ABSTRACT
Vaccination against viruses has rarely been associated with Guillain-Barre syndrome (GBS). An association with the COVID-19 vaccine is unknown. We performed a population-based study of National Health Service (NHS) data in England and a multicentre surveillance study from UK hospitals, to investigate the relationship between COVID-19 vaccination and GBS. Firstly, we present a retrospective analysis of every GBS patient in England in the National Immunoglobulin Database (NID) linked with their COVID-19 vaccination data. Cases of GBS identified in the National Immunoglobulin Database (NID) from 8 December 2021 to 8 July 2021 were linked to data from the National Immunisation Management System (NIMS) in England to identify exposure to a COVID-19 vaccine. For the NID/NIMS linked dataset, GBS cases temporally associated with vaccination within a 6-week risk window of any COVID-19 vaccine were identified. Secondly, we prospectively collected incident UK GBS cases from 1 January 2021 to 7 November 2021 in a separate UK multicentre surveillance database, regardless of vaccine exposure, with vaccine timings and GBS phenotypic data. For this multicentre UK surveillance dataset, we explored phenotypes of reported GBS cases to identify features of COVID-19 vaccine-associated GBS. 996 GBS cases were recorded in the NID from January to October 2021. A spike of GBS cases above the 2016-2020 average occurred in March-April 2021. In England, among all cases of GBS, 198 occurred within 6 weeks of the first-dose COVID-19 vaccination (0.618 cases per 100,000 vaccinations, 176 ChAdOx1 nCoV-19 (AstraZeneca), 21 tozinameran (Pfizer), 1 mRNA-1273 (Moderna)). The excess of GBS occurs with a peak at 24 days; first-doses of ChAdOx1 nCoV-19 accounted for the excess. No excess was seen for second-dose vaccination. The absolute number of excess GBS cases was between 98-140 cases for first-dose ChAdOx1 nCoV-19 vaccination from January-July 2021. First-dose tozinameran and second-dose of any vaccination showed no excess GBS risk. 121 patients were reported in the separate multicentre surveillance dataset with no phenotypic or demographic differences identified between vaccinated and non-vaccinated GBS cases. Data from the linked NID/NIMS dataset suggest that first-dose ChAdOx1 nCoV-19vaccination is associated with an excess GBS risk of 0.576 (95%CI 0.481-0.691) cases per 100,000 doses. However, further data reported from a multicentre surveillance dataset suggest that no specific clinical features, including facial weakness, are associated with vaccination-related GBS compared to non-vaccinated cases. The pathogenic cause of the ChAdOx1 nCoV-19specific first dose link warrants further study.
Subject(s)
COVID-19 , Guillain-Barre Syndrome , Glomerulonephritis, IGA , Muscle WeaknessABSTRACT
Background: For a targeted therapeutic strategy to show outcome benefit, there needs to be a strong biological and pathogenic rationale to underpin and direct personalised treatments. Relevant biological disease features and biomarkers identify patients for the correct therapeutic, delivered at an appropriate time, dose and duration for maximal efficacy. We evaluated whether serum levels of a wide range of proposed therapeutic targets in COVID-19 discriminated between patients with mild and severe disease or death.Methods: A search of clinicaltrials.gov identified immunological drug targets in COVID-19. We subsequently conducted an observational study investigating the association of serum biomarkers relating to putative therapeutic biomarkers with illness severity and outcome.Results: A search of clinicaltrials.gov identified 477 randomized trials assessing immunomodulatory therapies, including 168 different therapies against 83 different pathways. We measured levels of ten cytokines/signalling proteins including those related to the most common therapeutic targets (GM-CSF, IFN-α2a, IFN-β, IFN-γ, IL-1β, IL-1ra, IL-6, IL-7, IL-8, TNF-α), immunoglobulin G ( IgG) antibodies directed against either the COVID-19 spike protein (S1) or nucleocapsid protein (N), and neutralization titres of antibodies within the first 5 days of hospital admission in 86 patients, 44 (51%) with mild disease and 42 (49%) with severe disease. Six of the ten cytokine/signalling protein markers measured (IL-6, IL-7, IL-8, interferon- a, interferon- b, IL -1ra ) discriminated between patients with mild and severe disease, although most were similar or only modestly raised above that seen in healthy volunteers. A similar proportion of patients with mild or severe disease had detectable S1 or N IgG antibodies with equivalent levels between groups. Neutralization titres were higher among patients with severe disease.Interpretation: Some therapeutic and prognostic biomarkers may be potentially useful in identifying patients who may benefit from specific immunomodulatory therapies in COVID-19 disease, particularly interleukin-6. It is however noteworthy that absolute values of a number of identified biomarkers were either appropriately elevated or within the normal range. This implies that these immunomodulatory treatments may be of limited benefit.Funding: National Institute for Health Research UCLH Biomedical Research Centre (BRC756/HI/MS/101440) and the UCL Coronavirus Response Fund.Declaration of Interests: MeS reports grants and advisory board fees from NewB, grants from the Defence Science and Technology Laboratory, Critical Pressure, Apollo Therapeutics, advisory board and speaker fees (paid to his institution) from Amormed, Biotest, GE, Baxter, Roche, and Bayer, and honorarium for chairing a data monitoring and safety committee from Shionogi. All other authors have nothing to declare. Ethics Approval Statement: Ethical approval was received from the London-Westminster Research Ethics Committee, the Health Research Authority and Health and Care Research Wales (HCRW) on 2nd July 2020 (REC reference 20/HRA/2505, IRAS ID 284088). The SAFER study protocol was approved by the NHS Health Research Authority (ref 20/SC/0147) on 26 March 2020. Ethical oversight was provided by the South- Central Berkshire Research Ethics Committee.
Subject(s)
Multiple Sclerosis , COVID-19 , Hemoglobin SC DiseaseABSTRACT
Background: SARS-CoV2 is associated with neurological and psychiatric complications including cerebrovascular events, encephalopathy and peripheral nerve disease. Detailed clinical data, including factors associated with recovery, is lacking, hampering prediction modelling and targeted therapeutic interventions. We studied COVID-associated neurological and psychiatric complications, to investigate the key clinical features, including those associated with outcome.Methods: This UK-wide cross-sectional surveillance study of neurological and psychiatric complications of COVID-19 in adult hospitalised patients captured detailed data on demographics/risk factors, pre-COVID-19 Rockwood frailty score, comorbidities, neurological presentation and outcome. A priori clinical case definitions, based on criteria adopted by the World Health Organisation, were used, with cross-specialty independent adjudication for discrepant cases. Patients meeting multiple clinical case definitions were identified. Cases of stroke were compared to normative data during the equivalent time-period prior to the pandemic. Multivariable logistic regression was performed using demographic and clinical variables, to determine the factors associated with outcome.Findings: 267 cases were included. Cerebrovascular events were most frequently reported (131, 49%), followed by central disorders (95, 36%) including delirium (28, 11%), central inflammatory (25, 9%), psychiatric (25, 9%), and other encephalopathies (17, 7%), including a severe encephalopathy not meeting delirium criteria; and peripheral nerve-disorders (41, 15%). 27% of cerebrovascular events occurred in patients <60 years. Relative to those >60 years old, the younger patients presented with delayed onset from respiratory symptoms, higher rates of multi-vessel occlusion (31%) and more frequently had systemic thrombotic events. Nevertheless, in both younger and older stroke cases there was an association with conventional, modifiable, cerebrovascular risk factors. The timing of neurological presentation varied between disease groups. In 34 cases (13%), clinical case definitions overlapped, and these cases were more likely to require intensive care and ventilation. Regardless of clinical case definition, older age, a higher pre-COVID-19 frailty score, and a high admission white cell count independently associated with a poor outcome. Limited recovery was most common for those with cerebrovascular events. Interpretation: COVID-19 is associated with a broad spectrum of presentations throughout the nervous system, at varied time points relative to respiratory disease. Outcomes vary between disease groups, with cerebrovascular disease conferring the worst prognosis, but this effect was less marked than the pre-morbid factors of age and frailty. A severe encephalopathy occurs after COVID-19 and is associated with requiring intensive care and ventilation. COVID-19 is associated with large and multi-vessel stroke in young people, often with non-CNS thrombotic disease and requires further study. Nevertheless, conventional, modifiable risk factors were associated with stroke, even in younger people, suggesting the potential for public health intervention for this and future pandemics. These clinical data should be combined with blood and neuroimaging biomarkers so that patients can be stratified to targeted existing or novel therapeutics.