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Zika Virus Infection—Commentary

Commentary
02/02/16 Matthew E. Levison, MD, Drexel University College of Medicine|Drexel University;

Recent cable news and newspaper headlines include “WHO sounds strong alarm on Zika virus,” “…linked to severe birth defects in thousands of babies in Brazil,” which is "spreading explosively," “could infect as many as 4 million people in the Americas,” and WHO declares "Global Health Emergency." What is this all about?

What is Zika Virus?

Zika virus (ZV) is a flavivirus similar to the viruses that cause dengue, yellow fever, West Nile fever, and chikungunya disease; like these viruses, ZV is transmitted by the Aedes mosquitoes, Aedes aegypti and Aedes albopictus. A. aegypti, the main epidemic ZV vector, is restricted to the deep South; but A. albopictus, better adapted to colder climates, is present across a large portion of the southeastern US (see map). Although A. albopictus probably is a ZV epidemic vector in the tropics, it is not clear whether it will be an epidemic vector in the more temperate climate of the US.  


Aedes mosquito distribution in US

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What is the Epidemiology of Zika Virus?

ZV was first isolated from monkeys in the Zika Forest in Uganda in 1947, but it was not considered an important human pathogen until the first large-scale outbreaks appeared in the South Pacific islands in 2007. By March 2014, tourists were believed to have carried ZV to Easter Island, about 2,180 miles west of continental Chile. In May 2015, local transmission was first reported in South America, then in Central America, and then in the Caribbean, finally reaching Mexico by late November 2015.

Currently, ongoing local transmission of ZV has been reported in: 1 North American country (Mexico); 9 South American countries (Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Paraguay, Suriname, and Venezuela); 6 Central American countries (Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, and Panama); and 9 Caribbean islands (Barbados, Curacao, Dominican Republic, Guadeloupe, Haiti, Martinique, the Commonwealth of Puerto Rico, Saint Martin, and the U.S. Virgin Islands), for which the US Centers for Disease Control and Prevention (CDC) has issued travel alerts. Also, the CDC has issued a travel alert for Cape Verde, a nation of islands off the northwest coast of Africa, and one for Samoa and American Samoa.

Areas of Zika virus transmission_tn

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Cases of ZV infection (ZVI) have appeared in travelers returning home after visits to places where local transmission is occurring. There have been over 30 documented "travel-associated cases" of ZVI in 11 US states.

During the first week of infection, ZV can be found in blood and passed from an infected person to mosquitoes. If travelers from endemic regions have ZV in their blood on arrival in their home country and competent vector mosquitoes are present, local transmission of ZV is possible. But, because contact between Aedes mosquitoes and people is infrequent in most of the continental US and Hawaii (due to mosquito control and people living and working in air-conditioned environments), local transmission of ZV is expected to be rare and limited. Because dengue also is transmitted by Aedes mosquitoes, ZVI in the mainland US is likely to occur in the same regions in which limited outbreaks of dengue have occurred (parts of Texas and southern Florida and Hawaii). Similarly, in areas of the US where dengue is now endemic (Puerto Rico and the U.S. Virgin Islands in the Caribbean, and American Samoa, Guam, and the Northern Mariana Islands in the Pacific Ocean), ZVI may also become endemic.

Although ZVI is transmitted primarily by mosquitoes, other modes of transmission are possible. There has been one report of possible spread through blood transfusion and one report of possible spread through sexual contact. Transmission of ZV can also occur from mother to child during pregnancy, as with dengue virus, chikungunya virus, West Nile virus, and yellow fever virus. Breast milk transmission has also been reported for dengue and West Nile virus.

What are the Manifestations of Zika Virus Infection?

Only one in five people who become infected with ZV will feel sick. Symptoms of ZVI include: fever, maculopapular skin rash, conjunctivitis (pink eye), pains in joints, pain behind the eyes, headache, and muscle pains (myalgias). Symptoms last 4 to 7days. Most ZVI are mild, but very uncommonly Guillain-Barre syndrome (GBS) may follow ZVI; GBS has also been reported to follow dengue and chikungunya.

The manifestation responsible for most of the alarming headlines is microcephaly (a congenital condition associated with incomplete brain development), which has been linked epidemiologically with ZVI during pregnancy. The time frame and geographic location of reports of infants with microcephaly coincides with the outbreak of ZVI in Brazil. Although reporting was not required at the time and clinical criteria used to define microcephaly were inconsistent, it is notable that < 150 cases of microcephaly were seen in Brazil in 2014 before the ZV, whereas since October 2015 > 4000 cases have been reported there. However, a more intensive analysis of > 700 of those cases confirmed microcephaly in only 270 cases. Only a few cases of microcephaly and congenital ZVI have been laboratory-confirmed. The first case of microcephaly linked to the ZV within the US was reported recently in Hawaii. The child’s mother was probably infected when she lived in Brazil in May 2015, early in her pregnancy.

Patient Evaluation

Because many febrile tropical diseases (eg, malaria, leptospirosis, and other arbovirus infections) produce a clinical picture that is similar to that of ZVI, a diagnosis of ZVI that is suspected based on symptoms and places and dates of travel, requires laboratory confirmation by serologic testing or detection of viral RNA in the patient's serum by reverse transcriptase-polymerase chain reaction (RT-PCR). Virus-specific IgM and neutralizing antibodies typically develop toward the end of the first week of illness, but cross-reaction with related flaviviruses (eg, dengue and yellow fever viruses) is common. However, there are no commercially available diagnostic tests for ZVI, and testing in the US must be done at the CDC. State health departments can facilitate CDC laboratory testing.

The CDC has issued interim guidelines for pregnant women and interim guidelines for infants born to mothers who traveled to or resided in an area with ZV transmission during pregnancy.

These guidelines advise that blood tests be done only for at-risk pregnant women and for their infants after delivery. At-risk pregnant women are those who have both of the following:

  • Travel to an area in which ZVI is common
  • At least 2 symptoms of ZVI during or within 2 wk of travel (acute onset of fever, maculopapular rash, arthralgia, or conjunctivitis)

or

  • Had routine pregnancy ultrasonography that showed microcephaly or calcium deposits within the brain of the fetus

If the blood tests are positive, pregnant women should have ultrasonography to look for abnormalities in the fetus and monitor its growth.

Tests for ZV are not recommended for women who did not travel to an area where ZVI is common.

What’s the Bottom Line?

How likely is there actually an increased incidence of microcephaly? Undoubtedly there is a true increase given the numerous anecdotal reports of Brazilian pediatricians who are witnessing a dramatic increase in the number of cases of microcephaly.

How likely do we think the cause of this increase in microcephaly is ZVI?  The sharp rise in the incidence of microcephaly in Brazil over a short period of time suggests a common cause. The coincidence of the rise in microcephaly with the ZVI outbreak in time and place suggests that ZVI may be the cause, which has been confirmed in a few cases. Much more work has to be done urgently to firm up this association. For example, were the mothers of microcephalic infants infected with ZV during their pregnancy? When during the pregnancy did maternal ZVI take place? Is there evidence for congenital ZVI? Pending definitive proof, it is reasonable to take precautions.

How likely is the ZVI epidemic to continue to grow? The epidemiology of ZVI is similar to that of dengue and chikungunya, two other flaviviral infections transmitted by Aedes mosquitoes. ZVI predictably will spread wherever there is sustained transmission of dengue and chikungunya, unless its transmission is interrupted by an effective ZV vaccine or control of the mosquito population

Prevention: Until more is known, the CDC. has recommended that pregnant women consider postponing travel to places with active ZV transmission (http://www.cdc.gov/zika/pregnancy/question-answers.html).

Canadian Blood Services is asking all potential donors who have traveled anywhere other than Canada, the United States or Europe to delay donating blood until one month after their return. The American Red Cross has not yet taken a similar precaution

There is currently no vaccine to prevent ZVI. Control of this infection depends on control of Aedes mosquitoes and prevention of mosquito bites when traveling to countries where ZV is endemic. The following precautions should be taken:

  • Wearing long-sleeved shirts and long pants
  • Staying in places with air conditioning or that use window and door screens to keep mosquitoes out
  • Sleeping under a mosquito bed net in non-air conditioned environments
  • Using DEET insect repellent on exposed skin surfaces
  • Treating clothing and gear with permethrin insecticide


Dr. Levison is The Manuals' Editorial Board reviewer for Infectious Diseases.