Pathophysiology of acute respiratory syndrome coronavirus 2 infection: A systematic literature review to inform eular points to consider

Najm, A.; Alunno, A.; Mariette, X.; Terrier, B.; De Marco, G.; Mason, L.; Emmel, J.; McGonagle, D.; Machado, P. M.

Background: The severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Rheumatologists have the best experience of studying and treating these complicated hyperinflammatory processes. Objectives: To summarize the available information on pathophysiology of COVID-19. Methods: As part of a EULAR taskforce, two systematic literature reviews were performed one on pathophysiology and one on immunomodulatory therapies. Two reviewers independently identified eligible studies according to the following PICO framework: P (population): patients with SARS-CoV-2 infection;I (intervention): any intervention/no intervention;C (comparator): any comparator;O (outcome) any clinical or serological outcome including but not limited to immune cell phenotype and function and serum cytokine concentration. The results pertaining to pathophysiology of COVID-19 are presented here. Results: Of the 55496 records yielded, 85 articles were eligible for inclusion. Included studies were at variable risk of bias and exploring various aspects of disease pathogenesis from immune to non-immune cells (Table 1). Pro-inflammatory cytokines' expression including IL-6, was increased, especially in severe COVID-19, although not as high as other states with severe systemic inflammation. Innate and adaptative immune cell compartments were differentially affected by SARS-CoV-2 infection: neutrophils displayed an immature differentiation state and also increased neutrophil extracellular traps (NETs) formation. Dendritic cell number was reduced and classical monocytes was increased although displaying a reduced expression of HLA-DR. The lymphoid compartment was also affected: lymphopenia was present with a reduced number of CD4+ and CD8+ T lymphocytes and more frequent PD1+CD8+ T cells corresponding to an exhausted phenotype. Antibody response to SARS-CoV-2 infection showed a high variability across individuals and disease spectrum. Multiparametric algorithms showed variable diagnostic performances in predicting survival, hospitalization, disease progression or severity, and mortality. Differences in SARS-CoV-2 manifestations in adults and children were highlighted. Conclusion: Overall, SARS-CoV-2 infection affects both innate and adaptative immune responses in a variable way, according to both disease severity and individual parameters. This SLR informs the EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19.