IntroductionThe new coronavirus disease, COVID-19, poses complex challenges exacerbated by several factors, with respiratory tissue lesions being notably significant among them. Consequently, there is a pressing need to identify informative biological markers that can indicate the severity of the disease. Several studies have highlighted the involvement of proteins such as APOA1, XPNPEP2, ORP150, CUBN, HCII, and CREB3L3 in these respiratory tissue lesions. However, there is a lack of information regarding antibodies to these proteins in the human body, which could potentially serve as valuable diagnostic markers for COVID-19. Simultaneously, it is relevant to select biological fluids that can be obtained without invasive procedures. Urine is one such fluid, but its effect on clinical laboratory analysis is not yet fully understood due to lack of study on its composition.MethodsMethods used in this study are as follows: total serum protein analysis; ELISA on moderate and severe COVID-19 patients’ serum and urine; bioinformatic methods: ROC analysis, PCA, SVM.Results and discussionThe levels of antiAPOA1, antiXPNPEP2, antiORP150, antiCUBN, antiHCII, and antiCREB3L3 exhibit gradual fluctuations ranging from moderate to severe in both the serum and urine of COVID-19 patients. However, the diagnostic value of individual anti-protein antibodies is low, in both blood serum and urine. On the contrary, joint detection of these antibodies in patients’ serum significantly increases the diagnostic value as demonstrated by the results of principal component analysis (PCA) and support vector machine (SVM). The non-linear regression model achieved an accuracy of 0.833. Furthermore, PCA aided in identifying serum protein markers that have the greatest impact on patient group discrimination. The study revealed that serum serves as a superior analyte for describing protein quantification due to its consistent composition and lack of organic salts and drug residues, which can otherwise affect protein stability.