Sepsis is a complicated condition and still a big challenge to both the developed and developing world. The reported morbidity of sepsis is constantly increasing, with severe sepsis and septic shock remaining among the major causes of death worldwide [
The neutrophil-to-lymphocyte ratio (NLR), as a readily accessible biomarker, can be calculated based on a complete blood count. Although a growing body of evidence has shown that NLR is proposed as an independent predictor of poor survival in various clinical circumstances ranging from oncological patients [
In this prospective observational study, we sought to evaluate the potential association of NLR on intensive care unit (ICU) admission with the clinical prognosis in a consecutive series of adult patients with sepsis.
This prospective trial recruited consecutive adult patients with sepsis admitted to the ICU of the Department of Emergency, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, from October 2013 to October 2015.
For each patient with suspected infection, a complete diagnostic work-up was performed. The work-up comprised demographic and clinical characteristics, conventional risk factors, and important laboratory data including leukocyte counts, blood biochemistry, blood cultures, urine cultures, chest X-ray, and chest or abdominal computed tomography if necessary. Broad spectrum antimicrobial therapy was administered within 1 hour from the recognition of the septic status, always after collecting samples for microbiological culturing.
The inclusion criteria were as follows in the study: (1) age of at least 18 years; (2) sepsis due to one of the following infections: community acquired pneumonia, hospital acquired pneumonia, ventilator-associated pneumonia, acute pyelonephritis, intra-abdominal infection, or primary bacteremia; and (3) blood sampling within 24 hours from the presentation of signs of sepsis. We formulated a priori criterion to exclude patients according to the following criteria: (1) missing neutrophil and lymphocyte data on ICU admission; (2) missing covariate data for multivariable adjustments; (3) patients with immunosuppressive diseases mainly including cancer and HIV infection or patients with receiving immunosuppressive therapy; and (4) patients who were already in ICU for many days and became septic secondary. Patients were eligible for the final study cohort if they met the inclusion criteria and none of the exclusion criteria.
All the eligible patients were further classified according to standard definitions of sepsis, severe sepsis, and septic shock [
The study was approved by Shanghai Jiaotong University Xinhua Hospital Ethics Committee and was carried out in accordance with the Declaration of Helsinki. All patients were informed about the study and consented to participate. If the patient was unable to be informed, the next of kin was informed and provided consent for the patient to participate.
Venous blood (3 mL) was collected from patients presenting to the ICU. The blood was drawn into an EDTA-containing tube (BD Vacutainer, Plymouth, UK) and centrifuged at 3,000 rpm for 15 min, and plasma was frozen at −80°C until analysis. Complete blood count was determined using the Beckman Coulter LH-750 Hematology Analyzer (Beckman Coulter, Inc., Fullerton, California). NLR was calculated as a ratio of circulating neutrophil and lymphocyte counts. The normal ranges for the leukocyte in our laboratory are 1.4–6.5 × 109/L for neutrophil count and 1.2–3.4 × 109/L for lymphocyte count.
To evaluate the severity of sepsis upon presentation, the validated Acute Physiology and Chronic Health Evaluation II (APACHE II) score was calculated in all enrolled patients on admission. This score ranges from 0 to 71, with higher scores indicating more severe disease.
Furthermore, patients who survived and discharged from hospital were further followed up by telephone calls. The primary outcome of the study was defined as death from any cause within 28 days after admission to the ICU.
Continuous variables were reported as mean values ± standard deviation (SD) or median with interquartile range (IQR), while categorical variables were expressed as count and percentage. The statistical significance of intergroup differences was compared through unpaired Student’s
During the study period, there were 333 consecutive patients (56.46% male; mean age,
Baseline clinical and laboratory characteristics of the study subjects.
Characteristics | Patient group | |||
---|---|---|---|---|
All patients | Survivors | Nonsurvivors |
|
|
Demographics and underlying conditions | ||||
Number of patients | 333 | 253 | 80 | — |
Males, number (%) | 188 (56.46%) | 137 (54.15%) | 51 (63.75%) | 0.131 |
Age (years) | 70.26 ± 15.79 | 67.82 ± 16.59 | 77.98 ± 9.49 | 0.000 |
COPD, number (%) | 38 (11.41%) | 23 (9.09%) | 15 (18.75%) | 0.017 |
Hypertension, number (%) | 157 (47.15%) | 115 (45.45%) | 42 (52.50%) | 0.271 |
CHD, number (%) | 84 (25.23%) | 55 (21.74%) | 29 (36.25%) | 0.008 |
Diabetes mellitus, number (%) | 105 (31.53%) | 80 (31.62%) | 25 (31.25%) | 0.950 |
Disease severity, number (%) | 0.008 | |||
Sepsis | 137 (41.14%) | 117 (46.25%) | 20 (25.00%) | — |
Severe sepsis | 149 (44.74%) | 107 (42.29%) | 42 (52.50%) | — |
Septic shock | 47 (14.11%) | 29 (11.46%) | 18 (22.50%) | — |
Baseline parameters | ||||
APACHE II score | 11 (6–19) | 9 (6–14.5) | 20 (14–29) | 0.000 |
WBC count (109/L) | 16.07 ± 6.63 | 15.35 ± 6.11 | 18.40 ± 7.67 | 0.000 |
Neutrophil (109/L) | 13.00 (9.80–17.55) | 12.30 (9.53–16.76) | 16.35 (11.16–20.14) | 0.001 |
Lymphocyte (109/L) | 0.77 (0.51–1.30) | 0.84 (0.54–1.40) | 0.61 (0.35–0.87) | 0.002 |
NLR | 17.85 (9.61–28.19) | 15.03 (8.94–24.67) | 25.49 (16.64–47.15) | 0.000 |
Platelet (109/L) | 191.24 ± 68.57 | 188.53 ± 61.15 | 199.96 ± 79.88 | 0.475 |
RBC count (109/L) | 4.10 ± 0.83 | 4.21 ± 0.79 | 3.74 ± 0.84 | 0.534 |
Hematocrit (%) | 36.58 ± 6.59 | 37.34 ± 6.12 | 34.13 ± 7.43 | 0.066 |
RDW (%) | 13.69 ± 1.87 | 13.40 ± 1.36 | 14.60 ± 2.79 | 0.000 |
Hemoglobin (g/L) | 123.11 ± 22.99 | 126.35 ± 21.69 | 112.75 ± 24.13 | 0.290 |
PCT (ng/mL) | 18.54 ± 7.28 | 17.89 ± 7.47 | 20.60 ± 7.13 | 0.521 |
CRP (mg/L) | 100.05 ± 46.10 | 97.45 ± 47.43 | 108.26 ± 45.70 | 0.140 |
BNP (ng/mL) | 173.0 (87.5–401.5) | 160.0 (79.5–327.0) | 181.0 (92.0–505.0) | 0.020 |
Myoglobin (ng/mL) | 83.8 (31.6–309.6) | 71.4 (29.3–256.6) | 153.0 (48.1–671.1) | 0.011 |
CK-MB (ng/mL) | 2.7 (1.4–6.0) | 2.5 (1.2–5.0) | 3.2 (2.1–9.0) | 0.348 |
Troponin T (ng/mL) | 0.03 (0.01–0.10) | 0.02 (0.01–0.07) | 0.08 (0.02–0.34) | 0.009 |
BUN (mmol/L) | 7.65 (5.13–11.70) | 6.80 (4.64–10.30) | 10.93 (7.70–19.20) | 0.076 |
Scr ( |
121.54 ± 50.63 | 109.45 ± 46.85 | 160.26 ± 67.97 | 0.004 |
Cystatin C (mg/L) | 0.92 (0.00–1.51) | 0.79 (0.00–1.32) | 1.69 (1.02–2.74) | 0.002 |
ALT (U/L) | 29.0 (19.0–49.8) | 28.0 (18.0–56.0) | 30.0 (19.0–48.5) | 0.075 |
AST (U/L) | 36.0 (25.0–67.0) | 35.0 (25.0–61.0) | 46.0 (23.0–76.0) | 0.056 |
Bilirubin (mg/dL) | 22.61 ± 11.43 | 22.11 ± 10.92 | 24.19 ± 13.07 | 0.453 |
Albumin (g/L) | 33.25 ± 6.04 | 34.25 ± 5.60 | 30.04 ± 6.32 | 0.000 |
FBG (mmol/L) | 8.37 ± 5.08 | 8.40 ± 4.86 | 8.26 ± 5.12 | 0.830 |
Lactic acid (mmol/L) | 2.0 (1.2–2.8) | 1.8 (1.0–2.4) | 2.3 (1.6–3.4) | 0.002 |
Inflammatory cytokine | ||||
IL-1B (pg/mL) | 5.00 (5.00–5.12) | 5.00 (5.00–5.00) | 5.00 (5.00–6.04) | 0.533 |
IL-2 receptor (U/mL) | 1222 (801–1921) | 1142 (764–1711) | 1574 (1070–3379) | 0.000 |
IL-6 (pg/mL) | 27.9 (14.0–68.4) | 26.1 (12.3–58.3) | 49.8 (20.0–133.0) | 0.052 |
IL-8 (pg/mL) | 53.9 (21.3–153.5) | 44.7 (18.7–139.0) | 106.5 (35.1–242.8) | 0.289 |
IL-10 (pg/mL) | 5.9 (5.0–12.6) | 5.7 (5.0–8.9) | 9.0 (5.0–26.7) | 0.099 |
TNF- |
22.6 (15.9–34.4) | 22.2 (15.6–33.7) | 26.8 (16.6–41.2) | 0.066 |
CD64 | 3.6 (1.6–6.2) | 2.9 (1.5–5.8) | 3.9 (1.7–6.3) | 0.034 |
Site of infection, number (%) | 0.602 | |||
Lung | 184 (55.26%) | 135 (53.36%) | 49 (61.25%) | — |
Abdomen | 70 (21.02%) | 56 (22.13%) | 14 (17.50%) | — |
Urinary tract | 55 (16.52%) | 44 (17.39%) | 11 (13.75%) | — |
Other | 24 (7.21%) | 18 (7.11%) | 6 (7.50%) | — |
Intervention, number (%) | ||||
Mechanical ventilation | 42 (12.61%) | 17 (6.72%) | 25 (31.25%) | 0.000 |
Renal-replacement therapy | 24 (7.21%) | 10 (3.95%) | 14 (17.50%) | 0.000 |
Length of stay | ||||
In the ICU (days) | 4.5 (2–9) | 4 (1–8) | 6 (2–12) | 0.041 |
In the hospital (days) | 10 (7–14) | 9 (7–13) | 11 (7–16) | 0.468 |
COPD: chronic obstructive pulmonary disorder; CHD: coronary heart disease; APACHE II: Acute Physiology and Chronic Health Evaluation II; WBC: white blood cell; NLR: neutrophil-to-lymphocyte ratio; RBC: red blood cell; RDW: red blood cell distribution width; PCT: procalcitonin; CRP: C-reactive protein; BNP: brain natriuretic peptide; CK-MB: creatine kinase-MB; BUN: blood urea nitrogen; Scr: serum creatinine; ALT: alanine transaminase; AST: aspartate transaminase; FBG: fasting blood glucose; IL: interleukin; TNF-
Data are expressed as number (%), mean (standard deviation, SD), or median (interquartile range, IQR) as appropriate.
Significant differences are marked by
The median NLR for the entire cohort was 17.85 (IQR, 9.61 to 28.19). The neutrophil count of nonsurvivors on admission was higher than that of survivors (
ROC curves were constructed to evaluate the performance of indicators in differentiating nonsurvivors from survivors, and the AUC for each indicator was compared. The AUC, optimal cutoff value, sensitivity, and specificity of each indicator are presented in Table
Performance of variables in predicting unfavorable outcome.
Variables | AUC ROC |
|
Cutoff value | Sensitivity (%) | Specificity (%) |
---|---|---|---|---|---|
APACHE II score | 0.828 ± 0.026 | 0.000 |
≥16.5 | 76.3 | 70.8 |
Neutrophil | 0.633 ± 0.036 | 0.000 |
≥14.2 | 73.8 | 45.8 |
Lymphocyte | 0.650 ± 0.035 | 0.000 |
≤0.64 | 75.0 | 58.1 |
NLR | 0.695 ± 0.036 | 0.000 |
≥23.8 | 81.3 | 53.6 |
AUC ROC: area under the receiver operating characteristic curve; APACHE II: Acute Physiology and Chronic Health Evaluation II; and NLR: neutrophil-to-lymphocyte ratio.
Significant differences are marked by
Receiver operating characteristic (ROC) curves for Acute Physiology and Chronic Health Evaluation II (APACHE II) score, neutrophil, lymphocyte, and neutrophil-to-lymphocyte ratio (NLR). NLR had a modest power for predicting unfavorable outcome as suggested by area under the curve (AUC) of
Furthermore, we performed univariate logistic regression analyses to examine the associations of each variable with unfavorable outcome and calculated the standardized regression coefficient (
Univariate odds ratios of variables for predicting unfavorable outcome.
Variables | Standard |
OR | 95% CI |
|
---|---|---|---|---|
APACHE II score | 0.2342 | 1.168 | 1.102–1.238 | 0.000 |
Neutrophil | −0.0875 | 0.916 | 0.766–1.096 | 0.339 |
Lymphocyte | 0.0671 | 1.069 | 0.808–1.416 | 0.639 |
NLR | 0.0378 | 1.038 | 1.008–1.070 | 0.013 |
WBC | 0.0195 | 1.020 | 0.955–1.089 | 0.558 |
Lactic acid | 0.0461 | 1.047 | 0.860–1.276 | 0.647 |
Age | 0.0813 | 1.085 | 1.039–1.132 | 0.000 |
APACHE II: Acute Physiology and Chronic Health Evaluation II; NLR: neutrophil-to-lymphocyte ratio; and WBC: white blood cell.
The OR indicates the risk of obtaining unfavorable outcome. Standard
Significant differences are marked by
We conducted a forward stepwise multivariate logistic regression model to determine the independent predictors of adverse outcome. The results are shown in Table
Independent predictors of unfavorable outcome by multivariate logistic regression analysis.
Variables | Standard |
OR | 95% CI |
|
---|---|---|---|---|
APACHE II score | 0.2639 | 1.168 | 1.108–1.230 | 0.000 |
NLR | 0.0471 | 1.043 | 1.012–1.083 | 0.016 |
Age | 0.0745 | 1.077 | 1.034–1.122 | 0.000 |
APACHE II: Acute Physiology and Chronic Health Evaluation II; NLR: neutrophil-to-lymphocyte ratio.
The OR indicates the risk of obtaining unfavorable outcome. Standard
Significant differences are marked by
Patients with severe sepsis or septic shock tended to have higher baseline levels of APACHE II score, neutrophil count, and NLR, as well as lower lymphocyte count compared with patients with sepsis (Table
Correlations of indicators with disease severity.
Variables | Sepsis | Severe sepsis | Septic shock |
|
---|---|---|---|---|
APACHE II score | 8.00 (5.00–11.50) | 13.00 (9.00–19.00) | 21.50 (14.75–30.25) | 0.000 |
Neutrophil | 11.75 (9.52–16.65) | 13.35 (10.44–18.22) | 15.98 (10.14–21.29) | 0.016 |
Lymphocyte | 1.12 (0.71–1.70) | 0.67 (0.45–0.95) | 0.51 (0.26–0.78) | 0.000 |
NLR | 11.11 (6.98–18.24) | 22.67 (12.35–31.89) | 31.50 (22.56–46.94) | 0.000 |
APACHE II: Acute Physiology and Chronic Health Evaluation II; NLR: neutrophil-to-lymphocyte ratio.
Significant differences are marked by
In the current prospective study, we further explored the prognosis significance of the NLR in patients with sepsis and found that the NLR measured at the time of admission to ICU was associated with 28-day mortality and correlated well with disease severity, according to APACHE II score. NLR was able to accurately stratify patients in terms of short-term mortality. These findings remained robust after adjusting for several potential covariates, suggesting that increased NLR was independently associated with unfavorable outcome in patients with sepsis. In our opinion, the strength of the NLR is the possibility of implementing this parameter simply by using already available biomarkers (neutrophil count and lymphocyte count). Therefore, this ratio is easy to integrate in clinical practice and cost effective.
Although the available information is still far from sufficient to comprehend thoroughly the economic burden of sepsis on an international scale, current studies demonstrate that sepsis has been a serious public health problem [
The cause responsible for NLR elevations correlating with poor outcome in patients with sepsis remains unclear, although there are a variety of plausible explanations. One of the most convincing explanations is based primarily on the physiological link between neutrophilia and lymphopenia with systemic inflammation and stress. The evolution of these leukocyte subpopulations may differ based on their respective role in the inflammatory response. Initially, Zahorec [
We assessed the association between NLR and outcome in patients with sepsis. Similar to the findings of a previous clinical trial [
This study has a number of limitations that should be taken into consideration. First, we undertook a single-center observational study, and, as with any observational study, the potential remains for residual confounding. Thus, the results should be validated in other settings. Second, for some patients, repeated measurement data were available on the first day. We always used the first one and thus missed some information related to intraday cell count variations. Third, we just analyzed circulating neutrophil and lymphocyte counts and did not explore the different subpopulations of lymphocytes. The further work in our laboratory is to compare the subpopulations of lymphocytes, but the research data have not been shown in this study at present. Fourth, recently developed infection markers like soluble urokinase plasminogen activator receptor, endothelin-1, and copeptin were not evaluated and compared with NLR in the study. Finally, our sample size was so limited that the results should be further confirmed in a larger scale.
The NLR was associated with 28-day mortality in patients with sepsis. Use of the NLR may better help the physician stratify patients into prognostic categories. The present study can be considered as a preliminary attempt to clarify the strengths of NLR in prognosis prediction. However, the mechanisms underlying the association are yet to be fully elucidated and should be the focus of future prospective clinical research.
Neutrophil-to-lymphocyte ratio
Intensive care unit
Acute Physiology and Chronic Health Evaluation II
Standard deviation
Interquartile range
Receiver operating characteristic
Area under the curve
White blood cell
Procalcitonin
C-reactive protein
Odds ratio
Confidence interval.
The authors declare that there is no conflict of interests.
This work was financially supported by the grant from the 2013-2014 National Clinical Key Specialty Construction Project and the Health Bureau Scientific Research Foundation of Shanghai (GWDTR201219).