Comorbidities and Inflammation: How Chronic Diseases Prime the Host Response in Sepsis

Considered a global public health priority, sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. Its heterogeneous clinical presentation arises, in part, from pre-existing chronic conditions such as hypertension, metabolic syndrome, diabetes, alcohol exposure, psychosocial stress, and periodontitis, which induce persistent systemic changes even before the infectious event. This narrative review synthesizes evidence from experimental models and clinical studies to clarify the molecular and immunological mechanisms by which chronic conditions influence the septic state. We discuss how these conditions converge on common pathophysiological mechanisms, including low-grade chronic inflammation, oxidative stress, endothelial and mitochondrial dysfunction, and changes in the microbiota and neuroimmune regulation. Pathways such as TLR-NF-κB signaling and the NLRP3 inflammasome are maintained in a basal state of activation, lowering the threshold for hyperinflammatory responses and increasing the risk of multiple organ dysfunction syndrome. In conclusion, understanding these phenotypes can guide the identification of biomarkers and the development of personalized therapeutic strategies, thereby moving beyond one-size-fits-all approaches to the management of sepsis and septic shock.