|Year : 2014 | Volume
| Issue : 4 | Page : 275-277
What's New in Critical Illness and Injury Science: The decades-long quest for a valid prognostic sepsis biomarker continues
Marissa S Cohen1, Anthony Cipriano2, Stanislaw P Stawicki3, Michael S Firstenberg4, Thomas J Papadimos5
1 Temple University/St. Luke's Medical School; Department of Surgery, St. Luke's University Health Network, Bethlehem, Pennsylvania, United States
2 Department of Surgery, St. Luke's University Health Network, Bethlehem, Pennsylvania, United States
3 Department of Surgery; Department of Research and Innovation, St. Luke's University Health Network, Bethlehem, Pennsylvania, United States
4 Northeast Ohio Medical University and The Summa Health Care System, Akron, Ohio, United States
5 Department of Anesthesiology, The Ohio State University College of Medicine, Columbus, Ohio, United States
|Date of Web Publication||23-Dec-2014|
Dr. Stanislaw P Stawicki
Department of Research and Innovation, St Luke's University Health Network, 801 Ostrum Street, Bethlehem, Pennsylvania - 18015
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Cohen MS, Cipriano A, Stawicki SP, Firstenberg MS, Papadimos TJ. What's New in Critical Illness and Injury Science: The decades-long quest for a valid prognostic sepsis biomarker continues. Int J Crit Illn Inj Sci 2014;4:275-7
|How to cite this URL:|
Cohen MS, Cipriano A, Stawicki SP, Firstenberg MS, Papadimos TJ. What's New in Critical Illness and Injury Science: The decades-long quest for a valid prognostic sepsis biomarker continues. Int J Crit Illn Inj Sci [serial online] 2014 [cited 2022 Jan 26];4:275-7. Available from: https://www.ijciis.org/text.asp?2014/4/4/275/147517
Sepsis is a leading cause of death in critically ill patients, accounting for over a quarter of a million deaths per year in the United States.  Despite increasing hospitalizations for sepsis, corresponding fatality rates have decreased recently (see [Figure 1] for the summary of new cases and mortality of severe sepsis) after a decade-long increase from early 1990s to mid-2000s. ,, Although this observed progress is a result of at least 4 decades of massive laboratory and clinical research efforts, ,, the current status quo seems to be unacceptable given the tremendous strides made in the late 20 th and the early 21 st century. ,,, One of the major impediments to our progress in the fight against sepsis is the continued lack of an accurate diagnostic point-of-care test that could help identify affected patients more promptly,  thus, allowing the more effective "early, aggressive, and goal directed" management approach advocated by the Surviving Sepsis campaign. ,, This, in turn, could theoretically help prevent many of the cases of advanced sepsis and septic shock that result in multiorgan failure, the need for end-organ support therapies, and ultimately the highest incidence of mortality. ,,
|Figure 1: Summary of new cases and mortality trends for severe sepsis in the US (2000-2007)|
Click here to view
Multiple factors, including the aging population, the growing number of immunocompromised hosts, the increasing use of invasive procedures, as well as antibiotic resistance among pathogens have all contributed to an increasing incidence of sepsis. ,,, Preventing sepsis in hospitalized patients is among the primary duties of the medical staff and multiple preventative measures are in place as standard of care (i. e., removing unnecessary lines and catheters, discontinuing inappropriate antibiotics, following contact precautions, etc.). The abovementioned increase in incidence of sepsis, along with decreasing case fatality, prompted the medical research community to focus much more attention on early identification and prevention of this continuously deadly entity. , One cornerstone of early identification of sepsis is the ability to quickly, accurately, and definitively diagnose it. ,
Conversely, in the aggressiveness in treating sepsis-borne from the fear of "missing" a potentially fatal problem can, and often, does result in an overtreatment of patients. , As many of the patients at greatest risk for sepsis while hospitalized are often recovering from major surgical procedures or an acute decompensation of a chronic medical problem (such as congestive heart failure), their inflammatory markers as a function of a stress response, are often elevated. An overreliance on single biomarkers, ,,, to the exclusion of other clinical variables, can result in patients undergoing often a series of extensive and expensive testing, imaging, and exposure to broad-spectrum antibiotics (which, even if for only a few days, might contribute to the worsening of hospital resistance patterns or other antibiotic associated complications). Hence, it is critical as we move forward in this search for more reliable biomarkers (or combinations thereof) that future studies also consider the overtreatment of false positives as well as the impact of false negatives. ,,,,, Newer approaches should also enable the identification of nonbacterial sources of sepsis, including fungal organisms. ,
Identifying sepsis early and accurately determining the degree of severity, which helps determine treatment and prognosis, remains a formidable challenge. Recognizing a single marker or set of markers to aid in this may help decrease the global impact of sepsis. , As of 2010, nearly 180 potential biomarkers had been evaluated for use in sepsis, none of which being sensitive or specific enough to be adopted as standard of care.  More recently, a number of publications have highlighted the potential use of red blood cell distribution width (RDW) in diagnosis and/or prognostication of sepsis in adults. ,,,, Although all efforts at increasing our biomarker armamentarium for diagnosis sepsis should be strongly encouraged and supported, RDW is admittedly quite nonspecific as it may be altered in anemia, malnutrition, vitamin deficiency states, hemorrhage, inflammation, renal insufficiency, pneumonia, acute pancreatitis, pulmonary embolism, pulmonary hypertension, acute dyspnea, and other conditions including heart failure and coronary artery bypass surgery. ,,,,,,,,,, Consequently, many of these factors may serve as confounders when considering the relationship between RDW and sepsis severity-an age-old problem with diagnosing sepsis in general. ,,,,
In the current issue of the International Journal of Critical Illness and Injury Science (IJCIIS), Mahmood et al.,  reported on RDW as a prognostic biomarker in sepsis as related to Acute Physiology and Chronic Health Evaluation II (APACHE II) scores and found that RDW of 16% was independently associated with an APACHE II score of 15 or higher, as well as with mortality. By noting that RDW of 16% can be utilized as a clinical breakpoint, these authors may have presented the medical community with a novel way to separate the more severe cases of sepsis from those that are less severe.  Although this is a single-center retrospective analysis, the study appears to have an effect size that would encourage the present authors and other researchers to proceed toward a prospective confirmation of these findings. Additionally, the suggestion that septic patients with an RDW > 16% may have a higher severity of illness accompanied by the demonstration of an independent association with mortality in the Mahmood et al., study,  is a further compelling facet of this work that should enjoin other researchers in pursuing this line of questioning. The research team from St Joseph's Regional Medical Center and Seton Hall University, South Orange, New Jersey also noted that baseline characteristics such as age, gender, chronic conditions, and medication lists, can act as potential confounders.  Although no study of sepsis is inherently perfect due to the multifaceted nature and complexities of this pathologic state, we congratulate Mahmood et al., on their outstanding contribution to our understanding of RDW as a potential diagnostic and prognostic tool in the septic patient.  Future studies examining RDW in patients with sepsis are clearly warranted, with added emphasis on multivariable diagnostic models that incorporate other biomarkers in addition to the RDW. With every new scientific effort, such as the one reported here in IJCIIS, we move closer to solving the enigma of sepsis and septic shock.
| References|| |
Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: A trend analysis from 1993 to 2003. Crit Care Med 2007;35:1244-50.
Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Facing the challenge: Decreasing case fatality rates in severe sepsis despite increasing hospitalizations. Crit Care Med 2005;33:2555-62.
Kumar G, Kumar N, Taneja A, Kaleekal T, Tarima S, McGinley E, et al
. Milwaukee Initiative in Critical Care Outcomes Research Group of Investigators. Nationwide trends of severe sepsis in the 21 st
century (2000-2007). Chest 2011;140:1223-31.
Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of mortality trends among patients with severe sepsis: A comparative meta-analysisFNx01. Crit Care Med 2014;42:625-31.
Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 1992;101:1481-3.
Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546-54.
Opal SM. Concept of PIRO as a new conceptual framework to understand sepsis. Pediatr Crit Care Med 2005;6:S55-60.
Vincent JL, Opal S, Torres A, Bonten M, Cohen J, Wunderink R. The PIRO concept: I is for infection. Crit Care 2003;7:252-5.
Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al
. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644-55.
Stawicki SP, Stoltzfus JC, Aggarwal P, Bhoi S, Bhatt S, Kalra OP, et al
. Academic college of emergency experts in India′s INDO-US joint working group and OPUS12 foundation consensus statement on creating a coordinated, multi-disciplinary, patient-centered, global point-of-care biomarker discovery network. Int J Crit Illn Inj Sci 2014;4:200-8.
Ahrens T, Tuggle D. Surviving severe sepsis: Early recognition and treatment. Crit Care Nurse 2004;2-13.
Vassalos A, Rooney K. Surviving sepsis guidelines 2012. Crit Care Med 2013;41:e485-6.
Dickinson JD, Kollef MH. Early and adequate antibiotic therapy in the treatment of severe sepsis and septic shock. Curr Infect Dis Rep 2011;13:399-405.
Stawicki SP, Gracias VH, Lorenzo M. Surgical critical care: From old boundaries to new frontiers. Scand J Surg 2007;96:17-25.
Miller A. Identifying sepsis too late. Nursing 2014;44:12-4.
Stawicki SP, Firstenberg MS, Lyaker MR, Russell SB, Evans DC, Bergese SD, et al
. Septic embolism in the intensive care unit. Int J Crit Illn Inj Sci 2013;3:58-63.
Rello J, Lipman J, Lisboa T. (Editors) Sepsis management: PIRO and MODS. Heidelberg: Springer; 2012. vi. p. 243.
Rello J, Restrepo MI. (Editors) Sepsis: New strategies for management. Berlin: Springer; 2008. xi, p. 142.
Evans DC, Cook CH, Christy JM, Murphy CV, Gerlach AT, Eiferman D, et al
. Comorbidity-polypharmacy scoring facilitates outcome prediction in older trauma patients. J Am Geriatr Soc 2012;60:1465-70.
Dalton RE, Tripathi RS, Abel EE, Kothari DS, Firstenberg MS, Stawicki SP, et al
. Polyneuropathy and myopathy in the elderly. HSR Proc Intensive Care Cardiovasc Anesth 2012;4:15-9.
Nelson CL. Prevention of sepsis. Clin Orthop Relat Res 1987:66-72.
Muscroft TJ, Deane SA. Prevention of sepsis in gastroesophageal surgery. World J Surg 1982;6:293-300.
Boucher BA, Hanes SD. Searching for simple outcome markers in sepsis: An effort in futility? Crit Care Med 1999;27:1390-1.
Balc IC, Sungurtekin H, Gürses E, Sungurtekin U, Kaptanoglu B. Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit. Crit Care 2003;7:85-90.
Ewig S. Against misleading predictions for severe community-acquired pneumonia. Am J Respir Crit Care Med 2007;175:289.
Zhou H, Hewitt SM, Yuen PS, Star RA. Acute kidney injury biomarkers-needs, present status, and future promise. Nephrol Self Assess Program 2006;5:63-71.
Pammi M, Flores A, Leeflang M, Versalovic J. Molecular assays in the diagnosis of neonatal sepsis: A systematic review and meta-analysis. Pediatrics 2011;128:e973-85.
Sabel KG, Wadsworth C. C-reactive protein (CRP) in early diagnosis of neonatal septicemia. Acta Paediatr Scand 1979;68:825-31.
Stawicki SP, Papadimos TJ. Challenges in managing amniotic fluid embolism: An up-to-date perspective on diagnostic testing with focus on novel biomarkers and avenues for future research. Curr Pharm Biotechnol 2014;14:1168-78.
Liaudat S, Dayer E, Praz G, Bille J, Troillet N. Usefulness of procalcitonin serum level for the diagnosis of bacteremia. Eur J Clin Microbiol Infect Dis 2001;20:524-7.
Mancini N, Carletti S, Ghidoli N, Cichero P, Burioni R, Clementi M. The era of molecular and other non-culture-based methods in diagnosis of sepsis. Clin Microbiol Rev 2010;23:235-51.
Gutierrez SM, Heredia M, Gómez E, Gómez JI, Tamayo E. Candidemia in ICU patients with sepsis. Crit Care Med 2013;41:e385.
Pierrakos C, Vincent JL. Sepsis biomarkers: A review. Crit Care 2010;14:R15.
Balta S, Demirkol S, Hatipoglu M, Ardic S, Arslan Z, Celik T. Red cell distribution width is a predictor of mortality in patients with severe sepsis and septic shock. Am J Emerg Med 2013;31:989-90.
Kim CH, Park JT, Kim EJ, Han JH, Han JS, Choi JY, et al
. An increase in red blood cell distribution width from baseline predicts mortality in patients with severe sepsis or septic shock. Crit Care 2013;17:R282.
Aksoy HT, Eras Z, Canpolat E, Dilmen U. Does red cell distribution width predict mortality in newborns with early sepsis? Am J Emerg Med 2013;31:1150.
Jo YH, Kim K, Lee JH, Kang C, Kim T, Park HM, et al
. Red cell distribution width is a prognostic factor in severe sepsis and septic shock. Am J Emerg Med 2013;31:545-8.
Ku NS, Kim HW, Oh HJ, Kim YC, Kim MH, Song JE, et al
. Red blood cell distribution width is an independent predictor of mortality in patients with gram-negative bacteremia. Shock 2012;38:123-7.
Balta S, Demirkol S, Aydogan M, Unlu M. Red cell distribution width is a predictor of mortality in patients undergoing coronary artery bypass surgery. Eur J Cardiothorac Surg 2013;44:396-7.
Forhecz Z, Gombos T, Borgulya G, Pozsonyi Z, Prohászka Z, Jánoskuti L. Red cell distribution width: A powerful prognostic marker in heart failure. Eur J Heart Fail 2010;12:415.
Oh HJ, Park JT, Kim JK, Yoo DE, Kim SJ, Han SH, et al
. Red blood cell distribution width is an independent predictor of mortality in acute kidney injury patients treated with continuous renal replacement therapy. Nephrol Dial Transplant 2012;27:589-94.
Karagoz E, Tanoglu A. Red blood cell distribution width: An emerging diagnostic factor of acute appendicitis? World J Emerg Surg 2013;8:54.
Desai N, Choudhry VP. Nutritional anemia in protein energy malnutrition. Indian Pediatr 1993;30:1471-83.
Kim J, Kim K, Lee JH, Jo YH, Rhee JE, Kim TY, et al
. Red blood cell distribution width as an independent predictor of all-cause mortality in out of hospital cardiac arrest. Resuscitation 2012;83:1248-52.
Hong N, Oh J, Kang SM, Kim SY, Won H, Youn JC, et al
. Red blood cell distribution width predicts early mortality in patients with acute dyspnea. Clin Chim Acta 2012;413:992-7.
Zorlu A, Bektasoglu G, Guven FM, Dogan OT, Gucuk E, Ege MR, et al
. Usefulness of admission red cell distribution width as a predictor of early mortality in patients with acute pulmonary embolism. Am J Cardiol 2012;109:128-34.
Lee JH, Chung HJ, Kim K, Jo YH, Rhee JE, Kim YJ, et al
. Red cell distribution width as a prognostic marker in patients with community-acquired pneumonia. Am J Emerg Med 2013;31:72-9.
Senol K, Saylam B, Kocaay F, Tez M. Red cell distribution width as a predictor of mortality in acute pancreatitis. Am J Emerg Med 2013;31:687-9.
Hampole CV, Mehrotra AK, Thenappan T, Gomberg-Maitland M, Shah SJ. Usefulness of red cell distribution width as a prognostic marker in pulmonary hypertension. Am J Cardiol 2009;104:868-72.
Zahar JR, Timsit JF, Garrouste-Orgeas M, Français A, Vesin A, Descorps-Declere A, et al
. Outcomes in severe sepsis and patients with septic shock: Pathogen species and infection sites are not associated with mortality. Crit Care Med 2011;39:1886-95.
Brun-Buisson C, Roudot-Thoraval F, Girou E, Grenier-Sennelier C, Durand-Zaleski I. The costs of septic syndromes in the intensive care unit and influence of hospital-acquired sepsis. Intensive Care Med 2003;29:1464-71.
Herzum I, Renz H. Inflammatory markers in SIRS, sepsis and septic shock. Curr Med Chem 2008;15:581-7.
McLean AS, Huang SJ, Hyams S, Poh G, Nalos M, Pandit R, et al
. Prognostic values of B-type natriuretic peptide in severe sepsis and septic shock. Crit Care Med 2007;35:1019-26.
Mahmood NA, Mathew J, Kang B, DeBari VA, Khan MA. Broadening of the red blood cell distribution width is associated with increased severity of illness in patients with sepsis. Int J Crit Illn Inj Sci 2014;4:3-7.