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Editorial
October 03, 2016

Zika Virus—A Public Health Emergency of International Concern

Author Affiliations
  • 1Department of Neurology, University of Chicago, Chicago, Illinois
JAMA Neurol. Published online October 3, 2016. doi:10.1001/jamaneurol.2016.3677

In 1982, the late father of neurovirology, Richard T. Johnson, wrote:

Virology will not become a static field. Patterns of infection and disease are altered by many variants, including animal behavior, genetic variation and human intervention. These are most obvious in diseases spread by arthropods and vertebrates.…The rapid changes of modern society and the almost infinite genetic variability of viruses continue to promise a changing scene of unpredictable events.1

How prescient of Johnson to realize at that time that we were in store for continuing epidemics of emerging viruses. Since then, we have seen outbreaks of human immunodeficiency virus, Norwalk virus, Hantavirus, Lassa virus, West Nile virus, Ebola virus, dengue virus, chikungunya virus, and now Zika virus. Emerging viruses such as Zika virus can conquer new lands as a result of global traffic of vectors or hosts. These emerging viruses usually come from an existing pathogen or, at times, a new sequence variant of the pathogen.

Our ability to stop the spread of emerging infections is unfortunately limited. The failure to contain epidemics is described in Edgar Allan Poe’s anxiety-producing “The Masque of the Red Death.”2 Poe presents a frightening scenario in which Prince Prospero secludes himself and a thousand friends from a fatal pestilence within walls that have gates of iron, only to have a masked spectral figure enter into the Prince’s celebration “like a thief in the night.” The story ends with overwhelming destruction: “And Darkness and Decay and the Red Death held illimitable dominion over all.”2

Fortunately, Zika virus is likely to be controlled in a reasonable time, both because it has become a focus of the scientific and medical communities and because critical tools for experimental studies are now available, such as experimental models of Zika virus infection.3 Zika virus was first isolated in the Zika forest in Uganda in 1947 from rhesus monkeys caged on platforms for yellow fever virus research investigations.4 The first major outbreak was recognized in the Yap Islands in Micronesia in 2007, followed later by an outbreak in French Polynesia. The most recent cause for concern is an outbreak in Brazil that began in April 2015. Since then, there have been thousands of cases of microcephaly and central nervous system (CNS) developmental abnormalities in the Americas that may be associated with Zika virus infection. On January 26, 2016, the Director-General of the World Health Organization declared, “Last year, the virus was detected in the Americas, where it is now spreading explosively. As of today, cases have been reported in 23 countries and territories in the region.”5 This situation prompted the World Health Organization on February 1, 2016, to designate the Zika virus epidemic “A Public Health Emergency of International Concern.”

Zika virus is an arthropod-borne flavivirus (as are yellow fever virus, dengue virus, and West Nile virus), which is transmitted primarily through the bite of an Aedes mosquito.68 The virus can be present in body fluids, including blood, urine, semen, saliva, spinal fluid, amniotic fluid, and breast milk. The virus can be spread through the placenta, during sex (vaginal, anal, and oral), and via blood transfusion. In approximately 20% of those infected, Zika virus can cause fever, a maculopapular rash, arthralgia, and conjunctivitis. The virus is neurotropic and can lead to microcephaly and a variety of other CNS-based and systemic congenital abnormalities. The devastating effect on fetuses is demonstrated by Melo et al9 in this issue of JAMA Neurology.

Zika virus infection has also been associated with Guillain-Barré syndrome (GBS). A recent article reported on a series of 42 patients who developed GBS during the outbreak of Zika virus in French Polynesia.10 Thirty-seven of 42 patients (88.1%) developed neurological symptoms a mean of 6 days after becoming infected. Of note, neurophysiological studies of these patients suggested acute motor axonal neuropathy rather than acute demyelinating inflammatory polyradiculoneuropathy.

As is true of many viral infections, Zika virus infection has raised sociopolitical, economic, public health, and ethical issues. Questions have arisen about the advisability of attending the 2016 Summer Olympics and about the appropriate level of research funding. In Zika virus–infected areas and among travelers from these areas, concerns have arisen related to the safety of blood transfusions and breast feeding, the need for contraception and postponement of pregnancy, and the possible abortion of fetuses affected by the virus.

Although we have limited ways to stop emerging pathogens, we now have powerful techniques to quickly identify the culprit, such as polymerase chain reaction and whole genome sequencing. We also have novel methods to control vectors and produce vaccines in an accelerated time frame. It is reassuring to know that there are now at least 18 manufacturers and institutions pursuing the development of a Zika virus vaccine.11 However, issues may complicate the development of a successful Zika virus vaccine. There may be difficulty in raising Zika virus neutralizing antibodies in dengue virus–endemic areas because of the serological cross-reactivity between these 2 viruses. In addition, exposure to Zika virus after vaccination may lead to immunological enhancement, as when secondary dengue virus infection leads to more severe illness than following primary infection with dengue virus.

Many unanswered questions remain. How frequently does asymptomatic infection or second- and third-trimester infection lead to CNS disease? Is Zika virus–induced GBS the typical immune-mediated disease or is there a direct virus invasion? What are the long-term sequelae of intrauterine Zika virus infection? What is the reason for the substantial size, severity, and unexpected complications of the recent Zika virus outbreak in the Americas compared with what has been seen with this virus in the past? Is it a result of immunological enhancement from prior dengue virus exposure in this population12 or has there been a key sequence change in the virus genome making it more neurovirulent? Or a proliferation or increase in the range of mosquitos in the area? And a broader question: how many CNS birth defects presently of unclear cause will be found to be virus-induced?

Another important question to answer is what we can do as neurologists. It would be valuable to have adult and pediatric neurologists network with the US Centers for Disease Control and Prevention to establish a surveillance system that could track Zika virus–induced GBS and CNS disease. This would facilitate the identification and characterization of disorders, the formation of a registry, and the mounting of comprehensive epidemiological studies. This approach would also help to identify long-term sequelae of intrauterine infection and clarify effective treatments of the GBS syndrome. Now is the time to make plans and strategies regarding Zika virus studies.

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Article Information

Corresponding Author: Raymond P. Roos, MD, Department of Neurology, University of Chicago, 5841 S Maryland Ave, MC2030, Chicago, IL 60637 (rroos@neurology.bsd.uchicago.edu).

Published Online: October 3, 2016. doi:10.1001/jamaneurol.2016.3677

Conflict of Interest Disclosures: None reported.

References
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Johnson  RT. Viral Infections of the Nervous System. New York, NY: Raven Press; 1982.
3.
Lazear  HM, Govero  J, Smith  AM,  et al.  A mouse model of Zika virus pathogenesis. Cell Host Microbe. 2016;19(5):720-730.
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World Health Organization. Zika virus. http://www.who.int/topics/zika/en/. Accessed July 1, 2016.
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Cugola  FR, Fernandes  IR, Russo  FB,  et al.  The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534(7606):267-271.
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Lazear  HM, Diamond  MS.  Zika virus: new clinical syndromes and its emergence in the western hemisphere. J Virol. 2016;90(10):4864-4875.
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Melo  AS, Aguiar  RS, Amorim  MMR,  et al.  Congenital Zika virus infection: beyond neonatal microcephaly  [published online October 3, 2016]. JAMA Neurol. doi:10.1001/jamaneurol.2016.3720
10.
Cao-Lormeau  VM, Blake  A, Mons  S,  et al.  Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet. 2016;387(10027):1531-1539.
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World Health Organization. Current Zika product pipeline. http://www.who.int/csr/research-and-development/zika-rd-pipeline.pdf. Accessed July 1, 2016.
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Dejnirattisai  W, Supasa  P, Wongwiwat  W,  et al.  Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nat Immunol. 2016;17(9):1102-1108.
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