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Zika Virus: Known Unknowns and Unknown Unknowns

Amesh A. Adalja, MD, FACP, FACEP, FIDSA February 19, 2016

The explosive spread of the Zika virus—which before 2015 was considered little more than a travel medicine trivia question—in South America has been declared a public health emergency of international concern because of its association with severe complications such as microcephaly and Guillain-Barré syndrome. This outbreak and the myriad public health actions it has prompted are occurring in a very fluid context in which new facts about the virus and its trajectory are being discovered almost daily. Understanding what is known, and the important questions that remain to be answered, is essential to optimize response to this emerging infectious disease.


The Facts About Zika

Zika virus is not a new virus; it was discovered in Uganda in the 1940s and was known to cause human infections by the 1950s. It is maintained in nature in a cycle that involves Aedes mosquitoes and primates. It is a member of the flavivirus genus of viruses, which also includes West Nile, dengue, and yellow fever. Distinct Asian and African lineages of the viruses exist. 

Infection with Zika occurs primarily through the bite of an Aedes mosquito, and after a 3- to 12-day incubation period symptoms may occur in a minority of those infected—80% experience no symptoms. Fever, myalgias, rash, conjunctivitis, and headache are common symptoms, and these usually abate after 1 week with no long-term sequelae. 

Previous outbreaks have been small but have yielded some information that, in retrospect, hinted at problems that have arisen in the current outbreak. For example, a suggestion of an association with Guillain-Barré syndrome and sexual transmission of the virus were noted in the past.


What Needs to Be Determined About Zika

The biggest question that needs to be answered is what role Zika virus plays in microcephaly. Microcephaly is a condition with several causes, and it will be crucial to isolate causal factors from mere associations when the cases that have been reported in Brazil are adjudicated. While some cases of microcephaly show direct evidence of infection with the virus in fetal tissues, others do not. There has also been evidence of a rise in microcephaly in Brazil before the purported arrival of the virus in the region, raising concern for another cause and for detection bias. Also, microcephaly cases are largely centered in Brazil but not in other countries with Zika transmission. In cases with a more direct link to Zika, understanding the trimester of infection and other possible infectious and noninfectious cofactors will need to be undertaken. A case-control study will be a means to untangle the potential role of Zika.

Similar research will need to be undertaken to determine the role of Zika in neonatal abnormalities of hearing and eyesight, which have also been associated with Zika, as well as Zika’s role in Guillain-Barré syndrome.

Substantive research on the genetic characteristics of the virus circulating in South America will help determine if there has been a viral change underlying the outbreak and its potentially severe associations. Determining the true burden of Zika in areas in which it has been historically endemic will be needed to understand whether infection early in childhood is the norm, precluding the chance for infection during pregnancy occurring. Questions regarding the duration of viral persistence in semen and blood, which will influence guidance, also need answers with full clarity. The role of prior infection with dengue and the ability of antibody-dependent enhancement, a hallmark of dengue, to influence the course of Zika should also be pursued.


Large Numbers

As became apparent during the Ebola outbreak, large outbreaks of infectious diseases allow complications to surface that occur with such rarity as to not be apparent in smaller outbreaks. Answering questions regarding whether what was previously known about Zika was just scratching the surface of the true breadth of infection is of high importance, as it is driving the public health and media response. It is important to determine the answers to the questions highlighted above (and many others) as quickly as possible.