Editorial
Special issue: Sepsis
A defining time for sepsis Christopher A. Pettigrew (Editor) Trends in Molecular Medicine
The term Shci (sepsis) was coined by Hippocrates in the fourth century BC to define the unsavory process of organic matter putrefaction. Medically, the term sepsis has been used since the late 1800s to define severe systemic blood toxicity and, consequently, it is understandable how this single word describing rotting and decay encompassed broad swaths of patients with infections. However, even today, we still lack a precise medical definition of sepsis. Under the broad umbrella of ‘sepsis’, we see heterogeneity arising at different levels, such as the pre-existing health state of the patient, the causative pathogen, and even the timing of diagnosis. This heterogeneity not only makes sepsis difficult to define with accuracy but also leads us to question whether sepsis should be considered a disease or a syndrome. This special issue of Trends in Molecular Medicine highlights the heterogeneity of sepsis, as well as the challenges and outstanding issues that remain because of this variation. Considering that we cannot even define sepsis, how can we treat it effectively? Because both the number of hospitalizations for sepsis, as well as the rate per 10 000 of the population doubled from 2000 to 2008 in the USA, sepsis is a burgeoning problem [1]. The fact that 17% of the hospitalizations in 2008 resulted in death emphasizes just how critical rapid diagnosis and immediate treatment are for patient survival. Over the past few months, two papers have described new devices and approaches for the diagnosis and detection of sepsis at early stages [2,3]. It remains to be seen how the integration of these and similar devices in a clinical setting will change current approaches. However, a quicker diagnosis and identification of the disease causing agent could help devise the ideal treatment program and allow for early intervention. These devices may also help with classification and stratification of cases, which may then lead to appropriate treatment trials. Indeed, Maslove and Wong review how modern gene expression profiling already highlights variation in the transcriptional response to infection, particularly among pediatric patients. The failure of clinical trials to clearly identify successful treatment strategies, as eloquently outlined by John Marshall, can be at least partially attributed to the heterogeneity of sepsis. It is unlikely that any one therapeutic intervention will work as a ‘magic bullet’ for all patients presenting with sepsis symptoms; however, subclassifications of patients (e.g., based on infectious agent or stage of infection) may help with identifying appropriate treatment strategies for each group. Hutchins et al. describe a novel therapeutic approach, which proposes using immunomodulatory agents to combat the immunosuppression observed in sepsis as a strategy to Corresponding author: Pettigrew, C.A. ([email protected]). 1471-4914/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2014.02.006
alleviate clinical morbidity. Although promising, there are currently no human trials underway for any of the immunomodulatory agents discussed. As outlined by Schorr and Dellinger, current guidelines for sepsis treatment from the Surviving Sepsis Campaign (www.survivingsepsis.org) are continually being assessed and refined. The product and core of their efforts to improve sepsis survival rates are ‘bundles’, which simplify the complexity of providing care to patients with severe sepsis. A bundle is a selected set of elements of care distilled from evidence-based practice guidelines that, when implemented as a group, have a combined effect on outcomes. Currently, the 3-h and 6-h bundles are indicative of the critical importance of intervention at early stages, and the rapid progression that can determine patient outcome. Implementing these bundles and improving hospital performance are key goals for the Campaign. Mittal and Coopersmith review the role of the gut as a contributor to the microbial and toxicological assault associated with sepsis. Although the concept is 30 years old, it is now clear that the feed-forward loops between the gut and systemic injury can exacerbate disease. Current understanding in this area comes mainly from rodent models. If the insights derived from model systems are applicable to human sepsis, then appropriate therapeutic interventions that disconnect these systems may be a key to controlling sepsis. Yende et al. describe the relationship between sepsis and chronic health. The long-term health consequences after surviving sepsis include frailty, defective cognitive responses, and reduced life expectancy. Further, a sepsis episode may exacerbate underlying chronic conditions such as diabetes or cardiovascular disease. It is clear, therefore, that alleviating the burden of sepsis does not necessarily end with clearing infection. Collectively, this issue is intended to focus on both the recent advances in sepsis research and the challenges that remain. I would like to thank all of the authors and reviewers for their contributions to this special issue, with a very special thank you to our guest editor Peter Ward for his assistance throughout the process. My appreciation also goes to the former editor of Trends in Molecular Medicine, Laurie Gay, for conceiving and planning this special issue. I hope you all enjoy reading this special issue, and I welcome your comments and ideas; feel free to contact us with any feedback or questions at [email protected]. References 1 Hall, M.J. et al. (2011) Inpatient Care for Septicemia or Sepsis: A Challenge for Patients and Hospitals. NCHS Data Brief, No. 62, National Center for Health Statistics 2 Kemmler, M. et al. (2014) Biochip point-of-care device for sepsis diagnostics. Sens. Actuat. B: Chem. 192, 205–215 3 Cooper, R.M. et al. (2014) A microdevice for rapid optical detection of magnetically captured rare blood pathogens. Lab Chip 14, 182–188 Trends in Molecular Medicine, April 2014, Vol. 20, No. 4
191
Special issue: Sepsis
A defining time for sepsis Christopher A. Pettigrew (Editor) Trends in Molecular Medicine
The term Shci (sepsis) was coined by Hippocrates in the fourth century BC to define the unsavory process of organic matter putrefaction. Medically, the term sepsis has been used since the late 1800s to define severe systemic blood toxicity and, consequently, it is understandable how this single word describing rotting and decay encompassed broad swaths of patients with infections. However, even today, we still lack a precise medical definition of sepsis. Under the broad umbrella of ‘sepsis’, we see heterogeneity arising at different levels, such as the pre-existing health state of the patient, the causative pathogen, and even the timing of diagnosis. This heterogeneity not only makes sepsis difficult to define with accuracy but also leads us to question whether sepsis should be considered a disease or a syndrome. This special issue of Trends in Molecular Medicine highlights the heterogeneity of sepsis, as well as the challenges and outstanding issues that remain because of this variation. Considering that we cannot even define sepsis, how can we treat it effectively? Because both the number of hospitalizations for sepsis, as well as the rate per 10 000 of the population doubled from 2000 to 2008 in the USA, sepsis is a burgeoning problem [1]. The fact that 17% of the hospitalizations in 2008 resulted in death emphasizes just how critical rapid diagnosis and immediate treatment are for patient survival. Over the past few months, two papers have described new devices and approaches for the diagnosis and detection of sepsis at early stages [2,3]. It remains to be seen how the integration of these and similar devices in a clinical setting will change current approaches. However, a quicker diagnosis and identification of the disease causing agent could help devise the ideal treatment program and allow for early intervention. These devices may also help with classification and stratification of cases, which may then lead to appropriate treatment trials. Indeed, Maslove and Wong review how modern gene expression profiling already highlights variation in the transcriptional response to infection, particularly among pediatric patients. The failure of clinical trials to clearly identify successful treatment strategies, as eloquently outlined by John Marshall, can be at least partially attributed to the heterogeneity of sepsis. It is unlikely that any one therapeutic intervention will work as a ‘magic bullet’ for all patients presenting with sepsis symptoms; however, subclassifications of patients (e.g., based on infectious agent or stage of infection) may help with identifying appropriate treatment strategies for each group. Hutchins et al. describe a novel therapeutic approach, which proposes using immunomodulatory agents to combat the immunosuppression observed in sepsis as a strategy to Corresponding author: Pettigrew, C.A. ([email protected]). 1471-4914/$ – see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2014.02.006
alleviate clinical morbidity. Although promising, there are currently no human trials underway for any of the immunomodulatory agents discussed. As outlined by Schorr and Dellinger, current guidelines for sepsis treatment from the Surviving Sepsis Campaign (www.survivingsepsis.org) are continually being assessed and refined. The product and core of their efforts to improve sepsis survival rates are ‘bundles’, which simplify the complexity of providing care to patients with severe sepsis. A bundle is a selected set of elements of care distilled from evidence-based practice guidelines that, when implemented as a group, have a combined effect on outcomes. Currently, the 3-h and 6-h bundles are indicative of the critical importance of intervention at early stages, and the rapid progression that can determine patient outcome. Implementing these bundles and improving hospital performance are key goals for the Campaign. Mittal and Coopersmith review the role of the gut as a contributor to the microbial and toxicological assault associated with sepsis. Although the concept is 30 years old, it is now clear that the feed-forward loops between the gut and systemic injury can exacerbate disease. Current understanding in this area comes mainly from rodent models. If the insights derived from model systems are applicable to human sepsis, then appropriate therapeutic interventions that disconnect these systems may be a key to controlling sepsis. Yende et al. describe the relationship between sepsis and chronic health. The long-term health consequences after surviving sepsis include frailty, defective cognitive responses, and reduced life expectancy. Further, a sepsis episode may exacerbate underlying chronic conditions such as diabetes or cardiovascular disease. It is clear, therefore, that alleviating the burden of sepsis does not necessarily end with clearing infection. Collectively, this issue is intended to focus on both the recent advances in sepsis research and the challenges that remain. I would like to thank all of the authors and reviewers for their contributions to this special issue, with a very special thank you to our guest editor Peter Ward for his assistance throughout the process. My appreciation also goes to the former editor of Trends in Molecular Medicine, Laurie Gay, for conceiving and planning this special issue. I hope you all enjoy reading this special issue, and I welcome your comments and ideas; feel free to contact us with any feedback or questions at [email protected]. References 1 Hall, M.J. et al. (2011) Inpatient Care for Septicemia or Sepsis: A Challenge for Patients and Hospitals. NCHS Data Brief, No. 62, National Center for Health Statistics 2 Kemmler, M. et al. (2014) Biochip point-of-care device for sepsis diagnostics. Sens. Actuat. B: Chem. 192, 205–215 3 Cooper, R.M. et al. (2014) A microdevice for rapid optical detection of magnetically captured rare blood pathogens. Lab Chip 14, 182–188 Trends in Molecular Medicine, April 2014, Vol. 20, No. 4
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