The evolving experience with therapeutic TNF inhibition in sepsis: considering the potential influence of risk of death.

INTRODUCTION: Septic shock is highly lethal and its incidence is increasing. Although TNF-α plays a key role in sepsis pathogenesis, past efforts to therapeutically inhibit it had limited success. However, there is continued interest in such therapies and there are now ongoing Phase II sepsis trials testing the effects of AZD9773, a TNF-directed polyclonal antibody fragment preparation. Experience with anti-inflammatory agents suggested that their efficacy may relate to sepsis-associated risk of death. AREAS COVERED: An overview of the biology of TNF and experimental data implicating TNF as a key mediator in sepsis pathogenesis; a review of the earlier clinical experience with anti-TNF therapies demonstrating that when examined across 12 trials, these agents had a highly consistent overall effect which although not reaching significance, was on the side of benefit; a review of data showing that sepsis-associated risk of death may influence the efficacy of anti-inflammatory agents like anti-TNF ones and a review of the rational and clinical experience to date with AZD9773 and its precursor, CytoFab. EXPERT OPINION: Discusses variables that may need to be accounted for to maximize the success of clinical trials in sepsis testing agents that modulate host inflammation.