No link between COVID-19 and Guillain-Barré syndrome

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Neuroscientists at UCL have found no significant association between COVID-19 and the potentially paralysing and sometimes fatal neurological condition Guillain-Barré syndrome.

Researchers say the findings, published in the journal Brain, along with a linked scientific commentary by UCL and other international experts, should provide the public with reassurance, as the UK’s national coronavirus vaccination programme is rolled out.

Guillain-Barré syndrome (GBS) is a rare but serious autoimmune condition that attacks the peripheral nervous system, typically affecting the feet, hands and limbs, causing numbness, weakness and pain.

While its exact cause is unknown, GBS often occurs after a gastroenteritis infection called Camplylobacter, with the immune system mistakenly attacking nerves rather than germs.

GBS is usually reversible, however in severe cases it can cause prolonged paralysis involving breathing muscles, require ventilator support and sometimes leave permanent neurological deficits. Early recognition by expert neurologists is key to proper treatment.

Historical context of virus- and vaccine-associated GBS

More cases of GBS were associated with the Zika virus outbreaks in Latin America (2016 and 2020) than expected by chance alone; and concerns have been raised in GBS research reports that a similar link may potentially exist between COVID-19 infection and GBS too.

Researchers also say fears of a global rise in GBS following mass vaccination may persist due to a historic small increase in GBS associated with the 1976 swine flu vaccination campaign in the U.S.. This vaccination campaign was halted because the risk of developing GBS was statistically increased from background, although subsequent statistical analysis found the risk of a link to be lower than initially thought. In every flu vaccination campaign since, the risk of GBS as a result of flu vaccination is estimated to be about one per million vaccination doses.

This study

In this epidemiological and cohort study, UCL researchers sought to investigate any causative association between COVID-19 infection and GBS.

The team assessed the number of GBS treatments reported to the NHS England National Immunoglobulin Database between 2016 and 2019. This was compared to the number of cases reported during the COVID-19 pandemic in the first half of 2020.

The annual incidence of GBS treated in UK hospitals between 2016 and 2019 was 1.65-1.88 per 100,000 individuals. Incidences of GBS fell 40-50% between March and May 2020 when compared to the same months of 2016-2019. This new finding contradicts that of other smaller and less extensive international studies.

First author, Dr. Stephen Keddie (UCL Queen Square Institute of Neurology) said: “The possibility of SARS-CoV-2 driving a global spike in GBS has been eagerly monitored with a number of published small case series already asserting a causal link. However, a surge in GBS cases after the SARS-CoV-2 pandemic has not been detected as happened in the Zika virus pandemic.

“Our epidemiological study shows there was no increased incidence in GBS during the first wave of COVID-19; rather, there was a decrease and therefore no causal link of COVID-19 to GBS can be made.”

Separately in this study the research team also tried to establish if there was any genetic or protein structure in SARS-CoV-2, the virus that causes COVID-19, which could trigger an immune response causing GBS. Unlike Camplylobacter, which contains human-like antigens causing an autoimmune response, no credible link was found with SARS-CoV-2.

Dr. Keddie added: “Most COVID-19 vaccinations are based on the SARS-CoV-2 spike protein, which drives a complex immune response creating antibodies to fight infection.

“Our analysis shows SARS-CoV-2 contains no additional immunogenic material known or proven to drive GBS. Concerns that COVID vaccination might cause GBS in any significant numbers are therefore almost certainly unfounded.”

Around 1,500 cases of GBS occur in the UK each year (two per 100,000 population). History suggests, researchers say, that mass vaccination might be blamed for cases of GBS when occurring by chance, particularly with billions of people expected to be immunised globally.

Corresponding author, Professor Michael Lunn (UCL Queen Square Institute of Neurology) said: “When we immunise the population against COVID-19, GBS (and other neurological illnesses) will occur, by chance alone, in the weeks after immunisation, the window for a normal response to the vaccine.

“These cases may cause concern in patients, politicians, and regulators and stoke anti-vaccination concerns, even though it is likely that most, if not all of the cases, will be associated with vaccination by chance alone.

“Such a severe illness may result in suspension or withdrawal of vaccination as a ‘knee jerk’ safety reaction but this must not happen unless there is a statistically demonstrated link through careful monitoring that is proven. We must accept small risks with any vaccination programme on this scale, and these are far lower than the risk from COVID infection.”


BUT ………………..

The pandemic we are facing in 2020 is unprecedented. The full effects of infection with the SARS-CoV-2 coronavirus, which causes COVID-19, are still to be determined, and new findings are coming to light every day regarding its transmission, symptoms, progression, new strains, immunity, and association with other pathologies.1

On the latter point, researchers have observed that this virus not only harms the respiratory system, but also affects other systems such as the vascular, renal, and central nervous systems.2

Cases have been reported at several healthcare centres of patients with Guillain-Barré syndrome (GBS) and active or resolved COVID-19; therefore, an association between both conditions has been suggested. Some authors report that COVID-19–associated GBS presents more acute symptom onset, which is suggestive of a form of pre-pandemic GBS.3

Other types of coronaviruses have been reported to infect the central nervous system, and are therefore considered potentially neuroinvasive viruses; central nervous system involvement leads to different manifestations and sequelae affecting neurons and glial cells.4

These manifestations may be classified into 3 types: viral encephalitis, described as inflammatory lesions of the brain parenchyma; acute/toxic infectious encephalopathy, described as a reversible brain dysfunction syndrome caused by systemic toxic symptoms, metabolic disorders and hypoxia during the period of acute infection; and lastly, acute cerebrovascular disease (cerebrovascular accident), which in recent months has been widely attributed to SARS-CoV-2, as the virus triggers a proinflammatory cytokine cascade, as well as high levels of D-dimer and low platelet levels, which can cause a cerebrovascular accident.4

GBS is a severe condition that manifests when the immune system attacks the patient’s own body, and specifically the cells of the peripheral nervous system. The cause is not clear, but this immune disorder is frequently associated with other viral or bacterial pathologies, including influenza, HIV, and herpes virus infection; an association with COVID-19 is currently being studied.5 While GBS may manifest at any age, its incidence is highest among individuals aged 30-50 years.

It is considered a demyelinating disease because the lesions mainly affect myelin in the peripheral nerves, leading to paresis, muscle weakness, and even bilateral ascending paralysis. If nerve damage reaches the diaphragmatic nerves, the patient may present respiratory symptoms ranging from mild respiratory failure to the need for invasive ventilatory support. Unfortunately, GBS is incurable; treatment focuses on symptom management and ventilatory support, when needed.5

Several pathological studies, including one by Hamming at al.,6 have shown that angiotensin-converting enzyme 2 (ACE2) acts as a functional receptor of SARS-CoV-2 in human tissues. Considering the similarity in the sequencing of the SARS-CoV and SARS-CoV-2 spike proteins, it has been suggested that SARS-CoV-2 also uses ACE2 as a functional receptor; this was confirmed by other studies in early 2020.7, 8

The potential mechanisms by which SARS-CoV-2 may cause neurological damage include the binding of the virus to ACE2 in the blood-brain barrier, enabling it to enter the central nervous system, as well as the existence of haematogenous, transcribrial, and neuronal retrograde dissemination pathways.9, 10

The aim of this review is to analyse the available evidence on the associations described between COVID-19 and GBS in the adult population, in order to communicate the clinical manifestations and progression of the reported cases and therefore provide relevant information for preventing the condition.

Discussion
It should be noted that all the hospitals where the studies were conducted have experienced an abnormal increase in the number of patients admitted with GBS, with higher prevalence among older patients (mean age of 60 years) than in the cases reported before the pandemic (mean age of 40 years).21

Therefore, it is important to analyse the 2 deceased patients, both aged older than 70 years, as well as the patient with a poor outcome. Considering that older age is an independent risk factor for mortality due to COVID-19,22 further studies (randomised control trials) are needed to establish more accurate results and conclusions about the causal relationship.

The most common symptoms appearing before onset of GBS were ageusia and hyposmia; COVID-19–associated symptoms, such as pneumonia, were also observed to be more severe.23 We should also emphasise the findings of Assini et al.24 regarding the differences in the manifestations of GBS before and after the pandemic.

According to these authors, impairment of several cranial nerves in association with a demyelinating peripheral neuropathy is a very infrequent characteristic that only affected 5% of previously reported cases; however, in the context of COVID-19, cranial nerve involvement was observed in 47% of the patients included in this review, and represents a distinctive characteristic of the cases associated with the disease.

The first neurological manifestations presented between 5 and 21 days after onset of COVID-19 symptoms.

Strikingly, CSF analysis was not performed for a considerable percentage of patients (26.6%); this is a relevant limitation as this assessment is very important for correct diagnosis and subsequent treatment, especially in critically ill patients.7

The studies analysed are case reports or case series with small samples, and are therefore considered to present a high risk of bias; however, despite this limitation, it is important to underscore that an association between the 2 pathologies, with a new form of presentation, is increasingly being observed.

Conclusion
The studies analysed show a clear association between both pathologies, with SARS-CoV-2 potentially triggering GBS. Further studies providing higher levels of evidence and including more representative samples are needed for a conclusive analysis of this topic; however, these cases seem to differ from those reported before the pandemic in the older age of onset and more severe clinical manifestations and cranial nerve involvement. In any case, appropriate treatment achieves favourable outcomes.

We hope that this review will lead to future studies that may help professionals and the general population to be more alert to the presence of this condition in their social circles.

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More information: Stephen Keddie et al, Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome, Brain (2020). DOI: 10.1093/brain/awaa433

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