Clinical and laboratory findings were retrospectively assessed. to admitted COVID19 patients with favorable disease course (n=32). The presence of antinuclear antibodies (ANA) and auto-antibodies against AT1R or ETAR in peripheral blood were compared between COVID19 with unfavorable and favorable disease course and age matched controls (n=20). Results The presence of ANA was not significantly different between COVID19 patients with unfavorable (n=7/33; 21%) and favorable disease course (n=6/32; 19%) (p= 0.804) and controls (n=3/20; 15%). Auto-antibodies against AT1R were significantly increased in unfavorable disease course (median 14.59 U/mL, IQR 11.28 C 19.89) compared to favorable disease course (median 10.67 U/mL, IQR 8.55 C 13.0, p< 0.01). ETAR antibody titers were also significantly increased in unfavorable disease course (median 7.21, IQR 5.0 C 10.45) as compared to favorable disease course (median 4.0, IQR 3.0 C 6.0, p <0.05). Conclusion Auto-antibodies against AT1R and ETAR are significantly increased in COVID19 patients with an unfavorable disease course. Keywords: COVID19, Endothelin Receptor Type A Antibody, Angiotensin II Receptor type 1 Antibody, Antinuclear antibody (ANA), Autoimmunity, Prognosis (D011379) Introduction The disease course of contamination with Severe Acute Respiratory Syndrome Coronavirus 2 (COVID19) is usually highly variable, from asymptomatic to pneumonia and acute respiratory distress syndrome with multiorgan failure (1). Lung histopathology demonstrates diffuse alveolar damage with vasculopathy, angiocentric inflammation and microthrombi in a subset of deceased COVID19 patients (2). Increasing evidence shows that endothelial dysfunction plays an important role in severe COVID19 disease progression and associated coagulopathy (2, 3). The observed pulmonary vascular damage in COVID19 patients resembles antibody-mediated rejection (AMR) after lung transplantation. Although AMR is usually caused by the formation of antibodies directed at the donor specific human leucocyte antigen (HLA) system, it has also been associated with non-HLA auto-antibodies against the G-protein coupled receptors Angiotensin II Receptor type 6-Maleimido-1-hexanol 1 6-Maleimido-1-hexanol (AT1R) and Endothelin receptor Type A (ETAR) (4, 5). The similarity between vasculopathy in severe COVID19 and AMR after lung transplantation raised the question whether comparable autoimmune mechanisms contribute to COVID19 pathogenesis. Method 6-Maleimido-1-hexanol We assessed AT1R, ETAR and antinuclear antibodies (ANA) in peripheral blood of n=65 COVID19 patients, admitted in March and April 2020 to the Erasmus University or college Medical Center (n=21) and Amphia Hospital (n=44) and n=20 age matched elderly controls. Contamination with SARS CoV2 was confirmed with polymerase chain reaction in all patients. Clinical and laboratory findings were retrospectively assessed. We defined the COVID19 disease course as unfavorable if patients were admitted to the rigorous care unit (ICU) and/or died during hospital admission (n=33) and favorable in patients treated on the general ward (n=32). Because of the non-interventional design, this study was exempt from ethics approval by the Institutional Review Table of Erasmus MC and Amphia Hospital. Laboratory measurements for the presence of AT1R and ETAR antibodies were performed on available BSPI blood samples from COVID19 patients at the Laboratory Medical Immunology of the Erasmus MC (Rotterdam, the Netherlands). Anti-AT1R and CETAR were decided in serum (obtained by venepuncture followed by 30?min. clotting of peripheral blood and 5?min. centrifugation at 3000?g) using a CE-marked enzyme immuno-assay (EIA), developed at CellTrend GmbH (https://www.celltrend.de/en/elisa/in-vitro-diagnostika-human/), according to the manufacturers instructions. Available blood samples were collected 6.4 days after admission in the favorable group, compared with 8.6 days in the unfavorable group (p = 0.037, Table 1A ). For both antibodies against AT1R and ETAR the same concentration of 10 U/mL was considered the cut-off value (10-17 U/ml borderline 6-Maleimido-1-hexanol and >17 U/ml positive) in line with the manufacturers recommendation based on previous validation (6). Anti-nuclear antibodies (ANA) were determined using classical indirect immunofluorescence on HEp2 cells, at 1:80 serum dilution, according to standard protocol. Only nuclear immunofluorescence patterns were considered ANA positive. Differences in clinical and laboratory characteristics were assessed between the control and overall COVID group and between the two outcomes in the COVID group. Continuous outcomes were analyzed.