RR:C19 Evidence Scale rating by reviewer:
Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.
Severe cases of COVID-19 are associated with acute respiratory distress syndrome (ARDS), a type of pulmonary failure associated with a diffuse, acute inflammatory response in the lung. Treatment with the steroid dexamethasone was recently shown to improve survival rates of COVID-19 patients on mechanical ventilation, suggesting that for a subset of patients, general immune suppression may be beneficial. However, as steroids like dexamethasone also inhibit beneficial immune responses, targeted anti-inflammatory interventions are likely to be both safer and more generally effective. This manuscript describes a potential driver of the hyper-inflammatory response to the SARS-CoV-2 virus. Building on previous observations with SARS-CoV, the authors demonstrate that anti-spike IgG antibodies from COVID-19 patients complexed with SARS-CoV-2 spike antigen in the presence of the double-stranded RNA mimic polyIC, induce human macrophages cultured in vitro to produce inflammatory cytokines often associated with ARDS, including IL-6. Serum from patients with a measurable anti-spike IgG response induce stronger pro-inflammatory cytokine production from macrophages in vitro when compared with serum from COVID-19 patients who did not mount a strong anti-spike IgG response. ARDS is associated with disruption of the microvascular endothelium and dysregulated clotting response. The authors demonstrate that conditioned supernatants of activated macrophages treated with anti-spike IgG from COVID patients significantly induce endothelial cell hyperpermeability and promote platelet adhesion in vitro, a phenomenon that models endothelial barrier integrity and is likely explained by the presence of proinflammatory cytokines in the macrophage supernatants. To address the question of how IgG initiates this response, the authors suggest that the aberrant proinflammatory phenotype may be explained through decreased levels of fucosylation on anti-Spike IgG compared to total sera IgG. Finally, the authors convincingly show that a significant portion of their phenotype requires Fcγ receptor signaling, and that pharmacological inhibition of FcγR signaling with a Syk inhibitor decreases the inflammatory response of macrophages. A minor concern with this study is that the authors utilize M2 polarized human macrophages as a model system. It is not completely clear that these macrophages are relevant to macrophages present in the lung in vivo during infection with SARS-CoV-2, or more specifically to the yet unknown cell type that drives the hyperinflammatory response in COVID-19 patients. Furthermore, in order to observe significant cytokine production by macrophages treated with anti-spike IgG, the authors must co-treat with polyIC, a viral mimic, suggesting that cells in vivo that respond to IgG must also be simultaneously exposed to viral stimuli. In general, however this manuscript addresses an important topic, and the findings reported are convincing. Although it remains unclear that FcR driven hyperinflammatory responses are relevant in COVID-19 patients, this study should motivate further investigation of this phenomenon as the ability to selectively inhibit FcR receptor driven inflammation could result in more targeted and effective interventions. Furthermore, these findings suggest that care should be taken when using convalescent serum as a therapy for COVID-19.