The prognostic value of red blood cell distribution width in patients with suspected infection in the emergency department

Sepsis is a clinical syndrome currently defined as a life-threatening organ dysfunction caused by a dysregulated host immune response to infections [1]. Sepsis has a high incidence, with up to global estimates of 31 million sepsis and 19 million severe sepsis cases, resulting in 5 million deaths annually [2].

Unfortunately, no good diagnostic tool is available for early identification of patients with sepsis and a golden diagnostic standard does not exist [3‐6]. In clinical practice, prognostic sepsis scores are often used to identify patients in need of immediate treatment. The Systemic Inflammatory Response Syndrome (SIRS) score, introduced in 1992 and updated in 2001 proved to be insufficiently specific to correctly identify patients most at risk of dying. The prognostic quick Sequential Organ Failure Assessment (qSOFA) score, introduced in 2016 to overcome this problem, lacks sensitivity to identify all patients that are the most at risk of developing sepsis and thus require immediate treatment [1, 7, 8]. The National Early Warning Score (NEWS) or Modified Early Warning Score (MEWS) have been suggested as better performing alternatives in the Emergency Department (ED) [9, 10] and use is adopted by many hospitals but they are not part of standardized care yet. Therefore, there is an urgent need for better prognostic markers in sepsis that can be used at bedside.

Red Blood Cell Distribution Width (RDW), a quantitative measure of variability in size of circulating erythrocytes usually determined in a complete blood count (CBC), is an inexpensive and readily available measurement, that may act as a prognostic factor in several diseases. For example, elevated RDW has been associated with adverse prognosis in various non-infectious [11‐17] and infectious diseases [18‐20], and in patients diagnosed with (severe) sepsis and septic shock [21‐26]. But it has also been demonstrated to be of prognostic value in undetermined populations [27]. The exact pathophysiologic mechanism underlying this association is unclear but systemic factors that alter erythrocyte homeostasis such as inflammation and oxidative stress, both essential components of the infection cascade, seem to play an important role [28‐36].

Though the independent association with adverse prognosis in various diseases and sepsis has been established, previous research has focused mainly on well-defined populations such as severe sepsis or septic shock, which hampers the generalizability as a prognostic tool in ED populations. Here, we determine the prognostic value of RDW in patients with suspected infection in the emergency department.

RDW is a common, inexpensive and relatively fast available laboratory measurement and in ED settings in patients with suspected infection it is independently associated with 30-day mortality and early clinical deterioration. Additional in our multivariate analysis the MEWS was also independently associated with 30-day mortality, as SIRS ≥2 and qSOFA ≥2 were not.

The prognostic power of RDW for 30-day mortality is comparable to that of SIRS, qSOFA and MEWS, but for early clinical deterioration RDW is outperformed by all these bedside scores. Our results are in line with previous studies, that showed an independent prognostic value of RDW in sepsis and comparable AUROCs. However, previous studies investigated more defined homogeneous patient groups (e.g. diagnosed sepsis or septic shock) and more severely ill patients. In patients with established diagnose of severe sepsis or septic shock in the ED, non-survivors had significantly higher RDW-levels [23, 25, 26]. In ICU patients with severe sepsis or septic shock, higher RDW-levels were also observed in non-surviving patients [21, 22, 24]. Our study shows that the independent prognostic value also applies to a more heterogeneous group of patients with suspected infection.

Higher sepsis scores are associated with higher RDW-levels suggesting more sick patients have higher RDW-levels. Even though this suggest an association between RDW and higher scores, RDW still remained an independent predictor for mortality after correction for disease severity.

The present study has several strengths. To our knowledge, this is the first study that examines RDW in a heterogeneous population, in which we did not use any exclusion criteria. The study population consisted of patients who were suspected of infection and were admitted to the ED. This is the exact patient population seen daily in EDs and exactly these patients are most at risk of developing sepsis. Therefore results obtained from this study are directly applicable to the daily practice. Additionally, our study had a fairly large sample size which made for precise results. Furthermore, all-cause mortality is an unbiased and relevant outcome in observational prognostic studies.

Certain limitations apply to the current study. Firstly, this was a retrospective single center study based on data from electronic medical records, which is a potential source of bias and errors at the time of data recording at the source. Furthermore, due to the heterogeneous population, there is an increased risk that not all confounding factors have been accounted for. Also, being a single-center study and conducted in a large tertiary care institution, results may not be generalizable to other health care institutions.

Although we took conditions that could have influenced RDW-values into account (i.e. hematologic malignancies, chronic renal failure and neutropenia), RDW-values also could have been influenced by nutritional status. This study did not take iron, vitamin B12, folic acid, erythropoietin levels into account. Additionally, blood transfusion records were not available. Though we did not correct for these factors this study shows that RDW-values are applicable for a heterogeneous group of patients and certain comorbidities or conditions should be taken into account when interpreting RDW-values.

Furthermore, a percentage of qSOFA (2,8%) and SIRS-scores (25,5%) could not be determined due to missing data on respiratory rates. We chose to score these as normal and analyzed the at least achieved score results. This under the assumption that if patients would have been tachypnoeic, clinicians would have entered the respiratory rate into the electronic medical file. Missing data in the ED on vital signs is a well-known problem. Especially completing all vital parameters in one single patient. Failure to register vital signs more often when they appear to be normal. Lower triage categories and less sick patients are associated with lesser recording of vital signs [37]. This could have led to underestimation of SIRS scores and to lesser extent qSOFA. To overcome this problem a complete case analysis has been performed which led to no different results.

RDW, a common and inexpensive laboratory measurement, usually determined in the CBC, was found to be a significant independent prognostic factor of 30-day mortality and early clinical deterioration in patients with suspected infection and has comparable prognostic accuracy compared to clinical sepsis scores as SIRS qSOFA or MEWS in predicting 30-day mortality. Therefore it can be a used as an extra marker besides these bedside scores in identifying patients at risk for worse outcome.