDC recommendations, and can be found at ACOG 2016 Aug 3 full-text
  • current CDC travel health notices

Guidelines for evaluation and management of infants

  • CDC interim guidelines for evaluation and management of infants with possible congenital Zika virus infection - United States, 2016
    • laboratory testing for infants with possible congenital Zika virus infection
      • indications for testing
        • infants with microcephaly or intracranial calcifications born to mothers with possible exposure while pregnant
        • infants born to mothers with positive or inconclusive test results for Zika virus infection
      • options for laboratory testing if indicated
        • perform both of
          • RT-PCR on infant's serum and urine samples
            • a positive infant serum or urine RT-PCR test result confirms congenital Zika virus infection
            • a negative result does not rule out infection
          • immunoglobulin M (IgM) antibodies on infant's serum samples
            • a positive IgM test result, with a negative RT-PCR result, indicates probable congenital Zika virus infection
        • collect initial sample directly from the infant within 2 days of birth, if possible
        • cerebrospinal fluid should also be tested if available by RT-PCR and IgM testing
        • whole blood can be tested by some RT-PCR tests that have Food and Drug Administration (FDA) Emergency Use Authorization (EUA)
        • testing of cord blood not recommended due to potential contamination with maternal blood
        • plaque reduction neutralization test (PRNT) also recommended in some circumstances
          • perform on infant’s initial sample if infant’s initial sample is IgM-positive but negative on RT-PCR test and if PRNT was not performed on mother’s sample
          • perform at age ≥ 18 months if infant’s initial sample is IgM-positive and if either the infant or mother had positive PRNT results
          • may be considered at age 18 months if infant’s initial sample is negative on both IgM and RT-PCR tests but clinical concerns remain (such as microcephaly with negative evaluation for other known causes)
            • a negative PRNT result at 18 months rules out congenital Zika virus infection
            • a positive PRNT result is indicative of presumable congenital Zika infection and cannot rule out postnatal infection, especially for children living in an area with active Zika virus transmission
          • not currently routinely recommended for testing of any specimens in Puerto Rico
        • if maternal testing not done during pregnancy, or testing performed more than 12 weeks after exposure, or test results not definitive, RT-PCR testing of placenta can be perform to confirm maternal infection
      • in United States, contact local health departments to facilitate laboratory testing at time of birth and specimen submission to CDC
    • infants with possible congenital Zika virus infection may be evaluated in a facility with access to pediatric subspecialty care, however decision should be made after considering risks and benefits and should not be based on only presence of maternal Zika virus infection
    • perform all of following for all infants with possible congenital Zika virus infection
      • comprehensive physical examination including careful measurement of occipitofrontal circumference, length, weight, and assessment of gestational age
      • general blood tests including complete blood count, platelet count, enzyme tests for alanine aminotransferase, aspartate aminotransferase, and bilirubin
      • evaluation for neurologic abnormalities, dysmorphic features, splenomegaly, hepatomegaly, and rash or other skin lesions
        • document full body photographs and any rash, skin lesions, or dysmorphic features
        • consult an appropriate specialist if an abnormality observed
      • cranial ultrasound before discharge, even if no brain abnormalities shown on prenatal ultrasound
      • evaluation of hearing by evoked otoacoustic emissions testing or auditory brainstem response testing, either before discharge from the hospital or within 1 month after birth - infants with abnormal initial hearing screens should be referred to an audiologist for further evaluation
      • referral to medical specialists including
        • pediatric neurologist for decision on brain imaging and additional evaluation
        • pediatric ophthalmologist for comprehensive eye exam and evaluation for possible cortical visual impairment, either before hospital discharge or within 1 month of birth
        • endocrinologist for assessment of hypothalamic or pituitary dysfunction
        • clinical geneticist to evaluate for other causes of microcephaly or other anomalies if present
        • pediatric infectious disease specialist for diagnostic testing of other congenital infections such as syphilis, toxoplasmosis, rubella, cytomegalovirus infection, lymphocytic choriomeningitis virus infection, and herpes simplex virus infection
      • other evaluations specific to infant's clinical presentation
    • consider other consultations such as
      • orthopedist, physiatrist, or physical therapist for hypertonia, club foot, or arthrogrypotic-like conditions
      • pulmonologist or otolaryngologist for concern about aspiration
      • lactation specialist, nutritionist, gastroenterologist, or speech or occupational therapist for feeding issues
    • for infants born to mothers with risk factors for maternal Zika virus infection and for whom maternal testing was not performed before delivery
      • perform comprehensive physical examination, including standardized measurement of head circumference
      • perform laboratory testing for maternal Zika virus infection; consider RT-PCR testing of placenta
      • perform laboratory testing for Zika virus infection in infants if mothers have laboratory evidence of Zika virus infection
      • if an infant is clinically well, further evaluation, including head ultrasound, ophthalmologic assessment, and infant laboratory Zika virus testing, can be deferred until maternal test results are available
      • if infant follow-up is a concern, perform head ultrasound, ophthalmologic assessment, and infant Zika virus testing before discharge
    • outpatient management and long-term follow-up for infants with laboratory evidence of Zika virus infection
      • case should be reported to local health departments and monitored
      • establish a medical home for outpatient care
      • provide families and caregivers with anticipatory guidance, psychosocial support, and assistance with coordination of care
        • anticipatory guidance should focus on developmental milestones, feeding and growth, sleep, irritability, and seizure recognition
        • caregivers should be monitored for depression during primary care visits
      • care for infants with abnormalities consistent with congenital Zika syndrome
        • follow-up monthly for at least first 6 months after birth
        • provide routine immunizations
        • monitor growth parameters and developmental milestones within first year of age; refer to a developmental specialist and early intervention services
        • assess for evidence of feeding difficulties; refer for consultations regarding lactation, occupational therapy, speech therapy, nutrition, and/or gastroenterology if necessary
        • repeat neurologic examination at 1 and 2 months of age; refer to a neurologist for any abnormalities or for any parental or provider concerns
        • repeat comprehensive ophthalmologic exam at 3 months of age; refer to an ophthalmologist for any abnormal findings or for any parental or provider concerns
        • repeat auditory brainstem response testing at 4-6 months of age; refer to an audiologist for any abnormal findings or for any parental or provider concerns
        • assess for hypothyroidism at 2 weeks and 3 months of age; refer to an endocrinologist for further evaluation of pituitary function
      • care for infants without apparent abnormalities
        • follow-up at each well-child visit
          • monitor growth parameters and developmental milestones
          • perform vision screening and assess visual regard; refer to an ophthalmologist for any abnormal findings or for any parental or provider concerns
        • refer to an ophthalmologist for comprehensive eye exam within 1 month of age
        • perform auditory brainstem response within 1 month of age
        • use a standardized, validated developmental screening tool at 9 months as currently recommended, or earlier for any parental or provider concerns
        • consider repeating auditory brainstem response at 4-6 months (with risk of sedation taken into account) or performing behavioral diagnostic testing at 9 months of age; refer to an audiologist for any abnormal findings or for any parental or provider concerns
  • CDC interim guidelines for breastfeeding for mothers with Zika virus infection - United States, 2016
    • no cases of breastfeeding-associated Zika virus infection have been reported
    • breastfeeding is encouraged in mothers with Zika virus infection and living in areas with ongoing transmission
  • References - CDC 2016 Nov 16, MMWR Morb Mortal Wkly Rep 2016 Aug 26;65(33):870  full-text

Guidelines for evaluation and management of infants and children with possible acute disease

  • CDC interim guidelines for evaluation and management of infants and children < 18 years old with possible acute Zika virus infection - United States, 2016
    • suspect acute Zika virus disease in infants ≥ 2 weeks old and children < 18 years old with
      • history of travel or residence in affected area in prior 2 weeks
      • ≥ 2 of fever, rash, conjunctivitis, and arthralgia
      • manifestations of arthralgia in infants and young children may include
        • irritability
        • walking with limp (in ambulatory children)
        • difficulty moving
        • refusal to move
        • pain on palpation
        • pain with passive or active movement of affected joint
    • suspect acute Zika virus disease in infants < 2 weeks old with
      • mother with history of travel or residence in affected area within 2 weeks prior to birth
      • ≥ 2 of fever, rash, conjunctivitis, and arthralgia
    • options for laboratory testing
      • test patient's serum sample for
        • Zika virus RNA and IgM and neutralizing antibodies
        • dengue virus IgM and neutralizing antibodies
      • cerebrospinal fluid may also be tested if available
    • laboratory evidence for diagnosis of Zika virus infection includes any of the following from any clinical specimen
      • detectable Zika virus in culture
      • Zika virus RNA or antigen
      • Zika virus IgM neutralizing antibody titers ≥ 4-fold higher than dengue virus neutralizing antibody titers
    • treatment is typically supportive
      • do not use nonsteroidal anti-inflammatory drugs
        • until dengue has been excluded due to potential for hemorrhagic complications
        • in children < 6 months old
      • do not use aspirin in children with acute viral illness due to association with Reye's syndrome

Complications and Prognosis

Complications

Complications in pregnancy

Epidemiologic association

  • increased incidence of infants born with microcephaly reported during Zika virus outbreaks
  • 30-33 week time lag reported between outbreaks of Zika virus-related acute illness and peak incidence of microcephaly in Salvador, Brazil during 2015 (Emerg Infect Dis 2016 Aug;22(8):1438 full-text)
  • no cases of microcephaly or brain abnormalities reported among neonates born to 573 women diagnosed with suspected or confirmed Zika virus infection during third trimester of pregnancy between August 2015 and April 2016 in Colombia (N Engl J Med 2016 Jun 15 early online)

Clinical syndrome associated with congenital Zika virus infection

  • additional epidemiologic studies report an increase in microcephaly and/or other brain deficits and help define the clinical syndrome associated with Zika virus infection during pregnancy
    • intrauterine growth restriction, fetal death, and cerebral calcification or other central nervous system lesions reported in fetuses whose mothers acquired acute Zika virus infection during pregnancy
      • based on prospective cohort study
      • 88 pregnant women (median age 29 years) presenting to acute febrile illness clinic with rash in preceding 5 days in Rio de Janeiro, Brazil were evaluated
        • all women had documented immunity to rubella and cytomegalovirus and negative results on syphilis serology
        • 88% were positive for dengue immunoglobulin G (IgG) serology at enrollment
        • no fetal malformation preceding illness observed in current pregnancy
      • 72 women (82%) had acute Zika virus infection confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) assay on blood, urine, or both specimens (time of infection range 5-38 gestational weeks)
      • among 42 women with acute Zika virus infection who had prenatal ultrasound studies
        • time of infection range 6-35 gestational weeks
        • 12 (29%) had abnormal findings, including
          • intrauterine growth restriction with or without microcephaly in 5 fetuses
          • cerebral calcification and other central nervous system lesions in 7 fetuses
          • abnormal arterial flow in cerebral or umbilical arteries in 4 fetuses
          • oligohydramnios and anhydramnios in 2 fetuses
          • fetal death in 2 fetuses (maternal infections acquired at 25 and 32 gestational weeks)
      • pregnancy outcomes consistent with fetal ultrasound findings in 8 women who had given birth
      • no ultrasound abnormalities seen in 16 women who tested negative for Zika virus infection, but pregnancy outcomes not reported
      • Reference - N Engl J Med 2016 Dec 15;375(24):2321 full-text, commentary can be found in J Adolesc Health 1995 Aug;17(2):120
    • association between Zika virus infection and neonatal microcephaly reported in Brazil outbreak, 2015
      • based on cohort study
      • 35 neonates with microcephaly born to mothers who had resided in or traveled to Zika virus-affected areas during pregnancy during August-October 2015 were reviewed
      • Zika virus-related microcephaly defined as head circumference ≥ 2 standard deviations below mean for sex and gestational age at birth
      • 26 mothers (74%) of the 35 affected neonates reported rash illness during first and second trimesters of pregnancy
      • among 35 neonates with microcephaly
        • 25 infants (71%) had severe microcephaly (> 3 standard deviations below mean)
        • 19 infants (47%) had at least 1 neurologic abnormality
        • 35 infants (100%) had negative testing for congenital infection with syphilis, cytomegalovirus, rubella, toxoplasmosis, and herpes simplex virus
        • presence of Zika virus RNA in cerebrospinal fluid samples under investigation, but results not yet reported
        • abnormal findings, including wide spread intracranial calcifications, in all of 27 infants who had neuroimaging studies
      • Reference - MMWR Morb Mortal Wkly Rep 2016 Jan 29;65(3):59 full-text
    • cerebral calcification, ventriculomegaly, and other central nervous system lesions reported in fetuses with confirmed congenital Zika virus infection
      • based on case series
      • 3 fetuses with intrauterine Zika virus infection (confirmed by RT-PCR of amniotic fluid) and severe brain lesions on ultrasound and MRI following 2013-2014 Zika outbreak in French Polynesia were reviewed
      • maternal Zika virus infection was documented in 2 cases during first trimester of pregnancy
      • prenatal ultrasound showed cerebral calcifications and ventriculomegaly in all 3 cases
      • MRI at 25-31 weeks gestation showed
        • micrencephaly in all 3
        • polymicrogyria with laminar necrosis and opercular dysplasia in all 3
        • low cerebellar biometry in 2
        • occipital subependymal pseudocysts in 2
        • absent or hypoplastic corpus callosum in 1 each
        • hypoplastic brainstem in 1
      • Reference - Pediatr Radiol 2016 Jun;46(7):1032
    • microcephaly, cerebral malformation, and neurologic dysfunction reported in fetuses and newborns during 2013-2014 Zika virus outbreak in French Polynesia
      • based on retrospective cohort study
      • 19 fetuses and neonates with congenital cerebral malformation and dysfunction with no known etiology following 2013-2014 Zika outbreak in French Polynesia were reviewed
        • 8 fetuses or newborns with cerebral lesions and severe microcephaly
        • 6 fetuses with cerebral lesions without microcephaly
        • 5 newborns with brainstem dysfunction without visible malformation
      • neurologic lesions on prenatal ultrasound or MRI included
        • destruction or absence of the corpus callosum and/or cavum septi
        • ventriculomegaly
        • abnormal neuronal migration
        • opercular dysplasia (agyria or polymicrogyria)
        • vermian dysgenesis
        • cerebellar hypoplasia
        • occipital subependymal pseudocysts
        • parenchymal calcifications
      • amniotic fluid in 7 cases collected at 20-29 gestation weeks was retrospectively tested for Zika virus (viral RNA and infectious virus)
        • 4 of 5 cases with severe microcephaly were positive
        • 2 cases with severe brain lesions without microcephaly were negative
      • pregnancy outcomes
        • pregnancy termination in 11 cases
        • neonatal death at age 1 month in 2 cases with brainstem dysfunction
        • severe neurologic impairment in 6 neonates
      • Reference - Euro Surveill 2016;21(13)
    • cerebral calcifications, malformations of cortical development, and ventriculomegaly common neuroimaging findings in children with microcephaly due to presumed congenital Zika virus infection
      • based on retrospective cohort study
      • 23 children with microcephaly due to presumed congenital Zika virus infection during 2015-2016 outbreak in Brazil were reviewed
      • children with other known causes of microcephaly excluded from study
      • among 22 children who had computed tomography (CT) scans at age < 1 day to 104 days
        • calcifications in 100% (mainly at the cortical and subcortical white matter junction)
        • malformations of cortical development in 95%
        • decreased brain volume in 91%
        • ventriculomegaly in 86%
        • hypoplasia of cerebellum or brainstem in 9.1%
      • among 8 children who had magnetic resonance imaging (MRI) scans at age 6-162 days
        • calcifications in the junction between cortical and subcortical white matter, malformations of cortical development occurring predominantly in the frontal lobes, and ventriculomegaly each in 100%
        • enlarged cisterna magna and delayed myelination each in 88%
        • moderate-to-severe decrease in brain volume, simplified gyral pattern, and abnormalities of corpus callosum (38% hypogenesis and 38% hypoplasia) each in 75%
        • malformations were symmetrical in 75%
      • Reference - BMJ 2016 Apr 13;353:i1901 full-text, correction can be found in BMJ 2016 Jun 6;353:i3182
    • severe microcephaly, hydrops fetalis, hydranencephaly, and fetal demise associated with suspected congenital Zika virus infection in a case report from Brazil (PLoS Negl Trop Dis 2016 Feb;10(2):e0004517 full-text)
    • ocular lesions have been described in addition to microcephaly and cerebral abnormalities
      • ocular lesions including pigmentary retinopathy and atrophy observed in infants with microcephaly due to presumed congenital Zika virus infection
        • based on case series
        • 29 infants (aged 1-6 months) born with microcephaly due to presumed congenital Zika virus infection had ophthalmic examination
        • 23 (79.3%) of 29 mothers had symptomatic Zika virus infection during pregnancy
        • among 58 eyes examined, 17 eyes of 10 infants had ocular abnormalities
          • bilateral findings observed in 7 infants
          • most common ocular lesions were
            • focal pigment mottling of retina and chorioretinal atrophy in 11 eyes (64.7%)
            • optic nerve abnormalities in 8 eyes (47.1%)
            • bilateral iris coloboma in 2 eyes (11.8%; 1 patient)
            • lens subluxation in 1 eye (5.9%)
        • all infants tested negative for toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and HIV
        • Reference - JAMA Ophthalmol 2016 Feb 9 early online, editorial can be found in JAMA Ophthalmol 2016 Feb 9 early online, commentary can be found in BMJ 2016 Feb 10;352:i855, JAMA Ophthalmol 2016 Aug 1;134(8):945, JAMA Ophthalmol 2016 Aug 1;134(8):946
        • case series describing similar ocular lesions in 10 infants born to mothers who had Zika virus infections in first trimester can be found in Arq Bras Oftalmol 2016 Feb;79(1):1
        • additional ocular findings including torpedo maculopathy, vascular changes, and hemorrhagic retinopathy also observed in 3 infants with microcephaly born to mothers who had viral syndrome during first trimester (Ophthalmology 2016 Aug;123(8):1788)
        • ocular and neurologic lesions without microcephaly reported in 57-day-old infant with congenital Zika virus infection confirmed by Zika-specific immunoglobulin M (IgM) serology on cerebrospinal fluid (Lancet 2016 Jun 18;387(10037):2502)

Biologic plausibility

  • Zika virus has been detected in the brain tissue of affected infants by multiple methods and has demonstrated neurotropism in vitro and in animal models
    • Zika virus detected in a brain on autopsy of fetus from woman with presumed Zika virus infection at 13 weeks gestation
      • based on case report
      • brain tissue from a fetus from a 25-year-old woman who had pregnancy termination at 32 weeks gestation analyzed by autopsy
      • mother had symptomatic Zika virus infection at 13 weeks of gestation and lived in endemic area (Brazil), though maternal diagnosis was not confirmed
      • first signs of fetal abnormalities on ultrasound at 29 weeks of gestation included
        • intrauterine growth retardation (estimated 3rd percentile of fetal weight)
        • numerous placental calcifications
        • microcephaly with head circumference below the 2nd percentile
        • moderate ventriculomegaly
        • transcerebellar diameter below the 2nd percentile
        • multiple intracranial calcifications
      • testing of fetal tissues on autopsy included histopathologic examination and RT-PCR of formalin-fixed paraffin-embedded samples
        • gross findings included
          • microcephaly with widely open sylvian fissures and a small cerebellum and brainstem
          • near complete agyria and internal hydrocephalus of the lateral ventricles
          • numerous cortical and subcortical calcifications throughout the brain
        • prominent histopathologic abnormalities included
          • filamentous, granular, and neuron-shaped calcifications in the cortex and subcortical white matter
          • diffuse astrogliosis and inflammatory response
          • granular intracytoplasmic reaction in destroyed neuronal structures (indicating a possible location of the virus in neurons)
          • spherical virus particles with morphologic characteristics consistent with viruses of the Flaviviridae family
        • Zika virus was detected by RT-PCR on fetal brain tissue, but no other autopsy samples
        • molecular studies for other flaviviruses and teratogenic pathogens were negative
      • Reference - N Engl J Med 2016 Mar 10;374(10):951, editorial can be found in N Engl J Med 2016 Mar 10;374(10):984
    • Zika virus identified in brain tissue of 2 infants born with microcephaly and fetal tissue from 2 miscarriages in women with first-trimester Zika virus infection
      • based on case series
      • formalin-fixed paraffin-embedded tissues from 2 infants both with microcephaly who died within 20 hours of birth and fetal tissue from 2 miscarriages (at 11 and 13 weeks) were tested by RT-PCR and immunohistochemistry
      • all mothers had symptomatic Zika virus infection during first trimester of pregnancy and no clinical signs of infection at time of delivery or miscarriage
      • Zika virus identified by RT-PCR in samples from all 4 cases, including in brain tissue samples of neonates
      • RT-PCR testing for dengue virus negative in all cases
      • mothers with miscarriage tested negative for all of toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and HIV
      • all histopathologic changes in newborns occurred in brain, including parenchymal calcification, microglial nodules, gliosis, cell degeneration, and necrosis
      • Reference - MMWR Morb Mortal Wkly Rep 2016 Feb 19;65(6):159 full-text
      • a second case series describing similar pathologic findings 3 infants with fatal congenital Zika virus infection and fetal tissue from 2 miscarriages in women with first-trimester Zika virus infection can be found in Lancet 2016 Aug 27;388(10047):898, editorial can be found in Lancet 2016 Aug 27;388(10047):847
    • Zika virus detected in amniotic fluid and autopsy samples of fetus from woman who acquired Zika virus infection at 11 weeks gestation
      • based on case report
      • amniotic fluid and autopsy tissues of a fetus from a 33-year-old Finnish woman who had pregnancy termination at 21 weeks gestation were analyzed
      • mother had symptomatic Zika virus infection after traveling to endemic areas (Mexico and Central America) at 11 weeks gestation
        • Zika viral RNA was detected by RT-PCR in serum samples from 16 weeks gestation until pregnancy termination
        • serum samples were negative for dengue and chikungunya immunoglobulin M (IgM) antibodies, but positive for dengue IgG antibodies
      • first signs of fetal brain abnormalities on ultrasound were observed at 19 weeks gestation, but with no findings of microcephaly or intracranial calcification
      • Zika viral RNA was detected in
        • amniotic fluid
        • fetal tissues from brain (highest viral load), placenta, membranes, and umbilical cord
      • mother and fetus tested negative for parvovirus B19, rubella, herpes simplex virus types 1 and 2, cytomegalovirus, varicella zoster virus, and Toxoplasma gondii
      • Reference - N Engl J Med 2016 Jun 2;374(22):2142
    • Zika virus detected in amniotic fluid and autopsy samples of fetus from woman who acquired Zika virus infection at 11 weeks gestation
      • based on case report
      • amniotic fluid and autopsy tissues of a fetus from a 33-year-old Finnish woman who had pregnancy termination at 21 weeks gestation were analyzed
      • mother had symptomatic Zika virus infection after traveling to endemic areas (Mexico and Central America) at 11 weeks gestation
        • Zika viral RNA was detected by RT-PCR in serum samples from 16 weeks gestation until pregnancy termination
        • serum samples were negative for dengue and chikungunya immunoglobulin (Ig) M (IgM) antibodies, but positive for dengue IgG antibodies
      • first signs of fetal brain abnormalities on ultrasound were observed at 19 weeks gestation, but with no findings of microcephaly or intracranial calcification
      • Zika viral RNA was detected in
        • amniotic fluid
        • fetal tissues from brain (highest viral load), placenta, membranes, and umbilical cord
      • mother and fetus tested negative for parvovirus B19, rubella, herpes simplex virus types 1 and 2, cytomegalovirus, varicella zoster virus, and Toxoplasma gondii
      • Reference - N Engl J Med 2016 Jun 2;374(22):2142 full-text
  • neurotropism of Zika virus in vitro and in animal models
    • virus has been shown to inhibit differentiation of human neural stem cells into neurospheres and brain organoids (Science 2016 May 13;352(6287):816 )
    • virus has been shown to infect neural progenitor cells derived from human induced pluripotent stem cells and induce apoptotic cell death in vitro (Cell Stem Cell 2016 May 5;18(5):587)
    • high viral loads in brain and spinal cord and presentations of neurologic disease and death following experimental inoculation with Zika virus in a mouse model lacking interferon receptor-expressing gene (Cell Host Microbe 2016 May 11;19(5):720 )
    • neuronal degeneration and viral inclusion bodies observed in damaged neurons in brain tissues of mice experimentally inoculated with Zika virus (Trans R Soc Trop Med Hyg 1952 Sep;46(5):521)

Neurologic complications

Guillain-Barre Syndrome

  • Guillain-Barre syndrome reported and causal association is likely but not firmly established
    • increased incidence of Guillain-Barre syndrome during Zika virus transmission period in endemic regions
      • based on population-based cohort study
      • Zika virus infection and Guillain-Barre syndrome diagnoses were obtained from country reports in Bahia state Brazil, Columbia, Dominican Republic, El Salvador, Honduras, Suriname, and Venezuela from April 1, 2015 to March 31, 2016
        • 164,237 cases of Zika virus infection reported
        • 1,474 cases of Guillain-Barre syndrome reported
      • increased rate of Guillain-Barre syndrome during Zika virus transmission period compared to pre-Zika virus transmission period
        • Venezuela (rate ratio [RR] 9.8, 95% CI 7.6-12.5)
        • Suriname (RR 5, 95% CI 1.5-17.3)
        • Columbia (RR 3.1, 95% CI 2.5-3.9)
        • Bahia, Brazil (RR 2.7, 95% CI 2-3.7)
        • Honduras (RR 2.6, 95% CI 1.7-4.1)
        • Dominican Republic (RR 2.5, 95% CI 1.5-4.3)
        • El Salvador (RR 2, 95% CI 1.6-2.6)
      • increased and decreased incidence of Guillain-Barre syndrome temporally aligned with changes in incidence of Zika virus infection
      • Reference - N Engl J Med 2016 Oct 20;375(16):1598
    • Guillain-Barre syndrome associated with Zika virus infection in Columbia
      • based on cohort study
      • 68 patients (median age 47 years) diagnosed with Guillain-Barre syndrome in Columbia from January to March 2016 were evaluated
        • Guillain-Barre diagnosis established with Brighton criteria
        • manifestations of Guillain-Barre syndrome included
          • limb weakness in 97%
          • ascending paralysis in 82%
          • paresthesias in 76%
          • facial palsy in 32%
      • 97% had symptoms compatible with Zika virus infection median 7 days before onset of neurologic symptoms
        • diagnosis of Zika virus infection
          • 17 patients (25%) had definitive infection (positive RT-PCR of urine, serum, or cerebrospinal fluid [CSF])
          • 18 patients (26%) had probable infection (negative RT-PCR with positive enzyme-linked immunosorbent assay [ELISA] of CSF and/or serum)
          • 33 patients (49%) had suspected infection (negative RT-PCR and ELISA)
      • RT-PCR for dengue virus RNA negative in all 39 patients tested
      • Reference - N Engl J Med 2016 Oct 20;375(16):1513, editorial can be found in N Engl J Med 2016 Oct 20;375(16):1581
    • Guillain-Barre syndrome associated with Zika virus infection during Zika virus outbreak in French Polynesia
      • based on case-control study
      • 42 patients (median age 42 years) diagnosed with Guillain-Barre syndrome during 2013-2014 Zika virus outbreak in French Polynesia and 98 matched controls with nonfebrile illness were analyzed for Zika virus serology
      • another 70 matched controls with Zika virus disease but no neurologic symptoms were included in analysis of dengue serology
      • among 42 patients with Guillain-Barre syndrome
        • 88% had acute Zika virus disease prior to neurological symptoms (median interval 6 days)
        • 29% required respiratory assistance
        • no deaths reported
        • serologic testing for Campylobacter jejuni, HIV, cytomegalovirus, Epstein-Barr virus, and herpes simplex virus types 1 and 2 negative
      • comparing Guillain-Barre syndrome group vs. nonfebrile illness control group
        • seropositivity for Zika virus-specific IgM or IgG antibodies in 98% vs. 36% (p < 0.0001)
        • presence of neutralizing antibodies against Zika virus in 100% vs. 56% (p < 0.0001)
      • no significant differences in dengue IgG seropositivity between Guillain-Barre syndrome group (95%) and either control group (89% or 83%)
      • Reference - Lancet 2016 Apr 9;387(10027):1531, editorial can be found in Lancet 2016 Apr 9;387(10027):1486, commentary can be found in BMJ 2016 Mar 1;352:i1242
      • report of clinical features of these 42 cases with Guillain-Barre syndrome during Zika virus outbreak in French Polynesia can be found in Medicine (Baltimore) 2016 Apr;95(14):e3257
  • several case reports/series describe detection of Zika virus infection in patients with Guillain-Barre syndrome
    • Guillain-Barre syndrome reported in 19 patients, a median of 10 days after clinical or confirmed Zika virus infection, in Colombia from December 2015 to December 2016 (J Crit Care 2016 Aug 18;37:19)
    • detection of anti-Zika virus IgM antibodies by enzyme-linked immunosorbent assay (ELISA), but not Zika virus RNA, in serum of 2 patients with Guillain-Barre syndrome in Brazil, 2015 (Am J Trop Med Hyg 2016 Nov 2;95(5):1157)
    • detection of Zika viral RNA in CSF, serum, urine, and saliva samples of 24-year-old woman with Guillain-Barre syndrome in Brazil, 2014 (Lancet 2016 Apr 2;387(10026):1482)
    • encephalopathy with presence of Zika viral RNA in plasma, urine, and CSF specimens (detected by reverse transcriptase-polymerase chain reaction assay) in 2 patients with Zika virus infection in Martinique, 2016 (Euro Surveill 2016 Apr 21;21(16) full-text)
    • Miller Fisher syndrome (a variant of Guillain-Barre syndrome) reported in 35-year-old Haitian man tested positive for anti-Zika virus IgM antibodies in serum and CSF but with no prior history of Zika virus infection-related symptoms (Neurology 2016 Jul 19;87(3):336)
  • MRI findings showing demyelination, ischemia, inflammation, and breakdown of blood nerve barrier in 51-year-old woman with Guillain-Barre syndrome due to Zika virus infection (Neuroradiology 2016 Aug;58(8):837)

Other neurologic complications

  • transient sensorineural hearing loss in 3 patients with confirmed or probable acute Zika virus infection in case series (Clin Infect Dis 2016 Dec 7 early online)
  • transient unilateral acute maculopathy in 64-year-old man with diffuse erythematous rash and arthralgia, plus positive Zika virus plaque reduction neutralization test (PRNT) in case report (Ophthalmology 2016 Nov;123(11):2432)
  • acute myelitis with presence of Zika viral RNA in serum, urine, and cerebrospinal fluid specimens (detected by real-time reverse transcriptase-polymerase chain reaction assay) 9 days after symptomatic Zika virus infection in 15-year-old girl (Lancet 2016 Apr 2;387(10026):1481)
  • fatal encephalitis, confirmed by detection of Zika virus RNA and virus specific antibodies in the cerebrospinal fluid in a 47-year-old woman in Brazil (J Clin Virol 2016 Oct;83:63)
  • sensory polyneuropathy (J Neurol Sci 2016 Oct 15;369:271)

Other complications

Prognosis

Prevention and Screening

Prevention

  • no vaccine or preventive medications are available(2)
  • Centers for Disease Control and Prevention (CDC) recommends enhanced precautions when traveling to regions with local Zika virus transmission (CDC Travel Health Notices 2017 Mar 22)
  • mosquito avoidance (2)
    • key to preventing illness when travelling to endemic or epidemic regions infected
    • advise patients to avoid mosquitoes during viremic phase (first week of illness) to prevent local transmission
  • additional considerations for pregnant women or women trying to become pregnant(4)
    • pregnant women should consider avoiding travel to areas of active transmission
    • mosquito avoidance strategies should be strictly adhered to, if travel undertaken
    • women trying to become pregnant should consult with their healthcare providers before travel
    • several national health agencies have recommended that women postpone pregnancy during the outbreak and avoid travel to regions with active transmission (BMJ 2016 Jan 26;352:i500, BMJ 2016 Jan 21;352:i383)
    • CDC advises that pregnant women should avoid travel to elevations < 2,000 meters (6,562 feet) in regions with active transmission (MMWR Morb Mortal Wkly Rep 2016 Mar 18;65(10):267 full-text)
  • CDC interim guidelines for preconception counseling and prevention of sexual transmission of Zika Virus - United States, 2016 (8)
    • sexual transmission is possible and concern may be highest in pregnancy
    • recommendations for couples in which a woman is pregnant
      • abstain from sexual activity for duration of pregnancy, or
      • consistently and correctly use condoms with any type of intercourse for the duration of pregnancy
    • recommendations for couples who are considering attempting contraception
      • wait at least 6 months after symptom onset or last possible exposure for couples in which a man has Zika virus infection or exposure, regardless of symptom status
      • wait at least 8 weeks after symptom onset or last possible exposure four couples in which a woman has Zika virus infection or exposure, regardless of symptom status
    • recommendations for couples who are not pregnant and are not trying to become pregnant
      • for couples in which a partner has confirmed Zika virus infection or clinical illness consistent with Zika virus disease, or for couples with possible Zika virus exposure
        • consider abstaining from sexual activity or consistently and correctly use condoms during sex
          • for at least 6 months after onset of illness for couples in which a man has Zika virus infection
          • for at least 8 weeks for couples in which a woman has Zika virus infection
    • recommendations for women of reproductive age who do not want to become pregnant, and who have had or anticipate future Zika virus exposure, should use the most effective method of contraception that can be used correctly and consistently
    • testing is not currently recommended for the purposes of assessing transmission risk
  • World Health Organization (WHO) recommends 6 months of safe sex for men and women returning from Zika-active areas, even if they are symptom-free (BMJ 2016 Sep 8;354:i4897)
  • CDC recommends use of standard precautions in healthcare settings for preventing transmission of Zika virus (MMWR Morb Mortal Wkly Rep 2016 Aug 26;65(33):870 full-text)

Guidelines and Resources

Guidelines

International guidelines

  • World Health Organization (WHO)
    • interim guidance update on prevention of sexual transmission of Zika virus can be found at WHO 2016 Sep 6 PDF
    • interim guidance on pregnancy management in the context of Zika virus can be found at WHO 2016 May 13 PDF
    • interim guidance for healthcare providers on psychosocial support for pregnant women and for families with microcephaly and other neurological complications in the context of Zika virus can be found at WHO 2016 Feb 26 PDF
  • Pan American Health Organization (PAHO)
    • Zika ethics consultation: ethics guidance on key issues raised by the outbreak can be found at PAHO 2016 Apr PDF
    • strategy on enhancing national capacity to respond to Zika virus epidemic in the Americas can be found at PAHO 2016 Feb PDF
  • Pan American Health Organization/World Health Organization and World Health Organization guidelines (PAHO/WHO)
    • provisional considerations for the care of pregnant women in setting with high Zika virus circulation can be found at PAHO/WHO 2016 PDF
    • Zika virus (ZIKV) surveillance in the Americas: 2015 interim guidance for laboratory detection and diagnosis can be found at PAHO/WHO 2015 Jun 29 PDF
    • interim guidance on breastfeeding in the context of Zika virus can be found at PAHO/WHO 2016 Feb 25 PDF or in Portuguese PDF
    • preliminary guideline on surveillance of microcephaly in newborns in setting with risk of circulation of Zika virus can be found at PAHO/WHO 2016 PDF
    • guideline on risk communication and community engagement for Zika virus prevention and control can be found at PAHO/WHO PDF, with a step-by-step guide at PAHO/WHO 2016 PDF
  • International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) interim guidance on ultrasound for Zika virus infection in pregnancy: information for healthcare professionals can be found in Ultrasound Obstet Gynecol 2016 Apr;47(4):530

United States guidelines

Canadian guidelines

  • Committee to Advise on Tropical Medicine and Travel (CATMAT) recommendations on prevention and treatment of Zika virus can be found at CATMAT 2016 May 5 PDF

European guidelines

  • Direção-Geral da Saúde guideline on Zika virus disease can be found at DGS 2016 [Portuguese]

Review articles

Additional resources

Patient Information

ICD-9/ICD-10 Codes

ICD-9 codes

  • 066.3 other mosquito-borne fever

ICD-10 codes

  • A92.8 other specified mosquito-borne viral fevers

References

General references used

DynaMed editorial process

  • DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
  • All editorial team members and reviewers have declared that they have no financial or other competing interests related to this topic, unless otherwise indicated.
  • DynaMed provides Practice-Changing DynaMed Updates, with support from our partners, McMaster University and F1000.

Special acknowledgements

  • Davidson H. Hamer, MD, FACP, FIDSA, FASTMH (Professor of Global Health and Medicine, Boston University Schools of Public Health and Medicine; Adjunct Professor of Nutrition, Tufts University Friedman School of Nutrition Science and Policy; Massachusetts, United States)
  • Dr. Hamer declares a financial relationship with Alere, Inc.
  • Renee Ridzon, MD (Adjunct Associate Professor, Boston University School of Public Health; Massachusetts, United States)
  • Allen Shaughnessy, PharmD, M Med Ed, FCCP (Professor of Family Medicine and Director of Master Teacher Fellowship, Tufts University Family Medicine Residency; Cambridge Health Alliance; Massachusetts, United States)
  • Esther Jolanda van Zuuren, MD (Head of Allergy, Dermatology, and Venereology, Leiden University Medical Centre; Netherlands; Editor, Cochrane Skin Group)
  • Alan Ehrlich, MD (Executive Editor; Clinical Associate Professor of Family Medicine, University of Massachusetts Medical School; Massachusetts, United States)
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How to cite

  • National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):
    • DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. 909469, Zika virus infection; [updated 2017 Mar 09, cited place cited date here]; [about 22 screens]. Available from http://search.ebscohost.com/login.aspx?direct=true&db=dnh&AN=909469&site=dynamed-live&scope=site. Registration and login required.

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