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Guillain-Barr? Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study
Van-Mai Cao-Lormeau, PhD†
, Alexandre Blake, MD†
, Sandrine Mons, MSc
, St?phane Last?re, PharmD
, Claudine Roche, MSc
, Jessica Vanhomwegen, PhD
, Timoth?e Dub, MPH
, Laure Baudouin, MD
, Anita Teissier
, Philippe Larre, MD
, Anne-Laure Vial, MSc
, Christophe Decam, MD
, Val?rie Choumet, PhD
, Susan K Halstead, PhD
, Prof Hugh J Willison, PhD
, Lucile Musset, PhD
, Jean-Claude Manuguerra, PhD
, Prof Philippe Despres, PhD
, Prof Emmanuel Fournier, PhD
, Henri-Pierre Mallet, MD
, Didier Musso, MD
, Prof Arnaud Fontanet, DrPH†
, Jean Neil, MD†
, Fr?d?ric Ghawch?, MD†
†Contributed equally
Published Online: 29 February 2016
DOI: http://dx.doi.org/10.1016/S0140-6736(16)00562-6 |
Article Info
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-Barr? syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barr? syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain-Barr? syndrome.
Methods
In this case-control study, cases were patients with Guillain-Barr? syndrome diagnosed at the Centre Hospitalier de Polyn?sie Fran?aise (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-Barr? syndrome using both ELISA and combinatorial microarrays.
Findings
42 patients were diagnosed with Guillain-Barr? syndrome during the study period. 41 (98%) patients with Guillain-Barr? 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-Barr? 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-Barr? 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-Barr? syndrome and those in the two control groups (95%, 89%, and 83%, respectively).
...
Research in context
Evidence before this study
The ongoing Zika virus disease epidemic in Latin America is the largest epidemic ever recorded. On Feb 1, 2016, the WHO declared the suspected link between Zika virus and neurological disorders and neonatal malformations a Public Health Emergency of International Concern. The WHO Secretariat briefed the Emergency Committee convened by the Director General on the clusters of microcephaly and Guillain-Barr? syndrome that have been temporally associated with Zika virus transmission in some settings, including French Polynesia, and urged further research to be conducted to confirm the link between Zika virus and these complications. We searched MEDLINE from Jan 1, 1990, to Feb 14, 2016, for evidence linking Zika virus and Guillain-Barr? syndrome. The simultaneous occurrence of Zika virus and Guillain-Barr? syndrome outbreaks has been reported in few studies in French Polynesia and Brazil, but only one case report provided serological evidence linking one patient with Guillain-Barr? syndrome to recent Zika virus infection in French Polynesia in November, 2013. We provide here a complete description of a series of 42 cases of Guillain-Barr? syndrome in French Polynesia, and serological evidence linking these cases to recent Zika virus infection.
Added value of this study
This is the first study to document a large series of patients who developed a Guillain-Barr? syndrome following Zika virus infection, a virus that was previously considered to cause only mild disease. This study not only confirms the link between Zika virus infection and Guillain-Barr? syndrome, but also provides useful findings regarding the clinical characteristics of the Guillain-Barr? syndrome cases: most had electrophysiological findings compatible with the acute motor axonal neuropathy (AMAN) type of the syndrome, and had rapid evolution of the disease. The clinical outcome of these patients with Zika virus and Guillain-Barr? syndrome was generally favourable, despite a rapid onset and short plateau phase, as may be seen in other patient groups suffering from the AMAN type of Guillain-Barr? syndrome. No clear pathophysiological mechanism for the Guillain-Barr? syndrome could be identified, because the typical AMAN-associated anti-ganglioside antibodies were rarely present. We also speculated whether past dengue history might have contributed to the development of Guillain-Barr? syndrome, but could not find any evidence for it.
Implications of all the available evidence
The results of our study support that Zika virus should be added to the list of infectious pathogens susceptible to cause Guillain-Barr? syndrome. As Zika virus is spreading rapidly across the Americas, at risk countries need to be prepared to have adequate intensive care beds capacity to manage patients with Guillain-Barr? syndrome.
...
Discussion
This is the first study to assess the role of Zika virus infection in a large number of patients with Guillain-Barr? syndrome diagnosed during a Zika virus outbreak. The serological investigations done on the blood samples from the 42 patients who developed a Guillain-Barr? syndrome during the Zika virus outbreak in French Polynesia confirm that all patients had experienced Zika virus infection. Moreover, the presence of IgM (93%) and the information that most patients (88%) reported a transient viral syndrome compatible with Zika virus disease in a median of 6 days before the onset of neurological symptoms, suggested a recent Zika virus infection. Patients with Guillain-Barr? syndrome were no longer viraemic for Zika virus at the time of admission, consistent with previous data showing that Zika virus viraemia rarely exceeds 5 days after disease onset.25 However, detection of virus in the urine by RT-PCR could be a valuable alternative.26 Because dengue serotypes 1 and 3 were co-circulating at the time of the Zika virus epidemic,18 we investigated whether dengue infection could have contributed to the occurrence of Guillain-Barr? syndrome. Analysis of dengue serology (immunofluorescent assay, microsphere immunoassay, and seroneutralisation) did not support recent dengue infection. Most patients (95%) with Guillain-Barr? syndrome had pre-existing dengue immunity, but this did not differ significantly from the control groups.
...
In conclusion, this is the first study to document a large series of patients who developed a Guillain-Barr? syndrome following Zika virus infection, a virus that previously used to be considered as causing only mild disease. Most (88%) of the patients with Guillain-Barr? syndrome reported symptomatic Zika virus infection that preceded the occurrence of neurological symptoms by a median of 6 days. All patients with Guillain-Barr? syndrome were of the AMAN type, characterised by distal motor nerve involvement, the absence of typical patterns and levels of anti-glycolipid antibodies, and faster recovery than usually observed in typical Guillain-Barr? syndrome. Because Zika virus is spreading rapidly across the Americas, at risk countries need to be prepared to have adequate intensive care beds capacity to manage patients with Guillain-Barr? syndrome.
...
Full text:
http://www.thelancet.com/journals/la...562-6/fulltext
Van-Mai Cao-Lormeau, PhD†
, Alexandre Blake, MD†
, Sandrine Mons, MSc
, St?phane Last?re, PharmD
, Claudine Roche, MSc
, Jessica Vanhomwegen, PhD
, Timoth?e Dub, MPH
, Laure Baudouin, MD
, Anita Teissier
, Philippe Larre, MD
, Anne-Laure Vial, MSc
, Christophe Decam, MD
, Val?rie Choumet, PhD
, Susan K Halstead, PhD
, Prof Hugh J Willison, PhD
, Lucile Musset, PhD
, Jean-Claude Manuguerra, PhD
, Prof Philippe Despres, PhD
, Prof Emmanuel Fournier, PhD
, Henri-Pierre Mallet, MD
, Didier Musso, MD
, Prof Arnaud Fontanet, DrPH†
, Jean Neil, MD†
, Fr?d?ric Ghawch?, MD†
†Contributed equally
Published Online: 29 February 2016
DOI: http://dx.doi.org/10.1016/S0140-6736(16)00562-6 |
Article InfoBackground
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-Barr? syndrome was reported, suggesting a possible association between Zika virus and Guillain-Barr? syndrome. We aimed to assess the role of Zika virus and dengue virus infection in developing Guillain-Barr? syndrome.
Methods
In this case-control study, cases were patients with Guillain-Barr? syndrome diagnosed at the Centre Hospitalier de Polyn?sie Fran?aise (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-Barr? syndrome using both ELISA and combinatorial microarrays.
Findings
42 patients were diagnosed with Guillain-Barr? syndrome during the study period. 41 (98%) patients with Guillain-Barr? 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-Barr? 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-Barr? 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-Barr? syndrome and those in the two control groups (95%, 89%, and 83%, respectively).
...
Research in context
Evidence before this study
The ongoing Zika virus disease epidemic in Latin America is the largest epidemic ever recorded. On Feb 1, 2016, the WHO declared the suspected link between Zika virus and neurological disorders and neonatal malformations a Public Health Emergency of International Concern. The WHO Secretariat briefed the Emergency Committee convened by the Director General on the clusters of microcephaly and Guillain-Barr? syndrome that have been temporally associated with Zika virus transmission in some settings, including French Polynesia, and urged further research to be conducted to confirm the link between Zika virus and these complications. We searched MEDLINE from Jan 1, 1990, to Feb 14, 2016, for evidence linking Zika virus and Guillain-Barr? syndrome. The simultaneous occurrence of Zika virus and Guillain-Barr? syndrome outbreaks has been reported in few studies in French Polynesia and Brazil, but only one case report provided serological evidence linking one patient with Guillain-Barr? syndrome to recent Zika virus infection in French Polynesia in November, 2013. We provide here a complete description of a series of 42 cases of Guillain-Barr? syndrome in French Polynesia, and serological evidence linking these cases to recent Zika virus infection.
Added value of this study
This is the first study to document a large series of patients who developed a Guillain-Barr? syndrome following Zika virus infection, a virus that was previously considered to cause only mild disease. This study not only confirms the link between Zika virus infection and Guillain-Barr? syndrome, but also provides useful findings regarding the clinical characteristics of the Guillain-Barr? syndrome cases: most had electrophysiological findings compatible with the acute motor axonal neuropathy (AMAN) type of the syndrome, and had rapid evolution of the disease. The clinical outcome of these patients with Zika virus and Guillain-Barr? syndrome was generally favourable, despite a rapid onset and short plateau phase, as may be seen in other patient groups suffering from the AMAN type of Guillain-Barr? syndrome. No clear pathophysiological mechanism for the Guillain-Barr? syndrome could be identified, because the typical AMAN-associated anti-ganglioside antibodies were rarely present. We also speculated whether past dengue history might have contributed to the development of Guillain-Barr? syndrome, but could not find any evidence for it.
Implications of all the available evidence
The results of our study support that Zika virus should be added to the list of infectious pathogens susceptible to cause Guillain-Barr? syndrome. As Zika virus is spreading rapidly across the Americas, at risk countries need to be prepared to have adequate intensive care beds capacity to manage patients with Guillain-Barr? syndrome.
...
Discussion
This is the first study to assess the role of Zika virus infection in a large number of patients with Guillain-Barr? syndrome diagnosed during a Zika virus outbreak. The serological investigations done on the blood samples from the 42 patients who developed a Guillain-Barr? syndrome during the Zika virus outbreak in French Polynesia confirm that all patients had experienced Zika virus infection. Moreover, the presence of IgM (93%) and the information that most patients (88%) reported a transient viral syndrome compatible with Zika virus disease in a median of 6 days before the onset of neurological symptoms, suggested a recent Zika virus infection. Patients with Guillain-Barr? syndrome were no longer viraemic for Zika virus at the time of admission, consistent with previous data showing that Zika virus viraemia rarely exceeds 5 days after disease onset.25 However, detection of virus in the urine by RT-PCR could be a valuable alternative.26 Because dengue serotypes 1 and 3 were co-circulating at the time of the Zika virus epidemic,18 we investigated whether dengue infection could have contributed to the occurrence of Guillain-Barr? syndrome. Analysis of dengue serology (immunofluorescent assay, microsphere immunoassay, and seroneutralisation) did not support recent dengue infection. Most patients (95%) with Guillain-Barr? syndrome had pre-existing dengue immunity, but this did not differ significantly from the control groups.
...
In conclusion, this is the first study to document a large series of patients who developed a Guillain-Barr? syndrome following Zika virus infection, a virus that previously used to be considered as causing only mild disease. Most (88%) of the patients with Guillain-Barr? syndrome reported symptomatic Zika virus infection that preceded the occurrence of neurological symptoms by a median of 6 days. All patients with Guillain-Barr? syndrome were of the AMAN type, characterised by distal motor nerve involvement, the absence of typical patterns and levels of anti-glycolipid antibodies, and faster recovery than usually observed in typical Guillain-Barr? syndrome. Because Zika virus is spreading rapidly across the Americas, at risk countries need to be prepared to have adequate intensive care beds capacity to manage patients with Guillain-Barr? syndrome.
...
Full text:
http://www.thelancet.com/journals/la...562-6/fulltext