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.

Abstract RATIONALE: Dyspnea and respiratory impairment are sequelae of COVID-19. OBJECTIVES The objectives of this study were to observe the prevalence and clinical relevance of ventilation (V) and perfusion (Q) impairment, evaluated by ventilation/perfusion-single-photon emission computed tomography-computed tomography (VQ-SPECT-CT), in individuals with no history of lung disease 4-weeks after recovery from noncritical COVID-19. METHODS We enrolled 25 COVID-19 patients’ post-recovery and 11 control subjects. All participants underwent VQ-SPECT-CT using 99mTc-Technegas for V and 99mTc-macroaggregated albumin for Q, spirometry, six-minute-walk-test, blood draw and completed the modified Medical Research Council (mMRC) dyspnea-scale and St. Georges Respiratory Questionnaire (SGRQ). VQ-SPECT-CT was reviewed to report lung function and structure abnormalities and ventilation-heterogeneity was quantified to evaluate associations with symptoms, exercise-capacity and inflammatory markers. MEASUREMENTS AND MAIN RESULTS: Of 25 post-COVID-19 participants, 9 were hospitalized and 16 home-isolated during acute-infection. A total of 88% of hospitalized and 44% of home-isolated participants were reported to have V defects (matched VQ defects: 63% and 44%; mismatched V defects: 38% and 13%), compared to 30% of never-COVID-19 controls (matched VQ defects: 30%, mismatched V defects: 10%) (P = 0.02 and P = 0.68, respectively). Ventilation-heterogeneity was greater in hospitalized (P = 0.003), but not home-isolated participants, compared to the never-COVID-19 controls. Post-COVID-19 ventilation-heterogeneity correlated with the dyspnea-scale (r = 0.45, P = 0.03), SGRQ-score (r = 0.41, P = 0.04), 6MWD (r=-0.49, P = 0.02), SpO2 (P = -0.55, P = 0.005), CT parenchymal opacities (r = 0.42, P = 0.04) and neutrophil percent (r = 0.45, P = 0.04), but not pro-inflammatory cytokines, C-reactive protein or D-dimer. CONCLUSIONS This small functional lung imaging study revealed ventilation impairment in individuals with no history of lung disease recovering from noncritical COVID-19 that was associated with parenchymal opacities, respiratory symptoms and exercise-capacity.

Accumulating evidence suggest that autoimmune phenomena are frequentduring Coronavirus Disease 2019 (COVID-19) and may lead to clinicallyovert disease. The breakdown of immune tolerance and/or impaired immunereconstitution after the initial phase may be involved in thepathogenesis [1]. The ensuing autoimmunity may also be involved inPost-Acute COVID syndrome (PACS) [2]. Herein, we evaluate thecurrent scenario based on anecdotal patient reports of new-onsetautoimmune disease/diagnosis as a sequalae of COVID-19.