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

Abstract

BackgroundAutoimmunity 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.MethodsA 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.ResultsCompared 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.InterpretationPersistently 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.

Clinical, imaging, serological, and histopathological features of pulmonary post-acute sequelae after mild COVID-19 (PASC)

“…Both autoimmunity and persistence of virus/viral particles are discussed as possible contributors in the pathophysiology of PASC [11,13]. Using immunohistochemistry and RT-PCR, we did not detect SARS-CoV-2 or virus-derived spike or nucleocapsid proteins in lung tissue samples from all but one (2%) of PASC patients.…”

“…It has been proposed that impaired lung function might be associated with dysregulated respiratory CD8+ T cell responses or damage to the pulmonary vasculature after acute COVID-19 [9,10]. Furthermore, presence of circulating antinuclear autoantibodies (ANA) have been shown to predict PASC in COVID-19 survivors [11]. This is of interest given the association between the presence of autoantibodies (ANA/ENA) and the severe course of acute COVID-19, which we have previously described [12].…”

Autoimmune complications of COVID-19 and potential consequences for long-lasting disease syndromes

“…These autoantibodies could be generated as a regulatory mechanism for controlling the excess of interferon release, but as for cytokines, in the presence of some extreme pathological conditions, they can deviate the immune response by interfering in their function. Among the autoantibodies described in patients with Covid-19 are those provoking Guillain-Barré syndrome, thrombocytopenia, and anti-nuclear antibodies [94] , [111] , [112] . Of special relevance is the Kawasaki disease, observed in a few children infected with SARS-Cov-2, which is an autoimmune vasculitis probably induced by autoantibodies to endothelial cells [113] , [114] .…”

High Prevalence of Alternative Diagnoses in Children and Adolescents with Suspected Long COVID—A Single Center Cohort Study

“…While potential explanatory patho-mechanisms for the development of LC have been described, no diagnostic biomarker for LC has been identified [ 6 , 7 , 8 , 9 , 10 ]. The thorough exclusion of other underlying somatic or psychiatric diseases that might cause the presented symptoms is an essential part of the work-up in suspected LC.…”