What's New in Critical Illness and Injury Science: The decades-long quest for a valid prognostic sepsis biomarker continues.

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.[1] 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.[234] Although this observed progress is a result of at least 4 decades of massive laboratory and clinical research efforts,[567] the current status quo seems to be unacceptable given the tremendous strides made in the late 20th and the early 21st century.[68910] 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,[11] thus, allowing the more effective “early, aggressive, and goal directed” management approach advocated by the Surviving Sepsis campaign.[121314] 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.[151617]

Figure 1

Summary of new cases and mortality trends for severe sepsis in the US (2000–2007)[4]

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.[18192021] 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.[2223] One cornerstone of early identification of sepsis is the ability to quickly, accurately, and definitively diagnose it.[1124]

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.[2526] 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,[11272829] 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.[262829303132] Newer approaches should also enable the identification of nonbacterial sources of sepsis, including fungal organisms.[3233]

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.[1134] 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.[34] 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.[3536373839] 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.[4041424344454647484950] 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.[3251525354]

In the current issue of the International Journal of Critical Illness and Injury Science (IJCIIS), Mahmood et al.,[55] 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.[55] 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,[55] 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.[55] 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.[55] 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.