Defining Pathologic Immune Dysregulation in 2019-CoV: Opportunities for Risk Stratification and Therapeutic Immune Modulation

COVID-19 is a coronavirus similar to SARS and MERS. Clinical features among critically ill patients infected with these new viruses includes features of pathologic inflammation, and increased inflammation in patients infected with COVID19 (elevated ferritin, elevated IL6, elevated d-dimer) has been associated with risk of death.1 For some patients, corticosteroids or other immune suppression may be detrimental.2 However, for others, control of extreme inflammation may be life-saving. This concept is illustrated by re-analysis of data from a phase 3 randomized study of IL-1 blockade with anakinra in patients with severe sepsis. Analyzed as a group, anakinra did not confer any benefit. However, in patients with hyperinflammation, there was a significant survival advantage.3 Similarly, cytokine profiling predicts risk of pathologic in inflammation with cancer immunotherapy, and tocilizumab (targets IL-6) and other agents that target cytokines show benefit in patients who develop cytokine release syndrome.4;5 Hemophagocytic lymphohistiocytosis (HLH) is a condition of extreme inflammation that may be caused by inherited defects in cytotoxicity that is fatal without immune suppression. In a mouse model of HLH, blocking IFN specifically improved survival where blocking other pro-inflammatory cytokines did not.6 Emapalumab (IFN antibody) has recently been approved for primary HLH based on results of a single arm trial.7 Our group has evaluated pre-therapy plasma in children with HLH and severe sepsis using unbiased analysis of >130 cytokines and found an IFN signature was specific to HLH and IL-6 to sepsis/SIRS (Figure 1). We hypothesize that analysis of cytokine prolife and immune function in patients infected with COVID19 may identify patients at risk of morbidity and mortality due to pathologic inflammation. Further, these analyses may identify pathways (e.g. IFN) that may be useful to prioritize therapeutic strategies that modulate inflammation. Team Organization: We have assembled an interdisciplinary team of scientific and clinical collaborators (Texas Medical Center: St. Luke's/Baylor College of Medicine, Houston Methodist Hospital, Ben Taub Community Hospital, Texas Children's Hospital; University of Cincinnati, Cincinnati Children's Hospital; and Mt. Sinai School of Medicine) that will provide access to tissue specimens, clinical data and expertise required to efficiency and comprehensively test the role of pathologic inflammation in clinical outcomes of children and adults infected with COVID19. In addition to gaining access to blood and clinical data from hospitalized patients, we will enroll patients with a spectrum of ages and clinical severity in prospective studies/registries which will allow analysis of changes in biomarkers and immune function over time.