Increased neutrophil percentage-to-albumin ratio is associated with all-cause mortality in patients with severe sepsis or septic shock

There has been no study exploring the prognostic values of neutrophil percentage-to-albumin ratio (NPAR). We hypothesised that NPAR is a novel marker of inflammation and is associated with all-cause mortality in patients with severe sepsis or septic shock. Patient data were extracted from the MIMIC-III V1.4 database. Only the data for the first intensive care unit (ICU) admission of each patient were used and baseline data were extracted within 24 h after ICU admission. The clinical endpoints were 30-, 90- and 365-day all-cause mortality in critically ill patients with severe sepsis or septic shock. Cox proportional hazards models and subgroup analyses were used to determine the relationship between NPAR and these clinical endpoints. A total of 2166 patients were eligible for this analysis. In multivariate analysis, after adjustments for age, ethnicity and gender, higher NPAR was associated with increased risk of 30-, 90- and 365-day all-cause mortality in critically ill patients with severe sepsis or septic shock. Furthermore, after adjusting for more confounding factors, higher NPAR remained a significant predictor of all-cause mortality (tertile 3 vs. tertile 1: HR, 95% CI: 1.29, 1.04–1.61; 1.41, 1.16–1.72; 1.44, 1.21–1.71). A similar trend was observed in NPAR levels stratified by quartiles. Higher NPAR was associated with increased risk of all-cause mortality in critically ill patients with severe sepsis or septic shock.


Introduction
Sepsis is a syndrome of physiological, pathological and biochemical abnormalities induced by infection [1]. Septic shock causes circulatory and metabolic abnormalities, leading to increased mortality in hospitalised patients, especially in intensive care unit (ICU) patients [2,3]. Studies showed that once sepsis advanced to septic shock, the mortality rate rose from 25% to 52%, despite adoption of therapeutic strategies according to international sepsis guidelines [4,5]. Given the poor prognosis of septic shock in critical illness, researchers have found multiple risk factors predicting the prognosis of these patients, with the aim of early intervention to reduce mortality [6,7]. Nevertheless, the mortality caused by sepsis remains high.
Neutrophils play crucial roles in the innate cellular immune system. Previous studies suggested that early higher neutrophil counts correlated with increased sepsis severity [8,9], and neutrophil percentage was predictive of bloodstream infection [10]. Albumin is a mediumsized molecule that is the most abundant protein in human plasma. For a variety of physiological mechanisms, albumin is indispensable. It has a variety of functions, including serving as a major buffer, extracellular antioxidant, immunomodulator, antidote and transporter in plasma [11,12]. Increased capillary leakage of albumin is one of the features of SIRS [13]. This means that lower albumin levels correlate with severe systemic inflammation and organ failure [14]. Moreover, several studies demonstrated that low albumin levels correlated with adverse clinical outcomes [11,15].
Recently, the neutrophil-albumin ratio has been identified as a prognostic predictor in patients with rectal cancer and palliative pancreatic cancer [16,17]. Nevertheless, to our knowledge, no previous study has focused on the neutrophil percentage-to-albumin ratio (NPAR). In this study, we hypothesised that NPAR is a novel marker of inflammation associated with all-cause mortality in patients with severe sepsis or septic shock.

Data source
Similar to our previous studies, we followed the methods of Wang et al., 2019 [18,19]. The study was based on a publicly accessible clinical database called the Multiparameter Intelligent Monitoring in Intensive Care III version 1.4 (MIMIC-III v1.4). It includes approximately 40 000 critical care patients at the Beth Israel Deaconess Medical Center (Boston, USA) Health data of all patients in this database were de-identified; therefore, informed consent was waived.

Population selection criteria
Inclusion criteria included: (1) adult patients (⩾18 years) diagnosed with severe sepsis or septic shock; (2) hospitalisation in the ICU at first admission for more than 2 days. Exclusion criteria were as follows: (1) no neutrophil percentage and albumin measured during ICU stay and (2) more than 5% of individual data missing. Severe sepsis was defined as systemic inflammatory response syndrome caused by infection combined with acute organ dysfunction (SOFA scoring system). Septic shock was defined as the presence of infection and systemic inflammatory response syndrome as defined in severe sepsis as well as the presence of arterial hypotension with a systolic blood pressure ⩽90 mmHg or a mean arterial blood pressure ⩽70 mmHg for at least 2 h or administration of a vasopressor (dopamine ⩾5 μg/ kg/min; norepinephrine, epinephrine, phenylephrine, or vasopressin in any dosage) to maintain systolic blood pressure ⩾90 mmHg or mean arterial blood pressure ⩾70 mmHg despite adequate fluid loading [21].

Statistical analysis
Continuous variables were presented as mean ± standard deviation (SD) or medians and interquartile range, and were tested   Yuqiang Gong et al.
by One-Way ANOVA (normal distribution) and Kruskal-Wallis H (skewed distribution). Categorical data were summarised as number or percentage and were compared using the chi-squared test.
The association between NPAR levels and 30-, 90-and 365-day allcause mortality was evaluated using Cox proportional hazards models. The results of the multivariate analysis were presented as hazard ratios (HRs) with 95% confidence intervals (CIs). Two multivariate models were used to evaluate the prognostic values of NPAR for each endpoint. In model I, covariates were only adjusted for age, ethnicity and gender. In model II, we further adjusted for age, gender, ethnicity, SBP, DBP, temperature, SPO 2 , anion gap, bicarbonate, chloride, haemoglobin, lactate, platelet, APTT, PT, BUN, WBC, vasopressor use, atrial fibrillation, liver disease, respiratory failure, SOFA and SAPSII. We selected these confounders based on a change in effect estimate of more than 10%. The receiver operating curve (ROC) test was performed to measure the sensitivity and specificity of NPAR and other variables (SOFA score, albumin and neutrophils percentage) and calculated the area under the curve (AUC) to ascertain the quality of NPAR as a predictor of 365-day all-cause mortality.
Subgroup analysis of the associations between NPAR and 90-day all-cause mortality was performed to examine whether the effect of the NPAR differed across various subgroups. All statistical analyses were performed using EmpowerStats version 2.17.8 (http://www.empowerstats.com/cn/, X&Y solutions, Inc., Boston, MA) and R software version 3.42; P < 0.05 was considered statistically significant.

Subject characteristics
A total of 2166 patients were eligible for this analysis. The demographic characteristics of participants stratified by NPAR tertiles are summarised in Table 1. Of these patients, there were 1204 (55.6%) men and 1595 (73.6%) white. According to NPAR levels, patients were divided into three groups (tertile 1: NPAR <24.4; tertile 2: NPAR ⩾24.4, <31.4; tertile 3: NPAR ⩾31.4), and the number of patients in each group was 722. Patients in the high tertile of NPAR (NPAR ⩾31.4) were more likely to use vasopressor, to report a history of malignancy, had lower SBP, DBP, MBP, haematocrit, haemoglobin and had higher values of chloride, BUN, WBC and mortality.

NPAR as a predictor of the clinical endpoints
In multivariate analysis, we stratified NPAR levels by tertiles and quartiles, to assess whether NPAR was associated with 30-, 90and 365-day all-cause mortality (  Figure 1. The AUCs for NPAR, albumin, neutrophils percentage and SOFA scores were 0.655, 0.618, 0.528 and 0.737, respectively. The findings indicated that NPAR was a better predictor of 365-day all-cause mortality than either albumin or neutrophil percentage alone (P < 0.0001). Moreover, we compared NPAR with neutrophil: lymphocyte (NLR) and lymphocyte in the supplementary materials, and the AUCs for NPAR, NLR and lymphocyte were 0.655, 0.646 and 0.576, respectively.

Discussion
Our main findings can be summarised as follows. First, higher NPAR was associated with increased risk of 30-, 90-and 365-day all-cause mortality in critically ill patients with severe sepsis or septic shock after adjustments for age, ethnicity and gender. Furthermore, after adjustments for more potential confounders, higher NPAR remained significantly associated with all-cause mortality. To our knowledge, this was the first study to investigate the prognostic value of NPAR in critically ill patients with severe sepsis or septic shock; we found that higher NPAR was a novel predictor of poorer prognosis, and it was a better predictor than either albumin or neutrophil percentage alone.
Clinically, we found a phenomenon in which the high neutrophil percentage and the low albumin levels are associated with poor outcomes in patients with severe sepsis or septic shock.   6 Yuqiang Gong et al. Previous studies focused on the neutrophil-to-albumin ratio, mainly in significantly predicting prognosis of palliative pancreatic cancer treatment and rectal cancer [16,17]. Neutrophil percentage can be used as a practical marker to assess inflammation, and the serum neutrophil percentage and inflammatory cytokines are increased in infected patients [24,25]. Moreover, previous studies have described the relationship between hypoproteinemia and mortality in stroke, myocardial infarction and hip fracture [26][27][28]. These findings suggested that lower albumin values correlated with poorer prognosis of the disease. On the other hand, lower albumin values correlated with higher the values of NPAR. In our study, by comparing changes in NPAR values of patients with severe sepsis or septic shock, we found that increasing values of NPAR predicted poor sepsis prognosis. Russell et al., [29] showed that peripheral blood leucocyte ratios are useful biomarkers for infection. In critical illness due to sepsis, there is a signal and prognosis associated with NLR, and longitudinal measurements of these biomarkers during infection could be informative. Our findings also indicated that NPAR and NLR had similar predictive abilities for poor outcomes. Neutrophils are part of the differential of WBC counts that are typically sensitive to bacterial and fungal infections [30]. Walling et al., [31] demonstrated that neutrophil percentages above 80% provided a good distinction between positive and negative blood cultures among sepsis patients. However, the role of neutrophils in predicting bloodstream infection remained questionable, because stress, medication, trauma and abnormal bone marrow formation could cause these changes [32,33]. Therefore, looking for a simple and reliable clinical predictor of mortality in sepsis is significant. Albumin levels reflect nutritional status and organ function, and the underlying inflammatory state give rise to a decrease of albumin production in liver by increasing inflammatory factors, the primary cause of hypoalbuminemia that occurs early in sepsis [34,35]. Therefore, based on our findings, NPAR, a new biomarker composed of neutrophil percentage and albumin that closely related to the inflammatory response, can significantly predict the prognosis of sepsis.
Our study had some limitations. First, the study was a singlecentre retrospective design, and was therefore subject to selection bias. Second, we extracted NPAR in patients only upon admission to the ICU and did not assess changes during the ICU stay. Third, this database does not use the latest sepsis definitions (sepsis 3.0), and severe sepsis no longer forms part of the sepsis 3.0 definitions, this may affect the conclusion. Fourth, missing the aetiology of sepsis and specific cause of death in the MIMIC database failed to make the study more detailed and comprehensive. Fifth, although we have done our best to use a multivariate model to control bias, there remain numerous other known and unknown factors. Furthermore, the database contains a few inaccurate data elements. Therefore, multi-centre prospective studies are needed to confirm these findings.

Conclusions
Our findings demonstrated that higher NPAR was associated with increased risk of all-cause mortality in critically ill patients with severe sepsis or septic shock. Nevertheless, the conclusions need to be confirmed in large prospective multicentre studies.
Supplementary material. The supplementary material for this article can be found at https://doi.org/10.1017/S0950268820000771.