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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of COVID-19, which has affected more than 6 million people worldwide causing more than 400 000 deaths. The disease affects predominantly the upper and lower respiratory tracts causing severe pulmonary disease which often evolves to a multiorgan systemic disease.1 This is evidenced by thromboembolic lesions of the heart and lungs, pulmonary haemorrhage, muscle weakness, hyperbilirubinaemia and lymphopenia suggesting that COVID-19 affects epithelial barriers, endothelial cells, coagulation, fibrinolysis and the immune system.2 In patients who are severely ill, innate immune hyperactivity causes a cytokine storm which disturbs microcirculation resulting in shock and acute respiratory distress syndrome.3 Systemic disease perpetuation may be due to the virus itself, infecting cells via ACE2 receptor or, following the cytokine storm, due to autoinflammatory and/or autoimmune mechanisms.4
Earlier studies reported that certain autoantibodies such as anti-cardiolipin (a-CL), anti-β2GPI and lupus anticoagulant might associate with the thromboembolic complications occurring in many patients with COVID-19.5 These findings, along with the observation that certain clinical features of the infection can mimic those observed in systemic autoimmune diseases, prompted us to investigate serum autoantibodies in these patients and their clinical associations.
We tested the sera of 29 unselected severely ill patients with COVID-19 with positive SARS-CoV-2 PCR, admitted to the intensive care unit of Evangelismos Hospital, Athens, Greece (table 1). Twenty-one patients were male (72.4%) and eight were female (27.6%) with an average age of 64.2 years (range 43–85). Patients were hospitalised for an average of 25.6 days. Testing for anti-SARS-CoV-2 IgG antibodies revealed that 28/29 patients were positive with an average index of 8.54 (Euroimmun, Luebeck, Germany, positive cut-off >1.1). All patients were tested for the following autoantibodies using techniques routinely used in our laboratory: antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA,immunofluorescence), antibodies to extractable nuclear antigens (ENA, immunoblot), a-dsDNA, a-CL (IgG/IgM), a-β2GPI (IgG/IgM) and anti-cyclic citrullinated peptide (CCP,ELISA). We found that 10 patients were positive for antinuclear antibodies (34.5%), 2 were positive for p-ANCA (6.9%), 2 were positive for c-ANCA (6.9%, one with a high 1/640 titre), 7 were positive for a-CL antibodies (24.1%, 4 IgG, 3 IgG+IgM), 10 were positive for anti-β2GPI antibodies (34.5%, 2 IgG, 5 IgM, 3 IgG+IgM) and 1 was positive for anti-CCP antibodies (3.5%). ANCA positivity was further investigated with ELISA, but no known specificities, including proteinase 3 or myeloperoxidase, were identified. This has been previously reported for acute viral hepatitis E.6 None of the patients had a history of systemic autoimmune rheumatic disease. Overall, 20/29 patients with COVID-19 (68.7%) were positive for any kind of systemic autoantibody. Notable laboratory findings include: anaemia (44.9%), significant lymphopenia (62.1%), elevated lactic acid dehydrogenase levels (96.6%), increased fibrinogen levels (100%), elevated creatine kinase levels (41.4%) and increased C-reactive protein levels (89.6%). The average sequential organ failure assessment score of our patients was 7.89 (SD 2.44, range 2–11). Patients, with the exception of hydroxychloroquine (28/29 treated), were not treated with any immunomodulatory drugs.
The small sample size did not allow procurement of any statistically significant clinicolaboratory associations. Despite this and the lack of preinfection serological data, the presence of several systemic autoimmune reactivities in almost 70% of the patients suggests a post-SARS-CoV-2 or para-SARS-CoV-2 infectious autoimmune activation. This is not surprising, as cytokines present in the cytokine storm, for example, interleukin-6, can drive autoinflammatory reactions and autoimmunity, probably via pre-existing natural B cell clones or molecular mimicry. The possible autoimmune mechanism merits further investigation, therefore an autoimmune surveillance in larger cohorts is necessary to investigate possible mechanisms of COVID-19 perpetuation and to inform ongoing convalescence plasma therapeutic trials.7 8 As several of the reported autoantibodies are disease markers and can be pathogenic, one should be cautious before transferring autoantibodies, along with neutralising antibodies, into severely affected patients.
Handling editor Josef S Smolen
Contributors All authors contributed equally to this work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.