Immunostimulation is a Rational Therapeutic Strategy in Sepsis

It has recently been appreciated that patients with severe sepsis and septic shock suffer from altered innate and adaptive immune responses, leading to an impaired clearance of microorganisms. This explains their difficulty to fight their primary bacterial infection and their propensity to develop superinfections. A depressed immunological surveillance in some of these patients is also responsible for a reactivation of dormant viruses, such as cytomegalovirus. Leukocyte functions are profoundly affected during sepsis. Circulating phagocytes show a marked decrease in their capacity to mount a pro-inflammatory reaction in response to microorganisms. Monocytes express low levels of major histocompatibility class II molecules. These phenotypic changes are known as 'immune paralysis'. Massive lymphocyte and dendritic cell apoptosis has also been reported in patients dying of sepsis, responsible, at least in part, for the impairment of adaptive responses. This was highlighted by the defective skin tests to common antigens documented already three decades ago in patients with sepsis. Patients with severe sepsis and septic shock may therefore benefit from treatments aimed at stimulating innate and adaptive immune responses. The aims of immune stimulation are: (1) to help bacterial killing at the primary focus of infection; (2) to prevent the development of nosocomial infections; and (3) to prevent the reactivation of dormant viruses. Therapeutic strategies based on 'boosting' immune responses with interferon gamma, G-CSF, and more recently with GM-CSF have been initiated. Although results of pilot studies are encouraging, these will need to be confirmed in larger clinical studies. As a word of caution, one should not induce deleterious overwhelming inflammatory reactions, and therefore close monitoring of immune and inflammatory responses during immune stimulation therapy is necessary.