Sepsis as the Grand Mimic of Secondary Hemophagocytic Lymphohistiocytosis: Serratia marcescens Bacteremia with Concomitant Decompensated Cirrhotic Liver Disease.

Secondary hemophagocytic lymphohistiocytosis (HLH) is an elusive entity with sequelae that may be confused with sepsis. We discuss a 45-year-old man with decompensated liver cirrhosis with sepsis treated with broad-spectrum intravenous antibiotics. Further work-up initially supported sepsis-HLH overlap syndrome (SHLHOS) and corticosteroids were added. Ongoing refractory hypotension ensued, and the patient passed within 31 hours of presentation. Based on the patient's overwhelming immune activation and clinical course likely unsalvageable by cytotoxic immunosuppressive agents, the patient was diagnosed with sepsis with acute end organ dysfunction. This case report illustrates both the diagnostic challenge of sepsis versus HLH, which both require very different treatments, and the potential for rapid clinical decline without swift recognition and management of the true pathology.

Chemical genetics screening reveals KIAA1363 as a cytokine-lowering target.

Inflammation is a hallmark of many human diseases, including pain, arthritis, atherosclerosis, obesity and diabetes, cancer, and neurodegenerative diseases. Although there are several successfully marketed small molecules anti-inflammatory drugs such as cyclooxygenase inhibitors and glucocorticoids, many of these compounds are also associated with various adverse cardiovascular or immunosuppressive side effects. Thus, identifying novel anti-inflammatory small molecules and their targets is critical for developing safer and more effective next-generation treatment strategies for inflammatory diseases. Here, we have conducted a chemical genetics screen to identify small molecules that suppress the release of the inflammatory cytokine TNFα from stimulated macrophages. We have used an enzyme class-directed chemical library for our screening efforts to facilitate subsequent target identification using activity-based protein profiling (ABPP). Using this strategy, we have found that KIAA1363 is a novel target for lowering key pro-inflammatory cytokines through affecting key ether lipid metabolism pathways. Our study highlights the application of combining chemical genetics with chemoproteomic and metabolomic approaches toward identifying and characterizing anti-inflammatory smal molecules and their targets.