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      Provisional case definitions for COVID-19-associated neurological disease – Authors' reply

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          Abstract

          We read with interest the Correspondence by Hai-Feng Li and colleagues on our proposed definitions for COVID-19-associated neurological disease. 1 We thank the authors for recognising the importance of collecting cases together with accurate diagnostic evidence to elucidate disease mechanisms. 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 programme; existing influenza surveillance networks have been used for sentinel testing and to look for potential signs of community transmission worldwide, as supported 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

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          Neurological associations of COVID-19

          Summary Background The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is of a scale not seen since the 1918 influenza pandemic. Although the predominant clinical presentation is with respiratory disease, neurological manifestations are being recognised increasingly. On the basis of knowledge of other coronaviruses, especially those that caused the severe acute respiratory syndrome and Middle East respiratory syndrome epidemics, cases of CNS and peripheral nervous system disease caused by SARS-CoV-2 might be expected to be rare. Recent developments A growing number of case reports and series describe a wide array of neurological manifestations in 901 patients, but many have insufficient detail, reflecting the challenge of studying such patients. Encephalopathy has been reported for 93 patients in total, including 16 (7%) of 214 hospitalised patients with COVID-19 in Wuhan, China, and 40 (69%) of 58 patients in intensive care with COVID-19 in France. Encephalitis has been described in eight patients to date, and Guillain-Barré syndrome in 19 patients. SARS-CoV-2 has been detected in the CSF of some patients. Anosmia and ageusia are common, and can occur in the absence of other clinical features. Unexpectedly, acute cerebrovascular disease is also emerging as an important complication, with cohort studies reporting stroke in 2–6% of patients hospitalised with COVID-19. So far, 96 patients with stroke have been described, who frequently had vascular events in the context of a pro-inflammatory hypercoagulable state with elevated C-reactive protein, D-dimer, and ferritin. Where next? Careful clinical, diagnostic, and epidemiological studies are needed to help define the manifestations and burden of neurological disease caused by SARS-CoV-2. Precise case definitions must be used to distinguish non-specific complications of severe disease (eg, hypoxic encephalopathy and critical care neuropathy) from those caused directly or indirectly by the virus, including infectious, para-infectious, and post-infectious encephalitis, hypercoagulable states leading to stroke, and acute neuropathies such as Guillain-Barré syndrome. Recognition of neurological disease associated with SARS-CoV-2 in patients whose respiratory infection is mild or asymptomatic might prove challenging, especially if the primary COVID-19 illness occurred weeks earlier. The proportion of infections leading to neurological disease will probably remain small. However, these patients might be left with severe neurological sequelae. With so many people infected, the overall number of neurological patients, and their associated health burden and social and economic costs might be large. Health-care planners and policy makers must prepare for this eventuality, while the many ongoing studies investigating neurological associations increase our knowledge base.
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            Is Open Access

            Revision of clinical case definitions: influenza-like illness and severe acute respiratory infection

            Abstract The formulation of accurate clinical case definitions is an integral part of an effective process of public health surveillance. Although such definitions should, ideally, be based on a standardized and fixed collection of defining criteria, they often require revision to reflect new knowledge of the condition involved and improvements in diagnostic testing. Optimal case definitions also need to have a balance of sensitivity and specificity that reflects their intended use. After the 2009–2010 H1N1 influenza pandemic, the World Health Organization (WHO) initiated a technical consultation on global influenza surveillance. This prompted improvements in the sensitivity and specificity of the case definition for influenza – i.e. a respiratory disease that lacks uniquely defining symptomology. The revision process not only modified the definition of influenza-like illness, to include a simplified list of the criteria shown to be most predictive of influenza infection, but also clarified the language used for the definition, to enhance interpretability. To capture severe cases of influenza that required hospitalization, a new case definition was also developed for severe acute respiratory infection in all age groups. The new definitions have been found to capture more cases without compromising specificity. Despite the challenge still posed in the clinical separation of influenza from other respiratory infections, the global use of the new WHO case definitions should help determine global trends in the characteristics and transmission of influenza viruses and the associated disease burden.
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              • Article: not found

              SARS-CoV-2 detection in patients with influenza-like illness

              Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in Wuhan, Hubei Province, China in late December 2019. We re-analysed 640 throat swabs collected from patients in Wuhan with influenza-like-illness from 6 October 2019 to 21 January 2020 and found that 9 of the 640 throat swabs were positive for SARS-CoV-2 RNA by quantitative PCR, suggesting community transmission of SARS-CoV2 in Wuhan in early January 2020.
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                Author and article information

                Journal
                Lancet Neurol
                Lancet Neurol
                The Lancet. Neurology
                Elsevier Ltd.
                1474-4422
                1474-4465
                21 October 2020
                November 2020
                21 October 2020
                : 19
                : 11
                : 891-892
                Affiliations
                [a ]National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7BE, UK
                [b ]The Walton Centre National Health Service Foundation Trust, Liverpool, UK
                [c ]Queen Square Institute of Neurology, University College London, London, UK
                [d ]Christian Medical College, Vellore, India
                Article
                S1474-4422(20)30362-8
                10.1016/S1474-4422(20)30362-8
                7577679
                d606d70f-0aa1-4724-8f5f-e7b8d95c95cb
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Correspondence

                Neurology
                Neurology

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