Abstract
Background Autoimmunity has been reported in patients with severe COVID-19. We investigated whether antinuclear/extractable-nuclear antibodies (ANAs) 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.
Methods A rapid assessment line immunoassay was used to measure circulating levels of ANA/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 dyspnea were recorded at each timepoint. Multivariable logistic regression model and receiver-operating curves (ROC) were used to test the association of autoantibodies with patient-reported outcomes and pro-inflammatory cytokines.
Results 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 from 3 to 12 months (3.99 to 1.55) with persistent positive titers associated with fatigue, dyspnea, and cough severity. Antibodies to U1-snRNP and anti-SS-B/La were both positively associated with persistent symptoms of fatigue (p<0.028, AUC=0.86) and dyspnea (p<0.003, AUC=0.81). Pro-inflammatory cytokines such as tumour necrosis factor alpha (TNFα) and C-reactive protein predicted the elevated ANAs at 12 months. TNFα, D-dimer, and IL-1β had the strongest association with symptoms at 12 months. Regression analysis showed TNFα predicted fatigue (β=4.65, p=0.004) and general symptomaticity (β=2.40, p=0.03) at 12 months.
Interpretation Persistently positive ANAs at 12 months post-COVID are associated with persisting symptoms and inflammation (TNFα) in a subset of COVID-19 survivors. This finding indicates the need for further investigation into the role of autoimmunity in PASC.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflicts of interest: MM (Manali Mukherjee) is supported by early investigator award from Canadian Institutes of Health Research (CIHR) and Canadian Asthma Allergy and Immunology Foundation (CAAIF). MM reports grants from CIHR, grants from Methapharm Specialty Pharmaceuticals, personal fees from AstraZeneca, GlaxoSmithKline, consultant fees from Novartis, outside the submitted work. SS reports grants from Cyclomedica, personal fees from Arrowhead Pharmaceuticals, honorarium for lectures from AZ, honorarium for lectures from Novartis, and honorarium for lectures from Polarean, outside the submitted work. SW reports grants and consulting fees from Alk Abello, grants from Canadian Allergy, Asthma, and Immunology Foundation, Aimmune, grants and consulting fees from CSL Behring, grants from Takeda, personal and consulting fees from AZ, personal and consulting fees from GSK, consulting fees from Novartis, consulting and personal fees from Sanofi, consulting and personal fees from Medexus, consulting and personal fees from Miravo Health, consulting fees from AbbVie, consulting and personal fees from Bausch Lomb, outside of the submitted work. SW reports being president for CAAIF, board of directors for Asthma Canada, and medical advisor for Food Allergy Canada. PN reports grants and personal fees from AZ, grants and personal fees from Teva, grants and personal fees from Sanofi, personal fees from GSK, personal fees from Equillium, personal fees from Arrowhead pharma, grants from Foresee, grants from Cyclomedica, outside the submitted work. DB 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. DB reports being on the board of directors for Lung Health Foundation and being an expert witness testimony for the Government of Canada. KS, RJ, AC, Manan Mukherjee, CV, KM, KZ, ZP, BS, AY, KL, BC, KR, CH, MK, ADG, JS, QL, CR, TH, NB, IN, CC have nothing to report.
- Received May 10, 2022.
- Accepted August 4, 2022.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org
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