Circulating anti-nuclear autoantibodies in COVID-19 survivors predict long COVID symptoms.

Autoimmunity has been reported in patients with severe coronavirus disease 2019 (COVID-19). We investigated whether anti-nuclear/extractable-nuclear antibodies (ANAs/ENAs) were present up to a year after infection, and if they were associated with the development of clinically relevant post-acute sequalae of COVID-19 (PASC) symptoms. A rapid-assessment line immunoassay was used to measure circulating levels of ANAs/ENAs in 106 convalescent COVID-19 patients with varying acute phase severities at 3, 6 and 12 months post-recovery. Patient-reported fatigue, cough and dyspnoea were recorded at each time point. Multivariable logistic regression model and receiver operating curves were used to test the association of autoantibodies with patient-reported outcomes and pro-inflammatory cytokines. Compared to age- and sex-matched healthy controls (n=22) and those who had other respiratory infections (n=34), patients with COVID-19 had higher detectable ANAs at 3 months post-recovery (p<0.001). The mean number of ANA autoreactivities per individual decreased between 3 and 12 months (from 3.99 to 1.55) with persistent positive titres associated with fatigue, dyspnoea and cough severity. Antibodies to U1-snRNP and anti-SS-B/La were both positively associated with persistent symptoms of fatigue (p<0.028, area under the curve (AUC) 0.86) and dyspnoea (p<0.003, AUC=0.81). Pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and C-reactive protein predicted the elevated ANAs at 12 months. TNF-α, D-dimer and interleukin-1β had the strongest association with symptoms at 12 months. Regression analysis showed that TNF-α predicted fatigue (β=4.65, p=0.004) and general symptomaticity (β=2.40, p=0.03) at 12 months. Persistently positive ANAs at 12 months post-COVID are associated with persisting symptoms and inflammation (TNF-α) in a subset of COVID-19 survivors. This finding indicates the need for further investigation into the role of autoimmunity in PASC.

Copyright ©The authors 2023.

Conflict of interest: Manali Mukherjee is supported by early investigator award from Canadian Institutes of Health Research (CIHR) and Canadian Asthma Allergy and Immunology Foundation (CAAIF); and reports grants from CIHR and Methapharm Specialty Pharmaceuticals, personal fees from AstraZeneca and GlaxoSmithKline, consultant fees from Novartis, outside the submitted work. S. Svenningsen reports grants from Cyclomedica, personal fees from Arrowhead Pharmaceuticals, honorarium for lectures from AZ, Novartis and Polarean, outside the submitted work. S. Waserman reports grants and consulting fees from Alk Abello and CSL Behring, grants from Canadian Allergy, Asthma, and Immunology Foundation, Aimmune and Takeda, personal and consulting fees from AZ, GSK, Sanofi, Medexus, Miravo Health and Bausch Lomb, consulting fees from Novartis, Pfizer and AbbVie, outside of the submitted work; and is chairperson of an advisory board for Siolta, president for CAAIF, board of directors for Asthma Canada, and medical advisor for Food Allergy Canada. P. Nair reports grants and personal fees from AZ, Teva and Sanofi, personal fees from GSK, Equillium and Arrowhead pharma, grants from Foresee and Cyclomedica, outside the submitted work. N. Balakrishnan reports grants from Natural Sciences and Engineering Research Council of Canada, outside the submitted work. D.M.E. Bowdish reports grants from COVID-19 Immunity Task Force/Public Health Agency of Canada, grants from National Science and Engineering Research Council (NSERC), grants from Canadian Institutes of Health Research, personal fees from AZ Mexico, personal fees for invited presentations from academic institutions, outside the submitted work; and is on the board of directors for Lung Health Foundation, and has been an expert testimony witness for the Government of Canada. K. Son, R. Jamil, A. Chowdhury, Manan Mukherjee, C. Venegas, K. Miyasaki, K. Zhang, Z. Patel, B. Salter, A.C.Y. Yuen, K.S-K. Lau, B. Cowbrough, K. Radford, C. Huang, M. Kjarsgaard, A. Dvorkin-Gheva, J. Smith, Q-Z. Li, C.J. Ryerson, T. Ho, I. Nazy and C. Carlsten have nothing to report.