Tuesday, March 01, 2016

Lancet: Zika/GBS Case Control Study - French Polynesia


Until it sparked a large outbreak on Yap Island in 2007, the Zika virus had kept a very low profile; causing sporadic and mild infections as it slowly spread out of Africa into equatorial Asia (India, Indonesia, Malaysia, Pakistan) during the 1970s and 1980s.

Yap Island (pop. 7,000) in the Western Pacific was the first large outbreak of Zika recorded, with more than 70% of the island's population estimated to have been infected (see (see 2009 EID Journal Zika Virus Outside Africa by Edward B. Hayes), although no serious illness or deaths were reported. 

Zika re-emerged in 2013 in French Polynesia (pop. 276,000), and quite unexpectedly there, we began get reports of more severe illness associated with Zika infection (see Zika, Dengue & Unusual Rates Of Guillain Barre Syndrome In French Polynesia). The number of cases was small, but estimated to be 20 times greater (cite Eurosurveillance) than normal.

In 2015, when Zika began circulating widely in Brazil (and later spreading to much of South & Central America), we began to get similar reports of unexpectedly high GBS numbers in the region, although their association to Zika infection was far from established.

One of the tools epidemiologist’s use to find risks for a specific outcome is a case-control study, where they compare laboratory-confirmed cases to a large number of unaffected controls, matched for age, sex, and by neighborhood. 

While a case control study is not enough to prove causation, it can often provide compelling evidence of a link or an association between two or more events.

Although the exact cause of Guillain Barre Syndrome isn't known, we do know it often follows an infection (bacterial or viral), and it has been seen in both Dengue and Chikungunya patients in the past. 

Last night the The Lancet published a case control study conducted in French Polynesia which finds additional evidence supporting the idea that Zika may cause Guillain Barre Syndrome.

The abstract may be read at the link above, while the full study can be downloaded as a  PDF (204 KB).

Nicely summarizing their findings, The Lancet published a press release yesterday, which also includes comments from an accompanying editorial comment (see Zika virus and Guillain-Barré syndrome: another viral cause to add to the list).

The Lancet: Zika virus might cause Guillain-Barré syndrome, according to new evidence from French Polynesia

The Lancet

Analysis of blood samples from 42 patients diagnosed with Guillain-Barré syndrome (GBS) during the Zika virus outbreak in French Polynesia provides the first evidence that Zika virus might cause GBS, a severe neurological disorder, according to new research published in The Lancet today. Based on the analysis of data from French Polynesia, if 100000 people were infected with Zika virus, 24 would develop GBS.


The aim of the study was to determine the link between Zika virus infection and GBS. Since French Polynesia is also prone to outbreaks of dengue virus, the researchers also wanted to see whether dengue virus was an additional risk factor for GBS. 

All 42 patients with GBS diagnosed at the Centre Hospitalier de Polynésie Française in Papeete, Tahiti were included in the study. Researchers recruited two control groups. The first control group (CTR 1), matched for age, gender and island of residence, consisted of 98 patients who attended the same hospital but did not have a fever. The second control group (CTR 2) consisted of 70 patients who tested positive for Zika virus infection, but did not develop any of the neurological symptoms associated with GBS. Blood samples were collected from all patients. 

Most (88%) of the patients with GBS reported symptoms of Zika virus infection approximately 6 days before the onset of neurological symptoms. While none tested positive for a Zika virus infection once in hospital, blood tests showed that 41 (98%) were carrying Zika virus antibodies, and all (100%) had neutralizing antibodies against Zika virus. 

By comparison, only 54 (56%) of the patients without a fever (CTR 1 group) were carrying Zika virus neutralizing antibodies. Most patients with GBS (95.2%) had signs of past dengue virus infection, as did most patients in the two control groups (88.8% in CTL 1; 82.9% in CTL 2). The authors therefore concluded that, in this case, past infection with dengue virus did not increase the risk of GBS among patients infected with Zika virus. 

All 42 patients were diagnosed with a type of GBS called 'acute-motor axonal neuropathy' (AMAN), but few carried the biological markers typically associated with AMAN, suggesting a previously unknown disease mechanism. The patients in the study generally recovered faster than is usually expected with GBS.

Of the 42 patients with GBS, 16 (38%) were admitted to the hospital's intensive care unit and 12 (29%) required breathing assistance. On average, patients were hospitalised for 11 days, but those in intensive care remained for longer (51 days). Three months after discharge, 24 (57%) patients were able to walk without assistance. No patients with GBS died.

(Continue . . .)

Interestingly, this study finds those affected had a type of GBS called 'acute-motor axonal neuropathy' (AMAN), which is normally associated with pediatric cases in China.  The authors wrote:

No clear pathophysiological mechanism for the Guillain-Barré syndrome could be identified, because the typical AMAN-associated anti-ganglioside antibodies were rarely present.

The authors also looked for evidence that prior infection with Dengue might increase the risks of developing GBS, but found no evidence to support that idea.

Like all studies, this one suffered from some limitations.  It was relatively small, testing for Zika infection was retrospective, and based on ELISA testing for IgM and IgA antibodies, and not RT-PCR tests. 

Still, this adds to the evidence that Zika can, at least on rare occasions, cause serious illness.  We'll need to get more information in order to know if GBS is more common with Zika infection than with other flavivirus infections like Dengue or Chikungunya.