Increased Complement Receptor-3 levels in monocytes and granulocytes distinguish COVID-19 patients with pneumonia from those with mild symptoms

BACKGROUND: The reasons why some patients with COVID-19 develop pneumonia and others do not are unclear. To better understand this, we used multiparameter flow cytometry to profile circulating leukocytes from non-immunocompromised adult patients with PCR-proven COVID-19 and specifically compared those with mild symptoms with those who had developed pneumonia. METHODS: Using clinically validated antibody panels we studied leukocytes from 29 patients with PCR-proven COVID-19. Ten were hypoxic requiring ventilatory support, eleven were febrile but otherwise well, and eight were convalescing having previously required ventilatory support. Additionally, we analysed patients who did not have COVID-19 but received ventilatory support for other reasons. We examined routine Full Blood Count (FBC) specimens that were surplus to routine diagnostic requirements; normal ranges were established in a historic group of healthy volunteers. FINDINGS: We observed striking and unexpected differences in cells of the innate immune system. Levels of CD11b and CD18, which together comprise Complement Receptor 3 (CR3), were increased in granulocytes and monocytes from hypoxic COVID-19 patients, but not in those with COVID-19 who remained well, or in those without COVID-19 but ventilated for other reasons. Granulocyte and monocyte numbers were unchanged, however Natural Killer (NK) cell numbers were two-fold higher than normal in COVID-19 patients who remained well. INTERPRETATION: CR3 is central to leukocyte activation and subsequent cytokine release in response to infection. It is also a fibrinogen receptor, and its over-expression in granulocytes and monocytes of patients with respiratory failure tables it as a candidate effector of both the thrombotic and inflammatory features of COVID-19 pneumonia, and both a biomarker of impending respiratory failure and potential therapeutic target. NK cells are innate immune cells that retain immunological memory. Rapid expansion of memory NK cells targeting common antigens shared with other Coronaviruses may explain why most patients with COVID-19 do not develop respiratory complications. Understanding the innate immune response to SARS-CoV-may uncover why most infected individuals experience mild symptoms, and inform a preventive approach to COVID-19 pneumonia in the future.