Tuesday, March 1, 2016

Zika virus and Guillain-Barre syndrome

Researchers suspected that the Zika virus causes Guillain-Barré syndrome (GBS), a rare neurological syndrome, but now there’s actual proof of the relationship.

The association between Zika and 
microcephaly has received a lot of media attention recently, but there is another serious condition in connection with the mosquito-borne illness. According to a report from the World Health Organization (WHO), five of the more than 30 countries with ongoing local Zika transmission – Brazil, Colombia, El Salvador, Suriname, and Venezuela –experienced a 19% increase in GBS cases in 2015, compared with 2014. Up until recently, the connection has been circumstantial.

However, a collaborative team of researchers has uncovered the first evidence that shows a link between Zika and GBS and their 
results are published in a recent issue of The Lancet.

GBS is a rare neurological disorder that causes the immune system to attack the nerves. Patients commonly experience fatigue, fast heart rate, and shortness of breath. However, the primary concern is weakness and tingling in the lower body that then spreads throughout. In serious cases, muscle weakness can turn into paralysis. In the report, the team states that about 20% to 30% of patients with GBS experience respiratory failure and 5% die from the condition.

During the 2013 – 2014 Zika outbreak in French Polynesia, there was an increase in cases of GBS. Around 32,000 people sought medical attention for possible Zika infection. Blood samples taken between November 2013 and February 2014 identified 42 patients with GBS.

Two control groups were gathered – the first consisted of 98 people who went to the hospital with an illness without fever who were matched for age, gender, and island of residency and the second included 70 people who tested positive for Zika, but did not develop symptoms of GBS.

According to the report, 88% of the patients with GBS had Zika symptoms about six days before neurological symptoms occurred. None of the 42 patients tested positive for Zika by the time they were admitted to the hospital, however, 41 of them (98%) had Zika antibodies and all of them had neutralizing antibodies against the virus. In the first group of controls, 54 of the 98 patients (56%) had Zika neutralizing antibodies.

The patients with GBS were hospitalized for an average of 11 days; but for 16 individuals (38%) who were admitted to the intensive care unit, their average stay was 51 days. Twelve of the patients required breathing assistance. Three months after leaving the hospital, 24 patients (57%) were able to walk without help. No deaths were reported.

Because the dengue virus, another mosquito-borne illness, is also common in the French Polynesia, the researchers wanted to see if it was also a risk factor for GBS. About 95% of patients with GBS had signs of previous dengue infection (88.8% and 82.9% of patients in control groups 1 and 2, respectively, did as well). Since the history of dengue infection did not differ much between Zika and non-Zika patients, the researchers determined that the virus does not impact the risk of developing GBS due to Zika.

Based on the findings of The Lancet study, more GBS cases can be anticipated in the upcoming months. This data should be taken with some caution, however, since it is unknown whether the 2013 – 2014 Zika strain is the same as the current outbreak.

The team estimates that 24 out of 100,000 people infected with the Zika virus will develop GBS.

“This is the first study to look at a large number of patients who developed Guillain-Barré syndrome following Zika virus infection and provide evidence that Zika virus can cause GBS,” lead author Arnaud Fontanet, MD, from the Institut Pasteur in Paris, France, said in a news release.

“The results of our study support that Zika virus should be added of the list of infectious pathogens susceptible to cause Guillain-Barré syndrome,” Fontanet affirmed. 



Van-Mai Cao-Lormeau, Alexandre Blake, Sandrine Mons, Stéphane Lastère, Claudine Roche, Jessica Vanhomwegen, Timothée Dub, Laure Baudouin, Anita Teissier, Philippe Larre, Anne-Laure Vial, Christophe Decam, Valérie Choumet, Susan K Halstead, Hugh J Willison, Lucile Musset, Jean-Claude Manuguerra, Philippe Despres, Emmanuel Fournier, Henri-Pierre Mallet, Didier Musso, Arnaud Fontanet, Jean Neil, Frédéric Ghawché.  Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study.  Lancet.  Published online February 29, 2016.

Background Between October, 2013, and April, 2014, French Polynesia experienced the largest Zika virus outbreak ever described at that time. During the same period, an increase in Guillain-Barré syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barré syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain-Barré syndrome. 

Methods In this case-control study, cases were patients with Guillain-Barré syndrome diagnosed at the Centre Hospitalier de Polynésie Française (Papeete, Tahiti, French Polynesia) during the outbreak period. Controls were age-matched, sex-matched, and residence-matched patients who presented at the hospital with a non-febrile illness (control group 1; n=98) and age-matched patients with acute Zika virus disease and no neurological symptoms (control group 2; n=70). Virological investigations included RT-PCR for Zika virus, and both microsphere immunofluorescent and seroneutralisation assays for Zika virus and dengue virus. Anti-glycolipid reactivity was studied in patients with Guillain-Barré syndrome using both ELISA and combinatorial microarrays. 

Findings 42 patients were diagnosed with Guillain-Barré syndrome during the study period. 41 (98%) patients with Guillain-Barré syndrome had anti-Zika virus IgM or IgG, and all (100%) had neutralising antibodies against Zika virus compared with 54 (56%) of 98 in control group 1 (p<0·0001). 39 (93%) patients with Guillain-Barré syndrome had Zika virus IgM and 37 (88%) had experienced a transient illness in a median of 6 days (IQR 4–10) before the onset of neurological symptoms, suggesting recent Zika virus infection. Patients with Guillain-Barré syndrome had electrophysiological findings compatible with acute motor axonal neuropathy (AMAN) type, and had rapid evolution of disease (median duration of the installation and plateau phases was 6 [IQR 4–9] and 4 days [3–10], respectively). 12 (29%) patients required respiratory assistance. No patients died. Anti-glycolipid antibody activity was found in 13 (31%) patients, and notably against GA1 in eight (19%) patients, by ELISA and 19 (46%) of 41 by glycoarray at admission. The typical AMAN-associated anti-ganglioside antibodies were rarely present. Past dengue virus history did not differ significantly between patients with Guillain-Barré syndrome and those in the two control groups (95%, 89%, and 83%, respectively). 

Interpretation This is the first study providing evidence for Zika virus infection causing Guillain-Barré syndrome. Because Zika virus is spreading rapidly across the Americas, at risk countries need to prepare for adequate intensive care beds capacity to manage patients with Guillain-Barré syndrome.


  1. Nearly all patients in a small, case-control study who developed Guillain-Barré syndrome also tested positive for Zika virus, according to data from a Zika outbreak in French Polynesia.

    Described as the first study to assess the role of Zika virus in patients with Guillain-Barré syndrome during a Zika virus outbreak, Van-Mai Cao-Lormeau, MD, of the Institut Louis Malardé in Papeete, Tahiti, and colleagues, reported a statistically significant difference in the incidence of Zika virus antibodies between a small group of patients diagnosed with Guillain-Barré syndrome and a control group with a nonfebrile illness (P<0.0001).

    Of the 42 patients diagnosed with Guillain-Barré syndrome during the Zika virus outbreak, 41 of them had anti-Zika virus IgM or IgG compared with about a third (36%) of 98 age-matched, sex-matched and residence-matched controls, they wrote in the Lancet.

    In addition, all 42 patients (100%) had evidence of any antibodies ("a neutralizing response") against the Zika virus compared with a little over half (56%) of the control group (P<0.0001).

    "Although it is unknown whether attack rates of Zika virus epidemics will be as high in affected regions in Latin America than in the Pacific Islands, high numbers of cases of Guillain-Barré syndrome might be expected in the coming months as the result of this association," said co-author Arnaud Fontanet, MD, of the Institut PasteurThe incidence of Guillain-Barré syndrome during this outbreak (October 2013 to August 2014) was estimated to be 0.24 per 1,000 Zika virus infections. By comparison, the rate of Guillain-Barré syndrome following C jejuni infections -- a form of bacteria associated with food poisoning -- ranges from 0.25 to 0.65 per 1,000 cases. (continued)

  2. (continued)The potential link between Guillain-Barré syndrome and Zika virus was also addressed by Thomas Frieden, MD, director, CDC in a media conference call recently.

    "We would not be the least bit surprised if Guillain-Barré is definitely associated with Zika, and given the time course of clusters of Guillain-Barre' after peak Zika virus infection, I think most epidemiologists would say it's certainly related," he said.

    But in an accompanying editorial by David W. Smith, MD, of the University of Western Australia in Nedlands and John Mackenzie, MD of Curtin University in Bentley, Australia, pointed out that the authors faced "major challenges" in proving this association. in Paris in a statement. "The results of our study support that Zika virus should be added to the list of infectious pathogens susceptible to cause Guillain-Barré syndrome."

    "Unfortunately the patients were no longer [viremic] at the time of presentation, and urine samples, which remain PCR positive for longer, were not available for testing," they wrote. "They relied on serological criteria for diagnosis, a tricky procedure when there is a high background of dengue infection in this population."
    Cao-Lormeau's team investigated the possibility that incidence of Guillain-Barré may have been due to dengue, which was also circulating at the time of the Zika outbreak. They found about three quarters (74%) of those patients with Guillain-Barré syndrome had IgM against Zika virus, but not dengue.

    There were 19% of patients with both anti-Zika and anti-dengue IgM, but the authors suggested that was potentially due to cross-reactivity and not because of dengue infection. ..

    As suggested by other epidemiologists, symptoms of Guillain-Barré manifest after a mild viral or bacterial infection (such as Zika virus). The Guillain-Barré group here seemed to support this finding. There were 39 patients (93%) who had anti-Zika virus IgM (evidence of more recent infection), and a large majority (88%) who reported "transient viral syndrome compatible with Zika virus" prior to the onset of Guillain-Barré symptoms.

    The most common symptoms were generalized muscle weakness (74%) and facial palsy (64%). A little under half (44%) also reported incapacity to walk. There were 16 patients (38%) who were admitted to hospital ICUs and a little under a third (29%) required respiratory assistance and there were no deaths.

    There were electrophysiological findings compatible with the acute motor axonal neuropathy type of Guillain-Barré syndrome cases, the authors noted. This included rapid evolution of disease, with a median of 6 (IQR 4-9) days installation phase and a median 4 day (IQR 3-10) plateau phase.

    Four months later, researchers found an improvement in electrophysiological testing results in a cohort of 19 patients (P<0.05), which they cite as suggestive of acute motor axonal neuropathy. However, they noted that the typical anti-ganglioside antibodies, which are generally indicative of Guillain-Barré syndrome, were rarely present.


  3. Dos Santos T, Rodriguez A, Almiron M, Sanhueza A, Ramon P, de Oliveira WK, Coelho GE, Badaró R, Cortez J, Ospina M, Pimentel R, Masis R, Hernandez F, Lara B, Montoya R, Jubithana B, Melchor A, Alvarez A, Aldighieri S, Dye C, Espinal MA. Zika Virus and the Guillain-Barré Syndrome - Case Series from Seven Countries. N
    Engl J Med. 2016 Aug 31. [Epub ahead of print]

    To the Editor:

    Zika virus (ZIKV) disease had been described as a mild, self-limiting illness associated with fever, rash, joint pain, and conjunctivitis. However, during the outbreak in French Polynesia, 42 patients with ZIKV disease were found to have the Guillain–Barré syndrome, which represented a marked increase from the approximately 5 cases detected annually during the previous 4 years. A connection with the Guillain–Barré syndrome had previously been described in association with other flavivirus illnesses but not with ZIKV infection.

    From April 1, 2015, to March 31, 2016, a total of 164,237 confirmed and suspected cases of ZIKV disease and 1474 cases of the Guillain–Barré syndrome were reported in Bahia, Brazil; Colombia; the Dominican Republic; El Salvador; Honduras; Suriname; and Venezuela. To examine the temporal association between ZIKV disease and the Guillain–Barré syndrome, graphical and time-series analyses were applied to these two independent data sets, which were collected through official International Health Regulations channels or from ministry of health websites (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). The data obtained from country reports contained no personally identifiable information and were collected as part of routine public health surveillance; therefore, the analysis was exempt from review by an ethics board. Differences between the observed and expected numbers of cases of the Guillain–Barré syndrome during the ZIKV transmission period, as well as differences in the incidence of the Guillain–Barré syndrome and ZIKV disease according to age and sex, were analyzed with the use of Poisson regression models.

    The analysis suggests that changes in the reported incidence of ZIKV disease during 2015 and early 2016 were closely associated with changes in the incidence of the Guillain–Barré syndrome. During the weeks of ZIKV transmission, there were significant increases in the incidence of the Guillain–Barré syndrome, as compared with the pre-ZIKV baseline incidence, in Bahia State (an increase of 172%), Colombia (211%), the Dominican Republic (150%), El Salvador (100%), Honduras (144%), Suriname (400%), and Venezuela (877%)

    When the incidence of ZIKV disease increased, so did the incidence of the Guillain–Barré syndrome. (continued)

  4. (continued) In the six countries that also reported decreases in the incidence of ZIKV disease, the incidence of the Guillain–Barré syndrome also declined. When the seven epidemics of ZIKV disease are aligned according to week of peak incidence, the total number of cases of ZIKV disease and the Guillain–Barré syndrome are closely coincident, although the period from acquiring infection to reporting disease is approximately 2 weeks longer for ZIKV than for the Guillain–Barré syndrome, a pattern that is especially visible in data from Colombia and Venezuela. Whether the 2-week difference can be explained in terms of incubation periods or reporting delays is not yet known. We explored the potential effect of dengue virus circulation on the incidence of the Guillain–Barré syndrome and found no link (see the Supplementary Appendix). In any event, we infer from these two series of cases, which were collected independently of each other, that ZIKV infection and the Guillain–Barré syndrome are strongly associated. Additional studies are needed to show that ZIKV infection is a cause of the Guillain–Barré syndrome.

    Overall, females had a 75% higher reported incidence rate of ZIKV disease than did males (rate ratio, 1.75; 95% confidence interval [CI], 1.71 to 1.79); the rate was especially high among women 20 to 49 years of age (see the Supplementary Appendix). This difference was also observed in the Yap Island (Micronesia) epidemic1 and could be due to greater exposure to the intradomiciliary mosquito vector, to more severe symptoms among women in this age group, to active health care–seeking behavior by females, or to enhanced reporting by health workers, given the risk of infection during pregnancy. However, the greater apparent risk of ZIKV disease among women 20 to 49 years of age was not matched by a similarly higher incidence of the Guillain–Barré syndrome, which may indicate an age and sex bias in the reporting of ZIKV disease. The reported incidence of the Guillain–Barré syndrome was 28% higher among males than among females (rate ratio, 1.28; 95% CI, 1.09 to 1.50) and consistently increased with age, findings that are in line with previous reports.

    Approximately 500 million people in Latin America and the Caribbean are at risk for ZIKV infection, because they live in areas that are less than 2000 m above sea level where competent aedes vectors also are found. It is clear that increases in the incidence of the Guillain–Barré syndrome to a level that is 2.0 and 9.8 times as high as baseline, as we have reported here, impose a substantial burden on populations and health services in this region. Reports of the Guillain–Barré syndrome could serve as a sentinel for ZIKV disease and other neurologic disorders linked to ZIKV, including microcephaly.