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Ahead of Print: Epidemiologists Are Tracking Possible Links Between Zika Virus and Guillain–Barré Syndrome


Public health officials in the United States are gearing up surveillance efforts following reports that potentially link the Zika virus to an increased risk of Guillain–Barré syndrome (GBS) and microcephaly in fetuses and newborns.

Zika, a mosquito-borne virus, has been tracked to 21 countries and territories in South America, Central America, and the Caribbean, mostly in the last two months. At press time, two cases of Zika virus were detected in the US Virgin Islands and Puerto Rico.

The Centers for Disease Control and Prevention (CDC) has issued a travel advisory, warning pregnant women to avoid travel to these regions, and has asked health care professionals and state and local public health departments to report flu like-symptoms or GBS in patients (including pregnant women) who have traveled to and from the countries affected.

The "unusual and unexpected neurological manifestations are very troubling," James Sejvar, MD, a neurologist and epidemiologist at the CDC, told Neurology Today. "We are working hard to understand the virus and prevent its spread."

Dr. Sejvar is now in Brazil heading a team studying the epidemic to learn more about how the virus is associated with GBS and microcephaly.

At press time, the Zika virus had been detected in one person in Puerto Rico without a history of travel, and an infant in Hawaii born with microcephaly had evidence of Zika infection. According to public health officials, the mother was living in Brazil while pregnant.

Eighty percent of people infected with the Zika virus remain asymptomatic and 20 percent develop a mild flu-like illness that can last a week and include fever, rash, joint pain, and conjunctivitis. It is not yet known how often someone infected with the virus will go on to develop GBS; nor is the risk known for microcephaly in babies born to women exposed in pregnancy.

Daniel Pastula, MD, MHS, a neurologist and medical epidemiologist at the University of Colorado School of Medicine, told Neurology Today that Zika virus is transmitted from certain Aedes species of mosquitoes to humans. If an infected person gets bit by another Aedes mosquito, then that mosquito becomes infected and can spread the virus to other humans, creating a human-mosquito-human transmission cycle.

There are no current disease-modifying treatments or vaccines against Zika virus disease, he noted, adding that prevention is key. People can avoid mosquito bites "by wearing long sleeved-shirts and pants when feasible, applying insect repellent when outdoors, and using window screens and air conditioning when indoors," he said.

So far, outside of Puerto Rico, there are no reports of local Zika virus transmission on American soil. But it is only a matter of time before new areas are affected, experts agree. And the neurological signs have health officials worried.



Beginning in 2013, Zika virus disease started spreading throughout islands of the Pacific Ocean, affecting residents French Polynesia. Epidemiological evidence suggested that tens of thousands of people, or 10 percent of its inhabitants, were exposed to the virus. Those who got sick had only mild flu-like symptoms. But a few weeks after the symptoms subsided, medical centers began seeing a growing number of people presenting with GBS.

"It was magnitudes higher than normal," Dr. Sejvar said.  The island had another outbreak in 2014. Again, GBS escalated. Three thousand miles away, cases were detected in New Caledonia, and that same year, another GBS cluster was reported in Fiji.

Dr. Sejvar led a team that traveled to Fiji in 2014 but by the time they arrived it was not possible to definitively detect the virus in the serum of the patients who went on to develop GBS. Fiji was in the throes of a large dengue epidemic, which made interpretation of serologic results challenging because of cross-reactivity between the flaviviruses. From February to May, the island country had nine documented cases of GBS, which was up to five times the expected number.

By May 2015, local transmission of Zika virus was first reported in Brazil. Dr. Sejvar said that it is not clear how the virus arrived in Brazil; some hypothesize that Zika virus could have been carried into the country through someone who traveled there for the World Cup in June 2014. Hundreds of thousands of people, maybe millions, were infected with the Zika virus, he said. About 30,000 people developed mild flu-like symptoms. The peak of the infectivity may have been in the summer of 2015, he said, pointing out that around that time clinicians in northern Brazil started reporting higher than normal rates of GBS.

The CDC immediately launched a co-investigation with the Brazil Ministry of Health. In November, Dr. Sejvar arrived for initial discussions with the Ministry to review their data and assess the situation.  During these meetings, the Ministry demonstrated there was an approximate two to three week lag between the peak of reported Zika cases and the development of GBS.

"It was very convincing," said Dr. Sejvar. "At that time the country had PCR testing, which detects Zika-specific RNA during the early stages of illness.  However, by the time a person develops GBS signs, it is too late to find viral RNA in biological specimens from patients."

Dr. Sejvar completed his assessment and flew back to the US. Dr. Sejvar recommended to the Brazilian Ministry of Health that CDC epidemiologists return to conduct a case-control serological study; that study began last month.

There are 45 reported GBS cases in the state of Bahia in northern Brazil. Dr. Sejvar and his team are taking blood samples from these patients and an equal number of age-matched controls to conduct antibody tests for an immunoglobulin-G (IgG) response to the virus. These tests will be done at CDC facilities in Fort Collins, CO, and Atlanta.

"Given the fact that Brazil has only seen the Zika virus for one year, the IgG response should be a good indication of infectivity and tell us whether they had been exposed to Zika, though there are concerns about cross-reactivity of these antibodies to dengue," Dr. Sejvar said. The team will also test to determine whether the sera from people who developed GBS neutralizes or kills the Zika virus in culture.

A separate team from the United States is traveling to train local health practitioners to conduct serological testing in Brazil.

El Salvador also reported 46 cases of GBS in a one-month period from December to early January, Dr. Sejvar said. Two of these patients died. Normally, the country sees four cases a month. CDC epidemiologists were able to look at medical information on 22 of these patients and half of them had reported a fever and rash a few weeks before the onset of GBS.

Dr. Sejvar stressed that there are temporal and spatial links between the virus and GBS. A direct link is still being investigated. In French Polynesia, there were reports of other neurological conditions — meningitis, meningoencephalitis, and myelitis — in addition to GBS.  



It is not known whether Zika virus is directly responsible for microcephaly, but there is increasing evidence of a possible association. As of January, there have been as many as 3,893 women in Brazil who gave birth to a child with microcephaly. The government began testing for Zika infections in the mothers and found a high number of them reported being ill with the classic fever and rash during the pregnancy. The country usually documents, on average, 163 cases a year. Tissue from two fetuses lost during the pregnancy and two newborns who died within the first day of life tested positive for the Zika virus. All four had smaller than normal brains.

Local Brazilian scientists also found Zika virus in the amniotic fluid of two pregnant women and in the placenta of another woman who miscarried. The CDC is now seeking approvals from the Brazilian Ministry of Health to conduct a case control study to see if they can link the two conditions and learn more about how the virus might be causing birth defects.

The fetal and newborn tissue that was studied showed damage to the developing brain, Cynthia Moore, MD, PhD, director of the CDC's division of birth defects and developmental disabilities, said at a press briefing in mid-January.

 "It's very hard to say how much of an increase it [microcephaly] is," she said. "We're also seeing babies who have severe microcephaly, much more than we would expect."

 It seems that the mother's exposure [to Zika] was often during the first and second trimester, although studies are still underway, Dr. Moore said.

Lyle Petersen, MD, MPH, director of the division of vector-borne diseases in the National Center for Emerging and Zoonotic Infectious Diseases, added at the briefing: "I think we're just going to have to wait to see how this all plays out. These viruses certainly can spread in populations for some time. But, again, this is new. I think it's really impossible for us to speculate what may happen in three or four (weeks) or even next month for that matter."

J. David Beckham, MD, an associate professor at University of Colorado School of Medicine's division of infectious diseases, studies the pathogenesis of viral infections in the central nervous system, and is getting the proper regulatory approvals to begin testing Zika virus. His lab has focused on West Nile and other flaviviruses. When the Zika virus first emerged, Dr. Beckham contacted Aaron Brault, PhD, a virologist at the CDC, to collaborate on developing a model system for how the vector moves from source to source, and then study how it affects neurons. Dr. Beckham and his colleagues developed a laboratory model of the West Nile virus and he is hoping to do the same with the Zika virus.

"There are a lot of unanswered questions," said Dr. Beckham. "Right now, there is an epidemiological association. This has everyone in our field very concerned."






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