Zika virus infection – 7 Interesting Facts

What is Zika virus infection

Zika virus infection is a self-limiting flavivirus infection mainly transmitted by bites of infected Aedes mosquitoes

Synopsis

Key Points

  1. Zika virus infection is a nationally notifiable disease
  2. Symptoms are generally mild and nonspecific, including headache, rash, myalgia, arthralgia, and mild fever
  3. Diagnosis is typically clinical and confirmed by nucleic acid testing and serologic tests
  4. Treatment is mainly supportive and consists of rest, fluids, and analgesic and antipyretic medication if necessary; acetaminophen is recommended for pregnant women
  5. Coinfection with other flaviviruses, in particular dengue virus and potentially chikungunya virus, has been reported; when dengue fever coinfection is suspected or confirmed, monitor for hemorrhage and avoid NSAIDs
  6. Complications may include Guillain-Barré syndrome and, in infants born to women who contracted infection during pregnancy, congenital Zika syndrome, which is characterized by microcephaly and other developmental nervous system abnormalities
  7. Zika virus infections are typically asymptomatic, and if symptoms are present, they usually resolve within a week; if complications occur, prognosis depends on the respective disease 1

Pitfalls

  • Avoid NSAIDs until dengue fever can be ruled out, to reduce the risk of hemorrhage 1
  • Strong serologic cross reactivity between antibodies and various flavivirus antigens interferes with distinction between Zika virus and dengue virus or other flaviviruses; for example, persons who have received vaccination against yellow fever or Japanese encephalitis may have false-positive results 2
    • Nucleic acid testing can reliably distinguish between different flaviviruses, but in most cases it is suitable only for serum samples obtained up to 5 to 7 days after illness onset
      • An exception is its use in pregnant women up to 12 weeks following symptom onset 3
    • Plaque reduction neutralization assays may help to discriminate between these similar antibodies

Terminology

Clinical Clarification

  • Zika virus infection is a flavivirus infection primarily spread through bites of infected Aedes mosquitoes, causing a mild, nonspecific febrile syndrome 1
    • Self-limiting disease with no symptoms or mild nonspecific symptoms, including mild fever, arthralgia, myalgia, and headache 1
    • Can cause Guillain-Barré syndrome 1
    • Infection during pregnancy is associated with congenital fetal microcephaly and other severe neurologic abnormalities 1
    • Nationally notifiable disease: report suspected cases to state and local health departments and report laboratory-confirmed cases to CDC through ArboNET 1 4

Diagnosis

Clinical Presentation

History

  • 80% of infected patients are asymptomatic 5
  • Symptoms typically are mild and last only a few days to a week; therefore, infected patients often do not seek medical attention 1
  • If patients present with symptoms, these include: 6 7
    • Headache (45%-66%)
    • Arthralgia (63%-65%)
    • Myalgia (61%)
    • Rash (90%-97%)
    • Symptoms of conjunctivitis, including ocular pain or discomfort, discharge, pruritus, and/or dry eyes occur in over half of symptomatic patients
  • Exposure history is essential 8
    • Recent return from or residence in an area with active Zika virus transmission should raise suspicion if presentation includes characteristic signs or symptoms
    • Unprotected sex with a person known to have current or recent infection with the virus or who has recently been in an area with active transmission
    • Incubation period is 3 to 15 days

Physical examination

  • Clinical signs include:
    • Maculopapular eruption (90% or more) 7
    • Conjunctivitis (56%), presenting as conjunctival injection, conjunctival swelling, mild eyelid edema, and/or eyelid erythema 7
    • Fever (36%-65%) 6 7

Causes and Risk Factors

Causes

  • Infection with Zika virus 1
    • Vector-borne infection
      • Primarily transmitted through bite of infected Aedes mosquitoes
        • Aedes mosquitoes typically bite both day and night, peaking during early morning and late afternoon/evening
    • Direct (human-to-human) transmission
      • Sexual 9
        • Transmission from persons with laboratory-confirmed Zika virus infection to their sexual partners has been documented
          • Male-to-female transmission is most common, but female-to-male and male-to-male transmission have been reported 10
      • Through blood and possibly other bodily fluids
        • Several cases of transfusion transmission have been documented 11
          • During the 2013 to 2014 outbreak in French Polynesia, 2.8% of blood donors tested positive for Zika virus 12
        • Stem cell, tissue, or organ transplant 13
          • Assumed to be a risk factor; however, there are no documented cases of transmission through transplant of hematopoietic stem or progenitor cells, tissue, or solid organs 13
    • Congenital and perinatal infection
      • Intrauterine infection 14
        • Infection during pregnancy has been associated with fetal abnormalities including fetal microcephaly, intracranial calcifications, and abnormal cerebral artery flow, as well as intrauterine growth restriction and fetal death 14
      • Intrapartum infection is thought to be a possibility through the exchange of blood and bodily fluids during delivery
      • Virus has been detected in breast milk, but transmission through breastfeeding has not been reported 15

Risk factors and/or associations

Other risk factors/associations
  • Residence in or travel to an area with active Zika virus transmission 16
    • Before 2007, Zika virus infections were rare and only known to occur in tropical Africa, Southeast Asia, and the Pacific Islands 17
    • In 2007, a large outbreak occurred on the western Pacific Island of Yap in the Federated States of Micronesia 17
    • Brazil experienced an extensive outbreak in 2015 17
    • Since then, numerous outbreaks have occurred and have reached US territories; American Samoa, Puerto Rico, and US Virgin Islands have all experienced outbreaks of locally acquired disease 18
    • In July 2016, CDC officials confirmed locally acquired cases of Zika virus disease in Florida and Texas 19
    • Travel-related cases have been reported throughout the United States 20

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis is based on symptoms coupled with recent exposure or history of travel to areas with active virus transmission; it can be confirmed only by laboratory testing 2
  • For symptomatic, nonpregnant individuals:
    • For patients who present within 14 days of symptom onset, nucleic acid tests of blood serum and urine are recommended 21
      • Positive result for either test confirms Zika virus infection
      • If results from both nucleic acid tests are negative, perform IgM serologic tests 22
    • For patients who present more than 14 days after onset of symptoms, perform IgM serologic tests
  • For all diagnostic testing conducted on specimen types other than patient-matched serum and urine, it is necessary to concurrently obtain a patient-matched serum specimen for nucleic acid testing and/or IgM (serology) testing, as appropriate 22
  • Test pregnant women with recent possible Zika virus exposure and symptoms of Zika virus disease to diagnose the cause of their symptoms; concurrent nucleic acid tests (serum and urine) and serologic testing (serum) are recommended for pregnant women as soon as possible, through 12 weeks after symptom onset 3
  • Offer Zika virus nucleic acid test 3 times during pregnancy to asymptomatic pregnant women with ongoing possible Zika virus exposure 3
  • Zika virus testing is not routinely recommended for asymptomatic pregnant women who have been exposed but who do not have ongoing exposure, although it may be considered in some circumstances 3
  • Zika virus IgM testing as part of preconception counseling to establish baseline IgM results for nonpregnant women with ongoing possible Zika virus exposure is not warranted because Zika virus IgM testing is no longer routinely recommended for asymptomatic pregnant women with ongoing possible Zika virus exposure 3
  • CBC is not diagnostic, but if done may reveal thrombocytopenia 23
  • When Zika virus testing is indicated, consider also testing for dengue and chikungunya viruses
    • These diseases circulate in the same geographic areas and are transmitted by the same vector
    • Particularly consider testing for dengue virus, which can cause life-threatening illness

Laboratory

Differential Diagnosis

Most common

  • Chikungunya (Related: )Chikungunya virus disease
    • Viral infection primarily transmitted through bite of same mosquitoes that spread Zika virus, with acute onset of fever and severe polyarthralgia 25
    • Similar symptoms and signs: fever, maculopapular rash, arthralgia, myalgia, headache, and conjunctivitis 25
    • Differentiating symptoms: high fever (higher than 39°C), severe polyarthralgia, nausea, and vomiting 25
    • Diagnosed by nucleic acid testing, ELISA to detect IgM antibody against chikungunya virus, and plaque reduction neutralization tests 25
  • Dengue (Related: ) 26Dengue virus infection
    • Dengue infection is caused by any of 4 dengue virus serotypes, primarily transmitted through bite of same mosquitoes that spread Zika virus 26
    • Dengue infection can have 3 different clinical presentations: 26
      • Undifferentiated fever, typically at first contact with dengue virus 26
        • Symptoms identical to Zika virus infection 26
      • Dengue fever or dengue hemorrhagic fever 26
        • Similar symptoms and signs: myalgia, arthralgia, and maculopapular rash 26
        • Differentiating symptoms and signs: high fever (higher than 39°C), severe headache, retro-orbital eye pain; more severely ill patients have dyspnea, peripheral edema, and hemorrhage 26
      • Dengue shock syndrome 26
        • Potential consequence of dengue hemorrhagic fever characterized by extensive hemorrhage and hemodynamic collapse 26
    • Diagnosed by nucleic acid testing, ELISA (to detect IgM antibody against dengue virus), and plaque reduction neutralization tests (to confirm identity of antibody) 26

Other acute febrile syndromes

  • Malaria27
    • Disease caused by plasmodial parasites transmitted by anopheles mosquitoes 27
    • Similar symptoms: fever, myalgia, and headache 27
    • Differentiating symptoms and signs: cyclic fever, abdominal pain (variable); rash is not a typical feature 28
    • Diagnosis is confirmed by microscopic identification of parasites in RBCs, immunochromatographic testing, and nucleic acid testing 28
  • Tick-borne rickettsial diseases 29
    • Tick-transmitted bacterial infection causing nonspecific severe symptoms, sometimes with life-threatening complications 29
    • Similar symptoms: fever, maculopapular rash, myalgia, and headache 29
    • Differentiating signs and symptoms: eschar may be visible at site of tick bite
    • Diagnosed by indirect immunofluorescence antibody assay, blood smear microscopy, nucleic acid testing, and ELISA 29
  • Yellow fever 30
    • Viral infection transmitted by mosquitoes and characterized by sudden onset of fever; endemic areas are limited to parts of Africa and South America 30
    • Similar symptoms: fever and headache 30
    • Differentiating symptoms and signs: high fever (up to 40°C) occurs in some; severe infection characterized by jaundice, bleeding, and multiorgan failure may occur; rash is not a typical feature 30
    • Diagnosis is confirmed by ELISA to detect IgM antibody against yellow fever virus and plaque reduction neutralization tests 30

Treatment

Goals

  • Treatment is generally supportive 1
    • Alleviate symptoms such as fever, arthralgia, and myalgia 1

Disposition

Admission criteria

  • Patients suffering from severe dehydration require hospital admission and administration of IV fluids

Recommendations for specialist referral

  • Testing for Zika virus should be performed only by licensed public health laboratories with experience in these tests
  • Referral to an infectious disease specialist is not necessary but is strongly recommended, particularly for diagnosis
    • Fever in a returning traveler with or without mosquito exposure is a diagnostic challenge
  • For pregnant women at risk for Zika virus infection (because of travel to or residence in an endemic area or because of unprotected sex with partner at risk for infection): refer to obstetrician or maternal-fetal health specialist 31

Treatment Options

Treatment is only supportive, consisting of: 1

  • Rest 1
  • Adequate hydration 1
  • Analgesics and antipyretics, if necessary to control symptoms 1
    • For pregnant women, acetaminophen is recommended 31
    • Avoid NSAIDs until dengue fever can be ruled out, to reduce risk of hemorrhage associated with this condition 1
  • No specific antiviral treatment is available 1

Drug therapy

  • Analgesics/antipyretics 1
    • Acetaminophen 31

Nondrug and supportive care

Rest is recommended for all patients 1

Adequate hydration 1

  • In patients who become dehydrated, hospitalization may be necessary
  • Oral and/or IV fluids can be administered

Comorbidities

  • Coinfection with other flaviviruses (dengue virus in particular) and chikungunya virus has been reported 32
    • Treatment of patients infected with 1 or more of these viruses is similar, mainly consisting of rehydration, analgesics, and antipyretics, as necessary 25 26
    • Patients with dengue virus infection must be closely monitored, in anticipation of transition into hemorrhagic phase 26
      • During hemorrhage, transfusion of volume-replacing blood products may be necessary
      • Fluids must be administered judiciously, because increased capillary permeability is characteristic of dengue
    • Avoid NSAIDs unless dengue fever has been ruled out, to reduce risk of hemorrhage 1

Special populations

  • Pregnant women, whether symptomatic or not
    • All pregnant women in the United States and US territories should be asked about possible Zika virus exposure before and during the current pregnancy, at every prenatal care visit 3
    • Pregnant women with recent possible Zika virus exposure and symptoms of Zika virus disease should be tested to diagnose the cause of their symptoms 3
      • Updated recommendations include concurrent Zika virus nucleic acid and serologic testing as soon as possible through 12 weeks after symptom onset 3
    • Asymptomatic pregnant women with ongoing possible Zika virus exposure should be offered Zika virus nucleic acid test 3 times during pregnancy 3
      • Offer nucleic acid test for pregnant women without a prior laboratory-confirmed diagnosis of Zika virus at the initiation of prenatal care; if Zika virus RNA is not detected on clinical specimens, offer 2 additional tests during the course of the pregnancy coinciding with prenatal visits 3
      • IgM testing is no longer routinely recommended because IgM can persist for months after infection; therefore, IgM results cannot reliably determine whether an infection occurred during the current pregnancy 3
      • Additional Zika virus testing is not recommended for pregnant women who have received a diagnosis of laboratory-confirmed Zika virus infection (by either nucleic acid test or serology [positive/equivocal Zika virus or dengue virus IgM and Zika virus plaque reduction neutralization test results (PRNT) 10 or higher and dengue virus PRNT under 10]) any time before or during the current pregnancy 3
    • Asymptomatic pregnant women who have recent possible Zika virus exposure (ie, through travel or sexual exposure) but without ongoing possible exposure are not routinely recommended to have Zika virus testing, although testing may be considered on a case-by-case basis 3
      • With the decline in the prevalence of Zika virus disease, recommendations for the evaluation and testing of pregnant women with recent possible Zika virus exposure but without ongoing possible exposure are now the same for all areas with any risk for Zika virus transmission 3
    • Pregnant women who have recent possible Zika virus exposure and who have a fetus with prenatal ultrasound findings consistent with congenital Zika virus syndrome should receive Zika virus testing to assist in establishing cause of birth defects 3
      • Testing should include both nucleic acid and IgM tests 3
    • Zika virus IgM testing as part of preconception counseling to establish baseline IgM results for nonpregnant women with ongoing possible Zika virus exposure is not warranted because Zika virus IgM testing is no longer routinely recommended for asymptomatic pregnant women with ongoing possible Zika virus exposure 3
  • Testing is recommended for infants born to mothers with laboratory-confirmed Zika virus infection and for infants with abnormal clinical or neuroimaging findings suggestive of congenital Zika syndrome with a possible or confirmed maternal Zika infection 33
    • Send placental specimens to be examined with reverse transcription polymerase chain reaction and with histopathology for evidence of infection 33
    • Obtain infant serum and urine specimens within 2 days of birth and send for Zika IgM and nucleic acid testing 33
      • Positive result on nucleic acid test confirms congenital Zika virus infection
      • Positive result on Zika IgM antibody capture ELISA and negative result on nucleic acid test indicate possible congenital Zika virus infection 33

Monitoring

  • In infants with confirmed Zika virus infection or born to mothers with confirmed infection, arrange examination by an experienced pediatrician and monitor for ophthalmic, neurologic and developmental defects 33
  • Serial fetal ultrasonograms (eg, every 3 to 4 weeks) should be considered for women who have Zika virus infection during pregnancy 3

Complications and Prognosis

Complications

  • Infection during pregnancy can result in fetal abnormalities, including fetal microcephaly, intracranial calcifications, and abnormal cerebral artery flow, ocular abnormalities, sensorineural hearing loss, and arthrogryposis, as well as intrauterine growth restriction and fetal death 14 34
    • Degree of risk has not yet been established; frequency of congenital infection and of congenital Zika syndrome among infants born to women infected during pregnancy is unknown at present
    • It is likely that congenital infection in earlier stages of pregnancy results in more severe anomalies than that acquired toward end of pregnancy
    • It has been recognized that infants with congenital infection who have normal head size at birth may develop microcephaly and other complications over time 35
  • Guillain-Barré syndrome 36
    • During the 2013 outbreak of Zika virus infections, French Polynesia experienced an increase in Guillain-Barré syndrome cases; in a case-control study during this outbreak, all 42 patients with Guillain-Barré syndrome tested positive for Zika virus infection 36
    • An outbreak of Guillain-Barre syndrome associated with Zika virus infection has also been documented in Colombia in 2016 37
  • Zika virus–associated meningoencephalitis 38 and myelitis 39 have been reported but are rare

Prognosis

  • Infection is typically asymptomatic; symptomatic infection usually resolves within 2 to 7 days 1
  • In case of complications, such as Guillain-Barré syndrome or fetal neurologic complications, prognosis varies greatly, according to the respective condition 17
  • There is very limited experience with Zika virus infection in immunocompromised patients; available data suggest that response and prognosis are largely similar to those of immunocompetent patients
  • Latency of infection is not established and is unknown at this time; latency in flavivirus infections generally is rare, but it has been demonstrated in some viruses (eg, Japanese encephalitis virus) 40
  • It is not known whether infection results in protective immunity

Screening and Prevention

Screening

At-risk populations

  • CDC does not recommend screening of nonpregnant persons who live in or have traveled to areas of ongoing Zika virus transmission 16
  • Asymptomatic pregnant women with ongoing possible Zika virus exposure should be offered Zika virus nucleic acid test 3 times during pregnancy 3
  • Asymptomatic pregnant women with possible recent exposure to Zika virus (ie, through travel or sexual exposure) but without ongoing possible exposure are not routinely recommended to have Zika virus testing 3
  • Zika virus IgM testing as part of preconception counseling to establish baseline IgM results for nonpregnant women with ongoing possible Zika virus exposure is not warranted because Zika virus IgM testing is no longer routinely recommended for asymptomatic pregnant women with ongoing possible Zika virus exposure 3

Screening tests

  • Nucleic acid testing 3

Prevention

  • No vaccine or preventive medication against Zika virus infection is available currently 1
    • Several vaccine candidates are in various stages of development and animal/human testing
  • Prevention of mosquito bites reduces risk of contracting Zika virus infection 1
    • Advise patients to eliminate standing water where mosquitoes can breed (eg, flower pots, trash cans, discarded tires); eliminating standing water and spraying insecticides are part of the efforts to reduce the mosquito population 41
    • Advise use of intact screens for doors and windows (or air conditioning)
    • Advise use of mosquito repellents, including DEET (diethyltoluamide), icaridin (picaridin), oil of lemon eucalyptus, and ethyl butylacetylaminopropionate (IR3535)
      • Mosquito repellents are safe during pregnancy, but do not use them on infants younger than 6 months. Do not use oil of lemon eucalyptus on children younger than 3 years
    • Advise avoidance of outdoor activities or use of protective clothing (eg, long sleeves, full-length pants, socks) treated with permethrin
  • Precautions during pregnancy and for couples contemplating pregnancy: 14
    • CDC recommends that pregnant women not travel to any area with risk for Zika virus transmission 3
    • CDC recommends that pregnant women with a sex partner who has traveled to or lives in an area with risk for Zika virus transmission use condoms or abstain from sex for the duration of the pregnancy 3
    • Advise persons living in areas where local transmission of Zika virus occurs to consider postponing pregnancy or adopting stringent precautions against mosquito exposure
    • Advise women with symptomatic Zika infection not to attempt conception for 8 weeks after symptom onset
    • Advise men who have had symptomatic infection not to attempt conception for 3 months after onset of symptoms 42
      • Counsel men with symptomatic infection to refrain from sex with pregnant partner or to use condoms for duration of pregnancy
    • Advise travelers returning from areas of Zika activity who do not develop symptoms of Zika infection to delay attempting conception:
      • For women, until 8 weeks after last possible exposure 43
      • For men, until 3 months after last possible exposure 42
  • To minimize risk of transmission by blood transfusion or tissue donation, FDA has issued guidelines on donor screening 44
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