BACKGROUND:Critical illness in coronavirus disease 2019 may require extracorporeal membrane oxygenation support. We quantified immunothrombotic markers in patients with COVID-19 receiving ECMO and evaluated their predictive capacity for death. METHODS:We performed a retrospective analysis of 74 consecutive patients with COVID-19 on ECMO at a single academic medical center between March 2020 and February 2021. Severe acute respiratory syndrome coronavirus-2 nucleocapsid RNA and 16 immunothrombotic biomarkers were longitudinally quantified and their trajectories were used to predict death and decannulation across multiple models. RESULTS:Male sex, smoking, serum bilirubin levels, and low partial arterial oxygen pressure-fraction of inspired oxygen ratio were associated with increased risk of death. Plasma levels of 10 immunothrombotic markers were significantly elevated in fatal cases and some were associated with an increased hazard of death (eg, interleukin 8, von Willebrand factor) or decreased hazard for decannulation (eg, angiopoietin 2, interleukin 1β) when adjusting for sex, smoking status, and time to cannulation. Predictive models incorporating biomarkers were superior to demographics alone and equivalent to models including clinical information. CONCLUSIONS:We found that male sex, smoking, and select clinical variables and immunothrombotic markers were risk factors for death in patients with COVID-19 on ECMO informing pathogenesis and prognostication of severe COVID-19.

Understanding disease pathogenesis is essential to developing therapies in patients with infections that cause critical illness. Herein, we show that SARS-CoV-2-specific antibody levels and markers of neutrophil activation are associated with disease severity in patients hospitalized with COVID-19. We also provide a link between the adaptive and innate immune response by demonstrating an association between antibody levels and multiple markers of neutrophil degranulation and NETosis. We further demonstrate through a series of in vitro assays that SARS-CoV-2 antigen-antibody immune complexes can stimulate NETosis. Last, we discuss how this NETosis is more strongly associated with IgA immune complexes than IgG and can be ameliorated with spleen tyrosine kinase inhibition.

BACKGROUND:Sepsis is a leading cause of death worldwide. Identifying novel host-directed therapeutic targets may improve sepsis outcomes. METHODS:Six nonhuman primates were infected with Klebsiella pneumoniae to induce septic shock and provided supportive care for up to 72 hours. Flow cytometry was used to characterize whole-blood neutrophils (WBNs) and low-density neutrophils (LDNs) at time 0 (T0), T6, T24, and T48 hours postinfection, and postmortem examination (ie, necropsy). Dimensional reduction with clustering via FlowSOM and traditional gating strategies were used to compare WBNs to LDNs and delineate spleen tyrosine kinase (SYK) expression across neutrophils subsets. We measured soluble biomarkers of end-organ dysfunction and neutrophil activation, and quantified SYK and myeloperoxidase in tissue. RESULTS:At T6, we identified populations of active immature WBNs and a population of LDNs not detected at baseline. At T24, neutrophil heterogeneity increased across WBNs and LDNs with differential expression of myeloperoxidase (MPO). Compared to WBNs, LDNs were more activated with increased MPO expression. At T6, SYK expression surged in WBNs and LDNs and SYK+ WBNs and LDNs expressed higher levels of MPO and lactoferrin compared to SYK- neutrophils. Circulating levels of SYK+ LDNs significantly correlated with serum creatinine levels, indicative of acute kidney injury; prolonged prothrombin time and decreased fibrinogen, indicative of consumptive coagulopathy; and SYK expression in tissues. CONCLUSIONS:Bacterial sepsis leads to heterogenous populations of circulating neutrophils, including LDNs. Elevated SYK expression in WBNs and LDNs correlates with end-organ dysfunction, highlighting SYK as a potential therapeutic target in bacterial sepsis.

Nonhuman primate models that closely emulate the disease course, pathogenesis, and supportive care provided to human patients in the modern intensive care unit with bacterial sepsis are urgently needed to study pathogenesis and assess novel therapies. We therefore developed a non-human primate model of septic shock that includes supportive care akin to a modern intensive care unit. In this study, we characterized pathogen kinetics and evaluated the physiologic, immunologic, and pathologic responses in this model of septic shock induced by the clinically relevant pathogen Klebsiella pneumoniae across a three-log dose range. We observed dose-dependent bacteremia and circulating levels of Klebsiella pneumoniae DNA and endotoxin. Tachycardia and hypotension occurred in all animals and the study endpoint occurred in 8 of 12 animals that were euthanized. The infused bacterial dose was significantly associated with the severity of renal insufficiency and coagulopathy. Neutrophil activation evidenced by increased CD11b expression, decreased CD62L expression, and increased circulating levels of myeloperoxidase, lactoferrin, and neutrophil extracellular traps; monocyte activation evidenced by increased circulating levels of interleukin-6, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, and monocyte chemotactic protein-1; and endothelial activation evidenced by increased circulating levels of syndecan-1 and angiopoietin-II were all consistent with human sepsis. Our model provides an opportunity to study pathogenesis and investigate novel therapeutics for the treatment of bacterial sepsis in the setting of modern supportive care. IMPORTANCE There is currently a disconnect between the efficacy of sepsis therapies in pre-clinical animal models and human clinical trials. Therefore, developing nonhuman primate models that closely mimic human sepsis pathogenesis to study novel host-targeted therapeutics is a priority. In this study, we developed a model of septic shock with a clinically relevant bacteria (Klebsiella pneumoniae) that provides standard supportive care including mechanical ventilation, invasive hemodynamic monitoring, volume resuscitation, vasopressors, antibiotics, and steroids. In a dose-dependent manner, we observed that this model closely emulates the hemodynamic, end-organ dysfunction, and cellular and soluble responses associated with human sepsis. This validated model provides a unique opportunity to study the pathogenesis of acute septic shock and evaluate host-directed therapeutics in a large animal model that closely emulates the modern-day intensive care unit and supportive critical care.

Modulating SYK has been demonstrated to have impacts on pathogenic neutrophil responses in COVID-19. During sepsis, neutrophils are vital in early bacterial clearance but also contribute to the dysregulated immune response and organ injury when hyperactivated. Here, we evaluated the impact of R406, the active metabolite of fostamatinib, on neutrophils stimulated by LPS. We demonstrate that R406 was able to effectively inhibit NETosis, degranulation, ROS generation, neutrophil adhesion, and the formation of CD16low neutrophils that have been linked to detrimental outcomes in severe sepsis. Further, the neutrophils remain metabolically active, capable of releasing cytokines, perform phagocytosis, and migrate in response to IL-8. Taken together, this data provides evidence of the potential efficacy of utilizing fostamatinib in bacterial sepsis.

Abstract Background Critical illness in COVID-19 may require mechanical support with Extra-Corporeal Membrane Oxygenation (ECMO). Thromboinflammation, the interaction of thrombotic and inflammatory pathways, is seen in many conditions including sepsis and acute respiratory distress syndrome (ARDS) and may drive poor outcomes in critically ill patients. We sought to characterize thromboinflammation in critically ill patients with COVID-19 on ECMO and determine if it was associated with death. Methods 74 consecutive patients with COVID-19 who were cannulated and supported on ECMO at a single academic center between May 2020 and February 2021 were included in this study. Demographic, clinical and laboratory variables were collected daily and a panel of 16 thromboinflammatory biomarkers were measured in plasma on days 1, 3, 5, 8, 11, 15, 22, 29, and 40 of cannulation in a bead-based multiplex assay. Digital droplet PCR was used to measure plasma SARS-CoV-2 nucleocapsid RNA. Non-parametric mixed-effects models were used to estimate biomarker trajectories, and Cox regression was used to determine hazard ratios while controlling for demographics. Results Male sex, smoking status, high bilirubin, and low ratios of the partial pressure of oxygen in arterial blood to the fraction of inspired oxygen (P/F ratio) were associated with an increased risk of death. Non-parametric mixed-effect regression indicated angiopoietin, IL-1a, IL-1b, IL-6, IL-8, Syndecan-1, VCAM1, and ICAM were higher in patients who died. In Cox regression models IL-6, IL-8, S100A8, thrombomodulin, and von Willebrand factor among others were associated with hazard of death or decannulation when controlling for sex, smoking status, and time from symptom onset to cannulation. Viral RNA was highest in patients immediately after cannulation but did not predict death.Figure 1:Non-parametric mixed model of 16 thromboinflammatory markers over time, separated by patient outcome. Asterixis represent significant differences (p<0.05) between patients who lived vs died. Blue: patients who were decannulated. Red: patients who died.Figure 2:Cox regression models controlling for sex, smoking status, and time from symptom onset to cannulation. A) Hazard ratio of clinical, laboratory and thromboinflammatory measures for death. B) Hazard ratio of clinical, laboratory and thromboinflammatory measures for decannulation. Red bars indicate variables where the 95% confidence interval did not cross 1.Figure 3:SARS-CoV-2 RNA viral copy number in plasma decreases over time. Lines represent individual patients. Dashed line represents limit of detection. Blue: patients who were decannulated. Red: patients who died. Conclusion We found there was evidence for increased thromboinflammation in patients with COVID-19 on ECMO who died as compared to those who were decannulated. Multiple demographic and laboratory risk factors were also identified. These findings are important for understanding the pathogenesis of severe COVID-19 as well prognostication in the most critically ill patients and allocation of the scarce resource of ECMO support. Funded by NCI Contract No. HHSN261201500003I Disclosures All Authors: No reported disclosures

Abstract Background Disease severity in SARS-CoV-2 infection is associated with elevated levels of neutrophil extracellular traps (NETs) and antibodies. We previously demonstrated that plasma from patients with SARS-CoV-2 infection stimulates the release of NETs by healthy donor neutrophils and that this can be reversed by R406, a spleen tyrosine kinase (SYK) inhibitor. Immune complexes, stimulating through Fc receptors, induce robust NETosis through a SYK-mediated pathway. Therefore, we hypothesized that SARS-CoV-2 spike immune complexes can mediate the release of NETs from neutrophils and that this process can be reversed by R406. Methods To test this, we created spike specific immune complexes utilizing an optimized concentration of affixed spike-trimer and SARS-CoV-2 patient plasma and evaluated the ability of these complexes to stimulate NETosis from healthy neutrophils. We quantified both IgG and IgA spike specific immune complex formation by ELISA utilizing HRP conjugated secondary antibodies (Promega Glomax Plate Reader). Healthy donor neutrophils were isolated, added to wells containing the spike immune complexes with and without R406, and live cell imaging (Incucyte S3) was used to visualize and quantify NETs. Results Incubation of COVID-19 patient plasma with spike protein resulted in an average 7-fold and 9-fold increase in the formation of IgA and IgG spike specific immune complexes, respectively, compared to spike alone (Figure 1A). After stimulating healthy donor neutrophils with the spike immune complexes created from six SARS-CoV-2 patient plasma samples, we observed a mean 200% increase in the induction of NETs relative to spike alone (Figure 1B). There were positive correlations between immune complexes formation and NETs formed in cells exposed to those wells (IgA R2= 0.67, p=0.01 and IgG R2= 0.82, p=0.002). Preliminary data suggests that spike-immune complex NET formation can be reduced by R406 (n=3 COVID-19 plasma donors). Figure 1A-B A) Quantification of IgA and IgG spike immune complexes was measured through measurement of absorbance at 405 nm after exposure to ABTS for 15 minutes. Value normalized to the spike alone condition ran on each day, and data represents a fold change from that condition (Ordinary One-way ANOVA: ** indicates p < 0.01; *** indicates p < 0.001; **** indicates p <0.0001). B) Induction of NETs 6 hours after exposure, demonstrating percent increase in NETosis in plasma isolated from COVID-19 patients (n=6) and healthy patients (n=2) in the presence and absence of SARS-CoV-2 spike immune complexes. Area of NETs was quantified by calculating the area (µm2 ) of ecDNA, visualized by Incucyte® Cytotox Green Dye. Area of NETs at T0 was subtracted from all conditions, and the induction of NETs was calculated as percentage increase relative to NETosis induced by SARS-CoV spike alone condition run on each day (Ordinary One-way ANOVA: ** indicates p < 0.01; *** indicates p < 0.001; **** indicates p <0.0001). Conclusion Using our ELISA, we demonstrated that we can reliably generate spike-specific IgG and IgA immune complexes. Stimulation of healthy donor neutrophils by spike immune complexes increased NET-formation compared to spike alone providing evidence of immune complex mediated NET induction in SARS-CoV-2 infection. Disclosures All Authors: No reported disclosures

Introduction: Sepsis severity is associated with a dysregulated neutrophil response including increased neutrophil extracellular traps (NETs) and decreased margination. Here we query the effects of a spleen tyrosine kinase (SYK) inhibitor (R406) on neutrophil responses to lipopolysaccharide (LPS), an endotoxin common in gram negative sepsis. Methods: We isolated healthy donor neutrophils by negative selection immunomagnetic separation and stimulated with LPS from Klebsiella pneumoniae, Pseudomonas aeruginosa, or Escherichia coli with and without R406. We evaluated differences in neutrophil responses by assessing: 1) NETosis and viability using live cell imaging and 2) neutrophil activation by measuring surface expression of CD11b, CD62L, and CD16 using flow cytometry. All statistics were performed utilizing one-way ANOVA’s corrected for multiple comparisons by Bonferroni’s multiple comparisons test. Results: Compared to non-stimulated cells, stimulation with LPS from K. pneumoniae (1 ug/mL) induced a 2.2-fold increase in NETs, and a 5.83-fold decrease in viability 6 hours post-stimulation. At higher concentrations P. aeruginosa (5 ug/mL) and E. coli (25 ug/mL) LPS demonstrated similar results, with 8.9-fold and 2.5-fold increases in NETs and a 17.0-fold and 16.5-fold decreases in viability, respectively. Pre-incubation (30 minutes) with R406 significantly reduced this phenotype, resulting in significant fold reduction in NETosis across K. pneumoniae (p<.0001); P. aeruginosa (p = .003); and E. coli. (p = 0.0006) as well as significant increases in neutrophil viability; returning cells to baseline levels. Furthermore, in response to K. pneumoniae LPS, neutrophils showed an increase in CD11b MFI which was reduced in R406 pre-treated cells (p = 0.0498). Lastly, CD16 shedding was markedly blocked by R406 (p <.0001) while CD62L shedding was unaffected by the treatment. Conclusions: These results suggest that in response to multiple bacterial endotoxins SYK inhibition largely abrogates some neutrophil responses typically associated with inflammatory processes and severe illness. Inhibiting SYK-mediated signaling in neutrophils may improve neutrophil mediated pathogenesis in sepsis.

Background Existing models of Ebola virus infection have not fully characterized the pathophysiology of shock in connection with daily virologic, clinical, and immunologic parameters. We implemented a nonhuman primate critical care model to investigate these associations. Methods Two rhesus macaques received a target dose of 1000 plaque-forming units of Ebola virus intramuscularly with supportive care initiated on day 3. High-dimensional spectral cytometry was used to phenotype neutrophils and peripheral blood mononuclear cells daily. Results We observed progressive vasodilatory shock with preserved cardiac function following viremia onset on day 5. Multiorgan dysfunction began on day 6 coincident with the nadir of circulating neutrophils. Consumptive coagulopathy and anemia occurred on days 7 to 8 along with irreversible shock, followed by death. The monocyte repertoire began shifting on day 4 with a decline in classical and expansion of double-negative monocytes. A selective loss of CXCR3-positive B and T cells, expansion of naive B cells, and activation of natural killer cells followed viremia onset. Conclusions Our model allows for high-fidelity characterization of the pathophysiology of acute Ebola virus infection with host innate and adaptive immune responses, which may advance host-targeted therapy design and evaluation for use after the onset of multiorgan failure.

Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and mac-rophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10+CD33???), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DR???CD33+CD11b???). SYK inhibition was also associated with normalization of transcriptional activity in circulating monocytes rela-tive to healthy controls, an increase in frequency of circulating nonclassical and HLA-DRhi classical monocyte populations, and restoration of interferon responses. Together, these data suggest that SYK inhibition may mit-igate proinflammatory myeloid cellular and soluble mediator responses thought to contribute to immunopa-thogenesis of severe COVID-19.

Strich, Jeffrey1; Ramos-Benitez, Marcos2; Connelly, Mark3; Swerczek, Joanna4; Kendall, Heather4; Babyak, Ashley2; Stein, Sydney2; Valencia, Luis Perez2; Warner, Seth2; Ramelli, Sabrina2; Platt, Andrew5; Vannella, Kevin M2; Herbert, Richard4; Chertow, Daniel5 Author Information

Abstract Background COVID-19 disease severity and outcomes have been linked to high antibody titers and a dysregulated neutrophil immune response. Here we query associations and connections between the endogenous SARS-CoV-2 antibody response and neutrophil activation in COVID-19. Methods Baseline serum or plasma samples from 57 patients hospitalized on oxygen with COVID-19 were used to perform; 1) quantitative measurements of SARS-CoV-2 specific antibodies using a luciferase-based immunoprecipitation system assay, 2) quantitative measurements of neutrophil specific biomarkers using Luminex technology, and 3) neutrophil extracellular traps (NETs) as measured by myeloperoxidase-DNA (MPO-DNA) complexes by ELISA. Absolute neutrophil count (ANC) and immature granulocyte count (IGC) were measured from complete blood counts (CBC). Antibody levels were compared by disease severity using Wilcoxon rank-sum test and correlations were generated between antibody levels and neutrophil activation markers using Spearman’s correlation (SC). Results In a cohort of hospitalized patients, severe/critical COVID-19 was associated with higher levels of nucleocapsid-IgA (p=0.011) as well as spike-IgG (p= 0.0007) compared to moderate disease, while spike-IgA and nucleocapsid-IgG showed similar associations, trending towards significance (Figure 1A). Levels of IgG-spike and IgG-nucleocapsid both had significant correlations with the ANC (SC 0.33, p = 0.029; SC 0.38 p = 0.012). All four antibody titers showed strong correlations with IGC, lactoferrin and lipocalin-2, evidence of emergency granulopoiesis. Further, S100A9, a component calprotectin correlated with spike-IgG and nucleocapsid-IgA levels (SC 0.29, p = 0.030, SC 0.29 p = 0.029). Lastly, we found circulating NETs correlated with spike IgA levels (SC 0.38 p = 0.006), and its correlations with IgG-spike and IgA-nucleocapsid additionally approached significance with NETs levels as well (Figure 1B). Antibody Levels Correlate with Disease Severity and Neutrophil Activation Markers Figure 1: A) Levels of anti-Spike and anti-Nucleocapsid IgA and IgG levels measured in the serum of 57 unvaccinated hospitalized COVID-19 patients. Moderate illness represents ordinal scale 5 requiring low flow oxygen, while severe/critical patients represent ordinal scale 6 and 7, requiring high flow oxygen, non-invasive or mechanical ventilation, respectively. P values are compared by a Wilcoxon ranked sum test. B) Heatmap showing Spearman correlations between levels of anti-Spike and anti-Nucleocapsid IgA and IgG and markers of neutrophil activation. P values for individual correlations are represented in parentheses. MPO (myeloperoxidase), ANC (absolute neutrophil count), S100A9 (S100 calcium binding protein A9). Conclusion Higher anti-spike and anti-nucleocapsid IgG and IgA levels associate with more severe COVID-19 illness. Further, endogenous SARS-CoV-2 specific antibody levels associate with markers of emergency granulopoiesis and neutrophil activation. Inhibiting antibody mediated neutrophil activation may improve outcomes in COVID-19. Disclosures All Authors: No reported disclosures.

Understanding early innate immune responses to coronavirus disease 2019 (COVID-19) is crucial to developing targeted therapies to mitigate disease severity. Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 infection elicits interferon expression leading to transcription of IFN-stimulated genes (ISGs) to control viral replication and spread. SARS-CoV-2 infection also elicits NF-κB signaling which regulates inflammatory cytokine expression contributing to viral control and likely disease severity. Few studies have simultaneously characterized these two components of innate immunity to COVID-19. We designed a study to characterize the expression of interferon alpha-2 (IFNA2) and interferon beta-1 (IFNB1), both type-1 interferons (IFN-1), interferon-gamma (IFNG), a type-2 interferon (IFN-2), ISGs, and NF-κB response genes in the upper respiratory tract (URT) of patients with mild (outpatient) versus severe (hospitalized) COVID-19. Further, we characterized the weekly dynamics of these responses in the upper and lower respiratory tracts (LRTs) and blood of severe patients to evaluate for compartmental differences. We observed significantly increased ISG and NF-κB responses in the URT of mild compared with severe patients early during illness. This pattern was associated with increased IFNA2 and IFNG expression in the URT of mild patients, a trend toward increased IFNB1-expression and significantly increased STING/IRF3/cGAS expression in the URT of severe patients. Our by-week across-compartment analysis in severe patients revealed significantly higher ISG responses in the blood compared with the URT and LRT of these patients during the first week of illness, despite significantly lower expression of IFNA2, IFNB1, and IFNG in blood. NF-κB responses, however, were significantly elevated in the LRT compared with the URT and blood of severe patients during peak illness (week 2). Our data support that severe COVID-19 is associated with impaired interferon signaling in the URT during early illness and robust pro-inflammatory responses in the LRT during peak illness.

In this placebo-controlled, double-blind, randomized trial of adult patients on oxygen hospitalized with COVID-19, fostamatinib in addition to standard of care was safe and well-tolerated. Serious adverse events occurred in 10.5% of patients in fostamatinib compared with 22% in placebo. Background Coronavirus disease 2019 (COVID-19) requiring hospitalization is characterized by robust antibody production, dysregulated immune response, and immunothrombosis. Fostamatinib is a novel spleen tyrosine kinase inhibitor that we hypothesize will ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response. Methods We conducted a double-blind, randomized, placebo-controlled trial in hospitalized adults requiring oxygen with COVID-19 where patients receiving standard of care were randomized to receive fostamatinib or placebo. The primary outcome was serious adverse events by day 29. Results A total of 59 patients underwent randomization (30 to fostamatinib and 29 to placebo). Serious adverse events occurred in 10.5% of patients in the fostamatinib group compared with 22% in placebo (P = .2). Three deaths occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 +/- 0.3 vs -2.6 +/- 0.4, P = .035) and the median length in the intensive care unit was 3 days in the fostamatinib group vs 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs 28, P = .027). There were trends toward more rapid reductions in C-reactive protein, D-dimer, fibrinogen, and ferritin levels in the fostamatinib group. Conclusion For COVID-19 requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared with placebo. These results warrant further validation in larger confirmatory trials.

BACKGROUND Coronavirus Disease 2019 (Covid-19) requiring hospitalization is characterized by robust antibody production, dysregulated immune response and immunothrombosis. Fostamatinib, is a novel spleen tyrosine kinase inhibitor we hypothesize will ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response. METHODS We conducted a double-blind, randomized, placebo-controlled trial in hospitalized adults requiring oxygen with Covid-19 where patients receiving standard of care were randomized to receive fostamatinib or placebo. The primary outcome was serious adverse events by day 29. RESULTS A total of 59 patients underwent randomization (30 to fostamatinib and 29 to placebo). Serious adverse events occurred in 10.5% of patients in the fostamatinib group compared to 22% in placebo (P = .2). Three deaths occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 ± 0.3 vs. -2.6 ± 0.4, P = .035) and the median length in the ICU was 3 days in the fostamatinib group vs. 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs. 28, P = .027). There were trends towards more rapid reductions in C-reactive protein, D-dimer, fibrinogen and ferritin levels in the fostamatinib group. CONCLUSION For COVID-19 requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared to placebo. These results warrant further validation in larger confirmatory trials.