atypical presymptomatic or asymptomatic presentations of SARS-CoV-2 infection can occur before the onset of Guillain-Barré syndrome. Should we adopt the WHO-confirmed COVID-19 case definition 1 as the definition of SARS-CoV-2 infection? Moreover, should we use the screening date of a positive SARS-CoV-2 result as the onset of acute SARS-CoV-2 infection in all patients with Guillain-Barré syndrome without typical COVID-19 symptoms?
A possible association differs from a probable association in the evidence of other commonly associated causes. Although Ellul and colleagues 1 discuss evidence from other viruses as the cause of Guillain-Barré syndrome, influenza was not listed in their proposed case definitions for COVID-19-associated neurological disease. There is robust evidence on influenza-like illnesses as triggers for Guillain-Barré syndrome, and vaccination against influenza might reduce the risk of influenzaassociated Guillain-Barré syndrome. 2 Early data showed a co-infection with influenza virus in about 50% of hospitalised patients with COVID-19. 3 Co-infection of SARS-CoV-2 also exists in influenza-like illness. 4 Therefore, influenza should be included among the possible causes of Guillain-Barré syndrome. Moreover, evaluation of the safety of a SARS-CoV-2 vaccine will face the same questions on whether Guillain-Barré syndrome is related to the infection itself or to the vaccine. Thus, information on the exact infectious agent is crucial for defining the adverse events of SARS-CoV-2 vaccines.
A pathogenic mechanism to link COVID-19 and Guillain-Barré syn drome has not yet been described. However, a molecular mimicry mechanism, auto immune response against aberrant modification of nervous tissue by infec tion, and para-infectious immune dysfunction are common explanations for their potential associa tion. We suggest that all these mech anisms should be investigated in COVID-19-related Guillain-Barré In The Lancet Neurology, Mark Ellul and colleagues 1 propose case definitions for the association of COVID-19 with neurological diseases. We would like to discuss the practicality of their definitions and the potential causality behind the associations, through the example of Guillain-Barré syndrome. Guillain-Barré syndrome can be easily differentiated from neurovirulent neuropathies, such as West Nile virusassociated neuropathy, and there is surveillance on its incidence in several countries, which renders Guillain-Barré syndrome a good candidate for assessing the association between infection and neurological disease. Neurological disease occurring in the 6-week interval after acute infec tion is considered evidence for auto immune association. How ever, typical acute respiratory symp toms are not always indicators of acute severe acute respiratory syn drome corona virus 2 (SARS-CoV-2) infection; programme; existing influenza surveillance networks have been used for sentinel testing and to look for potential signs of community transmission worldwide, as sup ported by the WHO Global Influenza Surveillance and Response System. Furthermore, influenza-like illness is a syndromic definition and does not imply influenza to be the causative illness; its description aligns closely with the "acute respiratory infection" definition used to prompt testing for COVID-19 in earlier WHO and national guidelines. 4 Our group has shown previously that, in patients with new neurological disease and evidence of more than one infection, there are additional challenges in thinking about causality, particularly when the results are from specimens collected outside the CNS. 5, 6 TS was an advisor for the GlaxoSmithKline ebola vaccine programme, chaired the Siemens diagnostics clinical advisory board and healthineers clinical advisory board, and also has a pending patent test for bacterial meningitis based on a blood test (GB 1606537.7; April 14, 2016). BS reports non-financial support from UK National Institute for Health Research through its Global Health Research Group on Brain Infections, outside the submitted work. All other authors declare no competing interests. Any case criterion for a neurological syndrome associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection must incorporate a definition of acute SARS-CoV-2 infection, criteria for the diagnosis of the neurological syndrome itself, and an attempt to link the two in a temporal relationship, excluding other potential causes. The definition of acute SARS-CoV-2 infection must also reflect rapidly evolving diagnostic approaches.
In our proposed definition for SARS-CoV-2-associated Guillain-Barré syndrome, we selected a pragmatic definition of acute COVID-19 infection, reflecting the WHO definition of confirmed infection. 2 However, we accept that the timing of the infection onset is a challenge. A 6-week interval between viral symptoms onset and neurological disease is somewhat arbitrary, but from our knowledge of other infections triggering Guillain-Barré syndrome, a longer delay than this would cast the association into doubt. In patients without symptoms of SARS-CoV-2 infection but with positive RT-PCR or antibody testing, the true date of infection is even more difficult to elucidate.
We agree that it is important to exclude influenza as a potential trigger of Guillain-Barré syndrome, and viral symptoms might be difficult to distinguish. Epidemiological data can be informative, especially as the incidence of respiratory pathogens changes with the seasons around the world. RT-PCR testing for influenza and other respiratory viruses could be done alongside SARS-CoV-2 testing when possible. We advise caution in interpreting the results of studies using positive serum antibody testing for the diagnosis of influenza, which can be vulnerable to cross-reactivity and poor inherent test accuracy. Additionally, the study by Kong and colleagues 3 cited by Li and colleagues' Correspondence did not report co-infection, but rather early cases of COVID-19 in Wuhan, China, that were detected through the national influenza surveillance syndrome. For example, molecular mimicry with heat shock proteins (HSPs) was reported as a potential pathogenic mechanism of Guillain-Barré syndrome after SARS-CoV-2 infection. 5 HSPs might also promote a superantigen response, which contributes to the parainfectious response.
To establish association and potential causality, researchers should endeavor to collect data from as many cases with COVID-19 as possible from whom SARS-CoV-2 is presumed as the single or joint cause, on the basis of accurate and timely diagnosis of SARS-CoV-2 infection.