Sepsis: rethinking the approach to clinical research

The clinical syndrome of sepsis encompasses a highly heterogeneous group of clinical disorders, varying with respect to the site, bacteriology, and even presence of infection and with the clinical syndrome evolving in the host. Clinical trials of strategies to modulate the host response that mediates sepsis were first initiated 25 years ago. A continuing record of disappointment has characterized subsequent work, and only a single new therapy has been licensed for clinical use. Yet, these commercial disappointments obscure a vibrant body of new knowledge that has clarified the biology of the innate immune response whose deranged expression is responsible for sepsis and that has provided important new insights into the failings of the traditional model of clinical research in sepsis. This review highlights advances in basic biology and underlines insights from clinical research that may point to new and more effective ways of translating an understanding of innate immunity into effective treatments for a leading cause of global morbidity and mortality.