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 SARS-CoV-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 CLP-induced sepsis, the reconstituted pulmonary endothelial glycocalyx is structurally and functionally remodeled, such that immune responses are impaired, potentially increasing the risk of secondary infections. In the August 2020 issue of the Journal, Supinski et al. (21) emphasized the importance of the diaphragm during sepsis. In this study, the group used a mitochondrial targeted antioxidant, MitoTEMPOL, to restore diaphragmatic mitochondrial respiration and muscular function. Finally, Gotts et al. (10) presented a detailed study of murine pneumococcal pneumonia with the goal of establishing a clinically relevant model that also developed nonpulmonary organ dysfunction. They found that choice of pathogen, timing of fluids and antibiotics, and selection of end points all affected pulmonary and nonpulmonary organ dysfunction and need to be considered when using different models of pulmonary infection and sepsis. These studies, taken together, highlight the diversity of science in the field of sepsis and place AJPLung among the top journals in the field of pulmonary-relevant sepsis research.

Now for the future: What should our focus be over the next year to meaningfully advance our understanding of sepsis? I offer that there are three topics of particular impact:

• Defining the biologic underpinnings of sepsis heterogeneity. Clinicians and scientists have long recognized that sepsis, like asthma and acute respiratory distress syndrome (ARDS), is a heterogeneous syndrome. Yet, as a field, we lag behind others in defining the biologic drivers of heterogeneity and treating patients with a personalized approach. Here we can take a lesson from our oncology colleagues. Lung cancer treatment has been transformed in the past decade from a stage- and histology-based treatment algorithm to a personalized approach targeting tumor-specific mutations, with some remarkable clinical success stories. How did the field of thoracic oncology accomplish such personalization? First, researchers recognized heterogeneity of treatment effect in large clinical trials, asking why some patients responded to a particular therapy while others did not. These lessons allowed identification of biomarkers or mutations in treatment responders, leading to additional study in experimental models to understand the fundamental biology at play. New therapeutic approaches were tested in these model systems and then brought back to the clinical arena and studied in clinical trials. Thus, the translational cycle of clinical observation at the bedside, mechanistic study at the bench, and therapeutic trials in humans has been remarkably successful. This approach is feasible in sepsis, but it will take investment, time, and coordination between clinical and bench scientists.

• Studying sepsis as a systemic disease. Sepsis is a systemic syndrome, but, as a scientific community, we often become organ focused and lose sight of the global effects of sepsis on the human body. The reasons for this are complex and include compartmentalization of funding sources, clinical and scientific siloing in different departments, and organ-centered journals. Although a focused approach is necessary to define organ-specific effects of sepsis, key findings often do not make it beyond the organ of interest. While, as an AJPLung Associate Editor, I look forward to new manuscripts exploring sepsis-induced lung dysfunction, I encourage all of us to take a chance on a new line of inquiry by establishing collaborations with colleagues outside the lung field, thinking about organ cross talk in our scientific studies, and reading more papers from nonpulmonary journals, including the many excellent publications from the sister journals of the American Physiological Society.

• Embracing all types of in silico, in vitro, in vivo, and human models of disease. In order to make significant, clinically meaningful, globally impactful discoveries in sepsis we must embrace all model systems, all methods of scientific inquiry, and all types of scientists. We need to look no further than the current SARS-CoV-2 pandemic to see the power of diversity in science. Our scientific community has seen an unprecedented explosion of scientific publications related to the pandemic. Molecular modeling has taught us about the SARS-CoV-2 spike protein (22), and population modeling has informed estimates of future spread of disease (8). Cell culture has been critical for development of PCR-based SARS-CoV-2 testing (5) and in identifying potential therapeutic targets (3). Mouse models have been central to the development of antivirals (15) and vaccines (27). Ex vivo models help to define tropism of the virus (12), and nonhuman primate models have helped us understand the clinical differences between different coronaviruses (16). Finally, observational human studies have defined the clinical course of COVID-19 disease, and clinical trials have tested targeted therapies (23) and vaccines (26). Without these varied approaches to studying the current pandemic, we would not be where we are today in our understanding of SARS-CoV-2 and COVID-19. As a community of researchers, we can benefit from this approach in studying sepsis and can make progress by embracing our diversity.

As we at AJPLung pause during World Sepsis Day to reflect on our accomplishments and look forward to new opportunities, we have a feeling of great excitement. The SARS-CoV-2 pandemic has caused all of us to rethink everything in our personal and professional lives and to realize what we as a scientific community are capable of. I hope that we can take these lessons learned and apply them to understanding sepsis in the years to come. In the editorial by Schlapbach et al. (18) in this issue, we are reminded that our partners in advocacy in the Global Sepsis Alliance have helped to increase awareness of the tremendous global impact of sepsis and to help provide a roadmap to reduce the sepsis burden throughout the world. The future of sepsis research is bright, but maybe, as I have discussed, we need to think differently about how we approach this problem scientifically to make progress in new ways. I want to thank the authors who have submitted sepsis manuscripts this year and the readers who have continued to depend on the Journal for high-quality pulmonary science. I look forward to another outstanding year of sepsis research.

GRANTS

This work was supported in part by National Heart, Lung, and Blood Institute Grant HL135849.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

J.A.B. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.