Patient phenotypes and their relation to TNFα signaling and immune cell composition in critical illness and autoimmune disease

RationaleTNF inhibitors have shown promise in reducing mortality in hospitalized COVID-19 patients; one hypothesis explaining the limited clinical efficacy is patient heterogeneity in the TNF pathway. MethodsWe evaluated the effect of TNF inhibitors in a mouse model of LPS-induced acute lung injury. Using machine learning we attempted predictive enrichment of TNF signaling in patients with either ARDS or sepsis. We examined biological factors that drive heterogeneity in host responses to critical infection and their relation to clinical outcomes. ResultsIn mice, LPS induced TNF-dependent neutrophilia, alveolar permeability and endothelial injury. In humans, TNF pathway activation was significantly increased in peripheral blood of patients with critical illnesses and associated with the presence of mature neutrophils across critical illnesses and several autoimmune conditions. Machine learning using a gene signature separated patients into 5 phenotypes; one was a hyper-inflammatory, interferon-associated phenotype enriched for increased TNF pathway activation and conserved across critical illnesses and autoimmune diseases. Cell subset profiles segregated severely ill patients into neutrophil-subset-dependent groups that were enriched for disease severity, demonstrating the importance of neutrophils in the immune response in critical illness. ConclusionsTNF signaling and mature neutrophils are associated with a hyper-inflammatory phenotype of patients, shared across critical illness and autoimmune disease. This phenotyping provides a personalized medicine hypothesis to test anti-TNF therapy in severe respiratory illness. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/564631v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1e25724org.highwire.dtl.DTLVardef@c708bcorg.highwire.dtl.DTLVardef@10e7531org.highwire.dtl.DTLVardef@3014b8_HPS_FORMAT_FIGEXP M_FIG C_FIG