The future of sepsis research: Time to think differently?

This month marks the ninth World Sepsis Day, a time to celebrate the scientific advances in the last year and reflect on where the field should go in the future. This year, more than ever, the scientific community needs to pause, take a deep breath, and do both. Sepsis remains the focus of intense investigation, with over 2,700 PubMed-cited publications in the past year that included “sepsis” in the title. Sixteen of these manuscripts have been published in AJPLung, an average of one paper a month—a substantial focus of our journal, which publishes typically 16 total papers monthly. What has the sepsis community learned in the last year? First, the clinical advances: It has long been recognized that susceptibility to, and outcomes following, sepsis are related to a multitude of host, pathogen, and environmental factors. A large European genome-wide association study (GWAS) comparing sepsis patients with and without acute respiratory distress syndrome (ARDS) identified a novel susceptibility locus in the Fms-related tyrosine kinase (FLT1) gene that encodes the protein vascular endothelial growth factor receptor (VEGFR)-1 (11). Another study, published in this journal, found that micro-RNA (miRNA) 887 was differentially expressed in sepsis patients with and without ARDS (9). These studies implicate genetic and epigenetic factors in the development of sepsis-induced ARDS and have also identified promising pathways to be studied mechanistically. This past year saw the publication of several clinical trials in sepsis, among them the Phase 2 CITRIS-ALI study of high-dose intravenous vitamin C for sepsis-induced ARDS, which suggested a decreased mortality in the vitamin C group. However, these findings were in a planned secondary analysis, and the primary end point of change in organ failure was not significantly different between the two groups (6). In contrast, the VITAMINS randomized clinical trial of vitamin C, hydrocortisone, and thiamine versus hydrocortisone alone did not show a mortality benefit (7). Nevertheless, these findings are provocative, and the study of vitamin C in sepsis will undoubtedly remain a major focus in the field. Several studies increased our understanding of prognosis and outcomes in sepsis. In a retrospective study of two clinical populations, a group reported that the ARDS-attributable mortality in sepsis is 27–37% (2), highlighting the importance of ARDS as a driver of adverse outcomes in sepsis. Finally, the SARSCoV-2 pandemic has reminded us that viruses are an important cause of sepsis, prompting the Surviving Sepsis Campaign to publish guidelines for the management of critically ill COVID-19 patients (1). In the past year, there have also been significant advances in our mechanistic understanding of sepsis. In particular, I would like to highlight those published in AJPLung. The studies are impressive in their creativity, scope, and use of diverse model systems. In a provocative study of the ex vivo perfused human lung injury model, Ross et al. (17) showed that the intact lung has innate immune properties in the absence of circulating immune cells. They found that Streptococcus pneumoniae infused into the pulmonary vasculature was rapidly cleared from the circulation by the small number of neutrophils in the perfusate, alveolar macrophages, and possibly through interstitial pathways. In other translational studies, Leligdowicz et al. (13) found that leukocytes isolated from sepsis patients demonstrated significant variability in their production of cytokines and ability to induce lung microvascular permeability, a reflection of the disease heterogeneity seen in these patients. Three studies published in the Journal investigated the role of coagulation in sepsis-induced lung injury. The first used an interesting model of post-intensive care syndrome (PICS) by studying mice 8 days after cecal ligation and puncture (CLP) and found that coagulation, as measured by several parameters including clotting time and thrombin potential, was still significantly dysregulated even after clinical recovery of the animals (24). In a detailed study of both intrinsic and extrinsic coagulation cascade inhibition in a Klebsiella pneumoniae lung infection model, Stroo et al. (20) showed the complex interplay of these pathways during infection. Inhibition of factor VII (extrinsic cascade) increased lung bacterial counts but decreased distant organ injury, whereas inhibition of factor XII (intrinsic cascade) had none of these effects. Similarly, Ding et al. (4) showed that high-molecular-weight kininogen, a key component of the contact activation system of coagulation, did not have a significant role in K. pneumoniae sepsis. Together, these studies highlight the central role of coagulation in sepsis and stress the importance of publishing well-done positive and negative studies, particularly since the effects of coagulation are so nuanced. A dysregulated inflammatory response to infection underlies the definition of sepsis (19). Two recent papers in the Journal shed light on novel aspects of the inflammatory response during sepsis. The first, by Zheng et al. (25), identifies ghrelin, a gastrointestinal peptide hormone, as a modulator of alveolar macrophage inflammatory function during sepsis. Intraperitoneal delivery of ghrelin during CLP attenuated inflammatory signaling in alveolar macrophages and reduced lung inflammation. A second study in the Journal by Oshima et al. (14) found that during recovery from CLPinduced sepsis, the reconstituted pulmonary endothelial glycocalyx is structurally and functionally remodeled, such that immune responses are impaired, potentially increasing the risk Correspondence: J. A. Bastarache (julie.bastarache@vumc.org). Am J Physiol Lung Cell Mol Physiol 319: L523–L526, 2020; First published August 5, 2020; doi:10.1152/ajplung.00368. 2020.