Most patients with sepsis have underlying co-morbidities. Co-existing disease is typically thought to influence the pathophysiology and outcome of sepsis by reducing physiological reserve. Certainly this is true: A patient with chronic obstructive pulmonary disease (COPD) will tolerate pneumonia less well than a patient with previously healthy lungs. Additionally, many chronic disease states (or their treatments) alter the pre-existing inflammatory and immune milieu. This effect ranges from the obvious (as in the case of patients taking immunosuppressant therapy) to the under-appreciated (as in the inflammatory dysregulation associated with obesity). In seeking explanations for differences in the host response to infection, much has been made of the possible effects of genetic variability. However, subtle variations in the underlying state of the immune and inflammatory systems have received little attention.