What's new in the quagmire of sepsis?

This special issue of Trends in Molecular Medicine highlights some of the recent advances in studies of sepsis, both in humans and animals. Although the articles do not provide a comprehensive coverage of all that is ongoing, some of the areas of current discoveries as well as areas of contention are highlighted. Hopefully, the articles provide useful perspectives that will assist readers in trying to understand what has been accomplished, what is lacking, and where we might go from here.After the failure of more than 100 Phase III clinical trials in septic humans (see J. Marshall), together with the recent withdrawal of recombinant activated protein C for treatment of septic humans [1xDrotrecogin alfa (activated) in adults with septic shock. Ranieri, V.M. et al. N. Engl. J. Med. 2012; 366: 2055–2064Crossref | PubMed | Scopus (435)See all References[1], and the early shutdowns of two Phase III clinical trials that employed inhibitors of Toll-like receptor 4 (TLR4) [2xEffect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. Opal, S.M. et al. JAMA. 2013; 309: 1154–1162Crossref | PubMed | Scopus (187)See all References, 3xA randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Rice, T.W. et al. Crit. Care Med. 2010; 38: 1685–1694Crossref | PubMed | Scopus (100)See all References], it is important to appreciate how demoralizing these failures have been for clinicians and researchers who work in the sepsis area. To add insult to injury, in a recent article [4xGenomic responses in mouse models poorly mimic human inflammatory diseases. Seok, J. et al. Proc. Natl. Acad. Sci. U.S.A. 2013; 110: 3507–3512Crossref | PubMed | Scopus (865)See all References[4], the use of C57BL/6 mice as surrogates for the study of genomic responses (in sepsis, thermal injury, brain injury, and trauma) has been questioned, because the responses in mice did not seem to mimic genomic changes in white blood cells from humans under similar conditions. The implications for preclinical studies of sepsis related to this article are potentially enormous. Collectively, a pessimist could conclude that preclinical and clinical studies have resulted in what could be referred to as a ‘sepsis miasma’. A possible outcome could be that National Institutes of Health (NIH) Study Sections and reviewers of papers submitted to peer-reviewed journals might take a dim view of studies done in mice, questioning their relevance to data related to humans. The current assembly of papers may provide some suggestions of what directions preclinical and clinical studies might proceed. Marshall's presentation is a thoughtful and fairly thorough review of where we have gone in sepsis research, why we are there, and how we might proceed. He suggests developing a broad and deep clinical database similar to that of the Framingham study that was obtained over many years, but he admits that this would be a very expensive and time-consuming undertaking that would be unlikely to be funded by federal agencies, at least at this time.The Yende group (Pittsburgh, PA), using an epidemiological approach, describes emerging evidence for long-term complications (reduced life span, defective cognition, physical infirmity, etc.) in humans who have ‘recovered’ from sepsis. The authors describe ‘a bifunctional relationship’ in which chronic poor health (such as cardiovascular disease, diabetes mellitus, hypertension, etc.) is worsened by onset of sepsis, in which, after recovery from sepsis, there may be an exacerbation due to the underlying condition of poor health. Reciprocal pathways may also be coming into play. Several strategies that may diminish long-term complications following recovery from sepsis are suggested. The report from Maslove and Wong emphasizes accomplishments in gene expression profiling in pediatric septic patients, with some data suggesting that there may be distinct subclasses of patients in which there are distinctive patterns of transcriptional pathway activation, which may dynamically change during various phases of sepsis. This is a novel and important concept. In the section on ‘Concluding remarks and future directions’, the authors point out the short comings of the current genomic database and how these problems might be alleviated.The review from Mittal and Coopersmith describes evidence for the gut being a ‘driver’ of sepsis progression, related to bacterial translocation in the gut and appearance of ‘toxic gut-derived lymph’ as a cause for multiorgan dysfunction. This theory has been around for some time and extensive preclinical data exist for its support, especially in rodents. It is not entirely clear to what extent such observations can be translated to human sepsis, and whether infectious and/or ‘sterile’ sepsis are both linked to translocation of bacteria in the gut. The review by Hutchins et al. suggests in animal and human sepsis that the rapid development of immunosuppression may be countered by use of either interleukin-7 (IL-7) and/or granulocyte macrophage colony-stimulating factor (GM-CSF), as well as antibody-induced blockade of the programmed death receptor-1 (PD-1) and the B and T lymphocyte attenuator (BTLA). In sepsis, IL-7 and GM-CSF may resuscitate the depleted ranks of CD4 cells, whereas the latter two approaches may reduce further immunosuppression development. There are currently no clinical trials in septic humans to resolve these issues [5xSepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Hotchkiss, R.S. et al. Nat. Rev. Immunol. 2013; 13: 862–874Crossref | PubMed | Scopus (165)See all References[5]. Schorr et al. describe the history of the Surviving Sepsis Campaign (SSC), from 2002 to 2013. SSC is a worldwide network of clinicians in the sepsis field, attempting to standardize criteria for clinical intervention, using therapeutic ‘bundles’. Recently, 2 and 6 h sepsis bundles have been developed and include a new software program, with more clinical flexibility for the new bundles. SSC is a laudable attempt to standardize diagnosis of sepsis and improve effectiveness of clinical interventions.There are some generalities that can be drawn as related to this special issue of Trends in Molecular Medicine. There appear to be increasing concerns that the current clinical classifications of sepsis are too vague, and that ‘sepsis, severe sepsis, septic shock, and multiorgan failure’ have impeded clinical progress because of a great diversity of patients with too many different presentations (clinical, biochemical, etc.). Marshall underscores that clinical sepsis is a ‘syndrome, not a disease’. It may well be that clinical classifications of septic patients should be narrowed down to cohorts such as bacterial pneumonia, which would then be further broken down to Gram-positive and Gram-negative infections. Perhaps such stratifications would better define outcomes and result in more effective clinical interventions. To an extent, this could represent a paradigm shift that might be worthy of consideration. We would also have to deal with the broad issue of sepsis associated with ‘sterile inflammation’ (as after nonpenetrating trauma, ischemia/reperfusion, or hemorrhagic shock) [6xDanger signals activating the immune response after trauma. Hirsiger, S. et al. Mediators Inflamm. 2012; 2012Crossref | PubMed | Scopus (67)See all References[6] and the extent to which the pathophysiology of infectious and sterile sepsis are similar or different. There is certainly much to be done.