Neutrophil‐lymphocyte ratio and plasma lactate predict 28‐day mortality in patients with sepsis

Abstract Objective The predictive potential of the neutrophil‐to‐lymphocyte ratio (NLR) and plasma lactate was investigated in regard to the prognosis of patients with sepsis. Methods Sixty‐three nonsurgical and nontrauma adult patients with sepsis admitted to the intensive care unit (ICU) from September 2016 to October 2018 were consecutively included in the study. In addition, healthy subjects were assigned to a control group. Neutrophil and lymphocyte counts were evaluated via a complete blood count. Plasma lactate, procalcitonin (PCT), and C‐reactive protein (CRP) levels were measured. The main outcome was 28‐day mortality. Results Neutrophil‐to‐lymphocyte ratio and plasma lactate levels of the patients were significantly higher than those of control subjects: 19.44 (14.3‐34.53) vs 14.09 (8.17‐28.99), P = 0.049; and 3.7 (3‐6.6) vs 2.72 (2.13‐4.3) ng/mL, P = 0.008, respectively. There were no statistical differences in the concentrations of PCT and CRP between nonsurvivors and survivors: 6.1 (3.43‐33.59) vs 9.43 (4.24‐37.68) ng/mL, P = 0.44; and 108 (77.8‐153) vs 114.5 (71.43‐162) ng/mL, P = 0.672, respectively. With an optimal cutoff of 14.08, the sensitivity and specificity of NLR for prediction of 28‐day mortality were 78.3% and 50%, respectively. And the sensitivity and specificity of plasma lactate level to predict 28‐day mortality, at an optimal cutoff value of 2.99 mmol/L, were 82.6% and 55%, respectively. Conclusions Neutrophil‐to‐lymphocyte ratio and plasma lactate were associated with poor outcomes in patients with sepsis and predicted mortality.


| INTRODUC TI ON
Sepsis is the primary cause of death from infection. It is also one of the leading causes of intensive care unit (ICU) mortality, despite early administration of antibiotics and hemodynamic management. 1 Sepsis is a life-threatening organ dysfunction caused by a deregulated host response to an infection. It is a major public health concern, accounting for more than $20 billion in the US hospital costs in 2011. 2 Furthermore, survivors of sepsis often suffer from substantial and persistent new cognitive impairment and functional disability, imposing a great burden on healthcare systems and societies worldwide. 3 Therefore, finding tools that may assist physicians in early identification of patients with sepsis, especially those at high risk, may improve outcomes in patients with sepsis. Plasma biomarkers may have diagnostic, prognostic, and theranostic values, all of which are important factors influencing outcomes in patients with sepsis. 4 Indeed, procalcitonin (PCT) and C-reactive protein (CRP) had been applied in evaluation of the severity of an episode of sepsis along with patient therapeutic responses and guided duration of therapy in critically ill patients. 5 However, due to their unspecific character and insufficient predictive value for the individual, urgent identification of a more robust biomarker is essential. 6 Systemic inflammation is related to alterations in circulating blood cell composition as a response of the immune system to stress or sepsis. 7,8 White blood cell (WBC) count has been identified as an important systemic inflammation marker. 9 Recent reports demonstrated that the WBC count had an independent ability to predict all-cause mortality. 10,11 Data from previous research indicated that changes in WBC (neutrophil and lymphocyte) were associated with inflammatory diseases. The most well-known WBC disease is relative lymphopenia accompanied by neutrophilia. The neutrophil-tolymphocyte ratio (NLR) is a rapid and simple parameter of systemic inflammation and stress, which expresses the severity of the disease in the critically ill patients. 8 Lactate is a normal product of anaerobic metabolism. 12 The blood lactate levels are elevated not only due to tissue hypoxia or anaerobic glycolysis, but also due to secondary activation of the stress response. Characteristics of lactate production best fit the notion of an adaptive survival response that grows in intensity as disease severity increases. Measurement of blood lactate levels may aid prediction of mortality. Its presence and progression are widely appreciated by doctors as an indicator in the detection of very high-risk populations. 13 Lactate measurement was frequently used in hospital settings to identify patients with sepsis and to guide initiation of early treatment. 14 The primary purpose of this study was to determine the capability of NLR and plasma lactate to predict mortality during hospitalization and later (in 28 days) in patients with sepsis from the Department of Critical Care Medicine, compared to established sepsis-related biomarkers (PCT and CRP).

| Patients
We conducted a prospective, observational study at the Changhai  15 The exclusion criteria included the following: (a) age < 18 years or >90 years; (b) hematological disease, cancer, autoimmune disease; (c) hospitalization or receiving antibiotics within the past 28 days; and (d) being re-admitted to the ICU. All eligible patients were divided into two groups: (a) the survivor group, which included patients who survived 28 days after initial diagnosis, and (b) the nonsurvivor group, which included patients who died within 28 days following diagnosis ( Figure 1).
The protocol and procedure for obtaining informed consent were approved by the Institutional Ethical Committees, and consent forms were provided by first-degree relatives or patients.

| Measurements and data collection
Baseline characteristics of the patients including demographics (age and gender), comorbidities (cardiovascular disease, chronic lung disease, and diabetes, among others), and primary diagnosis were recorded. Blood samples were collected within

| Statistical analysis
All analyses were performed using SPSS 21.0 software, and statistical significance was set at P < 0.05. Box plots were used to present results. The chi-square test was used to compare the two sets of data, and the Mann-Whitney U test was used to compare the two sets of measurement data. Receiver operating characteristic (ROC) curves were constructed to compare prognostic performance and to determine the optimal cutoff points for the biomarkers. Spearman's rank correlation coefficient (rs) was used to determine correlation between conventional inflammation-related biomarkers.

| Patient population and characteristics
Sixty-three consecutive patients meeting the criteria of sepsis were  Table 1.

| Levels of NLR, plasma lactate, PCT, and CRP
Neutrophil-to-lymphocyte ratio and plasma lactate were higher

| Prediction of mortality
Receiver operating characteristic curves were used to analyze the relationship between NLR, lactate, and 28-day mortality. The area under the ROC curve was 0.634 (P = 0.049) for the ability of NLR to predict 28-day mortality, with a sensitivity of 78.3% and specificity of 50%.
The optimal cutoff was 14.08. The area under the ROC curve was 0.701 (P = 0.008) for the ability of plasma lactate level to predict 28day mortality, and the sensitivity and specificity, at an optimal cutoff value of 2.99 mmol/L, were 82.6% and 55%, respectively ( Figure 3).

TA B L E 1 Baseline characteristics of patients enrolled in the study
However, there was no significant correlation between NLR and CRP (rs = 0.142, P = 0.268) and PCT (rs = 0.221, P = 0.082). It has already been known that levels of PCT and CRP may allow for a better outcome prediction. In fact, our findings did not indicate significant differences in the plasma concentrations of PCT and CRP between nonsurvivors and survivors. This result seems to substantiate those of a previous study involving patients critically ill with sepsis and infection, where nonsurvivors and survivors had the same PCT plasma levels. 5 PCT levels have been shown to correlate with the severity of sepsis. 16,17 Furthermore, CRP levels of nonsurvivors did not differ significantly from those of survivors. This is consistent with other studies, demonstrating that CRP did not allow early discrimination of nonsurvivors from survivors with postoperative sepsis. 16 Results of the current study indicated that NLR was significantly elevated in the nonsurvivors compared to that in the survivors. NLR may simply reflect an appropriate tissue perfusion response that is adaptive. There was significant correlation between NLR and lactate (rs = 0.412, P = 0.001). The association between increased F I G U R E 2 Levels of neutrophil-to-lymphocyte ratio (NLR), plasma lactate, procalcitonin (PCT), and C-reactive protein (CRP) mortality and raised NLR was also consistent with that in prior studies; Shahidi reported that the NLR was a simple, cheap, rapidly accessible, and independent indicator of short-and long-term mortalities in critically ill patients. 18 WBCs, in particular neutrophils and lymphocytes, are known to play an important role in the inflammatory processes of chronic diseases, such as atherosclerosis. 19,20 NLR also had proven useful for predicting intensive care suitability and mortality in patients with community-acquired pneumonia. 21 Neutrophils played an especially crucial role in the acute inflammatory response to tissue injury and were related to reperfusion injury. 22 Lymphocytopenias were associated with cortisol production and neuroendocrine stress. 23 NLR indicated that these two were inversely related immune pathways: one representing unrestrained inflammation and the other a latent immune pathway. 24 25 Previous studies demonstrated that elevated lactate levels were associated with high mortality and poor prognostic outcomes. 26,27 Several biomarkers have been proposed to predict mortality, but lack sufficient sensitivity and specificity.

| D ISCUSS I ON
Both composite biomarkers may have significantly higher sensitivity and specificity than all the single biomarkers, suggesting the need for a joint interpretation of several biomarkers in sepsis prediction.
In conclusion, raised NLR and lactate levels showed significant association with increased mortality in patients with sepsis. NLR and lactate may be important prognostic biomarkers to optimize treatment and manage patients. Larger, multicenter trials may be needed to further verify these findings.

R E FE R E N C E S
F I G U R E 3 Receiver operating characteristics (ROC) of neutrophil-to-lymphocyte ratio (NLR) and plasma lactate levels for prediction of mortality in patients with sepsis. The area under the ROC curve was 0.634 for the ability of NLR level to predict 28-d mortality, with a sensitivity of 78.3% and specificity of 50%.
The area under the ROC curve was 0.701 for the ability of plasma lactate level to predict 28-d mortality, and the sensitivity and specificity were 82.6% and 55%, respectively F I G U R E 4 Receiver operating characteristics of neutrophilto-lymphocyte ratio (NLR), lactate, and NLR with added lactate in patients with sepsis in relation to 28-d mortality