Assessing complement activation in COVID-19 predicts hypoxemia and mortality

Background: Infection with SARS-CoV-2 triggers a thromboinflammatory response with widespread endothelial damage and micro-and macro-vascular thrombosis that is associated with impaired function of multiple organs. Mechanisms underlying the hyperacute innate response that drives coagulation and inflammation are incompletely understood. Several lines of evidence support a role for overactivation of complement. Aims: To better understand the involvement of complement in COVID-19. Methods: We prospectively studied 25 COVID-19 ICU-hospitalized patients for up to 21 days. Commercial ELISAs were used to quantify complement pathway proteins and activation markers in serum of the patients and 25 healthy controls. Correlative and regression analyses were performed to determine the predictive value of biomarkers, in terms of respiratory function and mortality. Results: On admission, all COVID-19 patients exhibited significantly increased serum levels of terminal products of complement activation, C5a and sC5b-9. C4d levels, reflecting activation via the classical/ lectin pathways, were variably increased. All patients had excess activation of the alternative pathway (AP) with significantly elevated levels of factor B activation fragments, Ba and Bb. This was associated with a significant reduction (∼25%) in FH, a negative regulator of the AP. Ba levels correlated strongly with serum creatinine, the latter being a strong predictor of in-hospital mortality in COVID-19. C5a, Ba, Bb and factor D (FD) were significantly associated with hypoxemia. C5a, Ba, and FD, but not D-dimer, were significant independent predictors of mortality. Notably, levels of all complement activation markers were sustained throughout the patients' ICU stays, a finding in contrast to serum levels of IL-6, C-reactive protein and ferritin, which were more variable. Conclusions: All severely ill COVID-19 patients have increased and persistent activation of complement, minimally mediated via the AP. Complement activation biomarkers may be valuable predictors of hypoxemia and mortality. Large-scale studies will reveal the relevance of these findings to thrombo-inflammation in acute and postacute COVID-19.

Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.