Study sheds new light on cytokine response in sepsis

Abstract

The immune response in severe sepsis caused by community-acquired pneumonia (CAP) is heterogeneous and continues after the resolution of clinical signs and symptoms in patients, according to fi ndings from a large US multicentre study. “We found that several of the past interpretations of the infl ammatory response to sepsis— at least in patients with CAP—may be incorrect or misleading, with important implications for the development of future therapies”, said lead author Derek Angus (University of Pittsburgh School of Medicine, Pittsburgh, PA, USA). Severe sepsis is common and frequently fatal; in the USA alone 1 million people are aff ected every year, and CAP is the leading cause. 30% of patients who develop sepsis will die, despite the availability of various therapies. Researchers recruited 1886 patients admitted to hospital with CAP, across 28 US hospitals, to determine if specifi c cytokine response patterns were associated with severe sepsis and death. Blood samples were analysed for the presence of interleukin 6, interleukin 10, and tumour necrosis factor. 583 (31%) patients developed severe sepsis of whom 149 died. Results showed that systemic cytokine level elevation occurred in 1546 (82%) of all subjects with CAP. “Mean cytokine concentrations were highest at presentation, declined rapidly over the fi rst few days, but remained elevated throughout the fi rst week, beyond resolution of clinical signs of infection”, said Angus. “Our results show that this response is much longer in duration and much more heterogeneous than suggested by previous studies”, he added. Highest risk of death was associated with combined high levels of proinfl ammatory interleukin-6 and anti-infl ammatory interleukin-10 cytokine activity (p<0·001). According to Angus, “Cytokine measurements were not part of routine clinical practice before our study, so the clinical consequences of our study are somewhat tangential”. At present, experts have an incomplete understanding of the complex pathophysiological nature of human sepsis; the few clinical studies done so far have often yielded results inconsistent with each other or with those of laboratory experiments and human volunteer studies. “We would hope the work will stimulate more rigorous eff orts to consider criteria beyond simple clinical signs and symptoms when enrolling patients into future sepsis trials”, he added. Djillali Annane (Universite de Versailles Saint-Quentin en Yvelines, Garches, France) said: “Whereas some patients with CAP never exhibit substantial infl ammation, in others it remains elevated for a week beyond the resolution of clinical signs and symptoms. Thus, the main clinical implication from that study is that any treatment targeting the cytokine response must be given for at least 1 week”.