Acute respiratory distress syndrome (ARDS) is a common cause of hospitalization in intensive care unit (ICU) (1) and a fatal clinical condition of hypoxemic respiratory failure (2). It is a type of acute diffuse, inflammatory lung injury, leading to increased permeability of alveolar-capillary barrier, formation of noncardiogenic pulmonary edema, and loss of aerated lung tissue (3). Over the last several decades, an increasing number of preclinical and clinical studies have provided substantial insights into ARDS (4, 5); however, the treatments were limited. Although improvement in the supportive care of patients with ARDS seems to be potentially beneficial, such as lung-protective ventilator strategies (6, 7), prone positioning (8), and neuromuscular blockade (9), the mortality remains as high as 40% (1). Thus, identifying the prognostic predictors of ARDS might be useful for assessing the disease severity and making optimal treatment decisions.
Systemic inflammation is an important cause of disease progression in critical ill patients and is commonly associated with the sepsis syndrome (10, 11). Inflammation also relates to the initiation and progression of ARDS, and sepsis is observed to be associated with the high risk of progression in ARDS (2, 12). As the physiological immune response of circulating leucocytes to stress is often characterized by rising neutrophils and decreasing lymphocytes (13), recently, neutrophil-to-lymphocyte ratio (NLR) has been shown to be a prognostic marker in various diseases, such as solid tumor (14, 15), cardiovascular disease (16), and chronic obstructive pulmonary disease (COPD) (17). In addition, NLR has been investigated as a predictor in critical ill patients. In a study of severe sepsis and septic shock, NLR was reported to be independently associated with the 28-day mortality (18). Furthermore, NLR has been shown to be an independent indicator of both short-term and long-term mortality in the critically ill patients (19). To our knowledge, the role of NLR to predict mortality in patients with ARDS admitted to ICU has not been studied yet. Based on the previous studies, we provided the hypothesis NLR might relate to the disease severity and mortality in ARDS. In this study, we sought to explore whether NLR is a prognostic factor in patients admitted to ICU with ARDS.
MATERIALS AND METHODS
A retrospective observational cohort study was performed in the ICU of a university-based tertiary care hospital (West China Hospital, Sichuan University, Chengdu, China) from December 2015 to April 2017. Institutional approval was provided by the West China Hospital of Sichuan University Biomedical Research Ethics Committee (Sichuan, China). Written informed consent was waived on account of the retrospective observational design. All patient data were anonymously recorded to ensure confidentiality.
Patients admitted to ICU with diagnosis of ARDS based on the 2012 Berlin definition (3) were included in our study if they meet the inclusion criteria and none of the exclusion criteria. All eligible patients had to be over 18 years old, had neutrophil and lymphocyte counts results within 24 h after ICU admission. Patients who were repeatedly admitted to ICU, missed the neutrophil and lymphocyte records or with chronic hematological disorder were excluded.
We collected demographic and clinical data at ICU admission of all eligible patients, including age, sex, height, weight, smoking status, alcohol abusing history, risk factors of ARDS (pneumonia related, aspiration, or other pulmonary related as direct ARDS and trauma/surgery or sepsis as indirect ARDS) and comorbidities (diabetes, chronic obstructive pulmonary disease, hypertension, immune deficiency, renal failure, and tumor), baseline vital signs (body temperature, heart rate, respiratory rate, and blood pressure), severity of illness score, manifested as the score of Acute Physiology and Chronic Health Evaluation (APACHE II) (20) and laboratory data. We recorded neutrophil and lymphocyte counts within 24 h after ICU admission and also at the third day and the fifth day. The NLR values were calculated by dividing the neutrophil count by the lymphocyte count. Two independent authors completed the data collection. The primary outcome was 28-day mortality. The secondary outcomes were ICU mortality and hospital mortality.
Baseline characteristics were presented as mean with standard deviation (SD) or median with interquartile range (IQR) for continuous variables and as number with percentage for categorical variables. Comparisons between continuous variables were analyzed by the Student t test, Mann–Whitney U test, and Kruskal–Wallis test based on variable distribution, and categorical variables were analyzed by chi-squared test or Fisher exact test. The data were tested to the Kolmogorov–Smirnov normality test and Bartlett test for homogeneity of variance.
We grouped the patients based on quartile of NLR values at ICU admission and used the first quartile as the reference group for all subsequent analyses. To assess the relationship between NLR and primary and secondary outcome, we built a univariate Cox regression model. Next, we did a multivariable Cox regression to adjust potential confounding with variables that are statistically significant in the univariate model, and we manually deleted the model variables that were not related to the outcome to avoid overfitting. The results were reported as hazard ratio (HR) and 95% confidence interval (95% CI). The following variables were considered for multivariable adjustment: age, sex, body mass index, smoking status, alcohol abusing status, risk factors, comorbidities, baseline vital signs, laboratory data and APACHE II score. Then we performed an analysis of patients with sepsis and we assessed the association between NLR and outcome in the cohort of patients with sepsis by using multivariable Cox regression. To assess the relationship between the NLR and mortality, we did the receiver-operating characteristics (ROC) curve and reported area under the ROC curve (AUC). Survival curves were plotted using the Kaplan–Meier method across quartiles of NLR, compared by log-rank test. All statistical analyses were performed with the IBM SPSS Statistical version 22.0 (IBM, Armonk, NY) and graphs were drawn by Graphpad Prism 6.0 (Graphpad Software, La Jolla, Calif). A two-sided P < 0.05 was considered statistically significant.
Finally, a total of 2,593 patients were admitted to ICU from December 2015 to April 2017 and 232 patients were diagnosed as ARDS. Among them, 3 patients were excluded because of lymphoid leukemia and 5 patients were excluded due to incomplete neutrophil and lymphocyte data at ICU admission. The patients included 140 (62.5%) males and 84 (37.5%) females, median age was 64 (IQR, 46–77) years, and median APACHE II score was 22 (IQR, 16–28). The main risk factors of ARDS were pneumonia (n = 157, 70.1%) and sepsis (n = 66, 29.5%). Upon admission, the patients in mild, moderate, and severe ARDS were 50 (22.3%), 119 (53.1%), and 55 (24.6%), respectively. The overall median NLR was 16.61 (IQR, 9.16–26.2). In total, the 28-day mortality was 31.3% (n = 70); the overall ICU and hospital mortality were 34.4% and 37.1%, respectively. The baseline characteristics and main laboratory findings of total cohort, survivors, and nonsurvivors are shown in Table 1.
Comparison between survivors and nonsurvivors
When the patients were stratified on hospital mortality (Table 1), we found nonsurvivors were more likely to be elderly (68, IQR: 52–81 vs. 62, IQR: 45–74.5, P = 0.027), had higher values of the APACHE II score (25, IQR: 20–31 vs. 20, IQR: 15.5–26, P < 0.001), and higher heart rates (111, IQR: 90–128 vs. 100, IQR: 86.5–118, P = 0.025) in comparison with survivors, whereas had lower PaO2/FiO2 at diagnosis (105.83, IQR: 89.75–146.33 vs. 148.75, IQR: 108.25–196.46, P < 0.001), lower body temperature (36.6, IQR: 36.2–37 vs. 36.9, IQR: 36.5–37.6, P = 0.002), and lower systolic blood pressure (124, IQR: 103–141 vs. 130, IQR: 110–150, P = 0.029) in comparison with survivors. Berlin classifications in the two groups were significantly different (P < 0.001). The ICU length of stay in survivors was longer than it in the nonsurvivors (14, IQR: 8–27 vs. 9, IQR: 4–17, P < 0.001), and the days free of mechanical ventilation at day 28 in survivors were longer than that in nonsurvivors (21, IQR: 15–24 vs. 5, IQR: 0–14, P < 0.001). The median NLR values dropped from 16.61 to 13.67 in the fifth day; however, NLR values were significantly higher in nonsurvivors from the day admitted to ICU and still remained higher until day 5 (Fig. 1).
Association between NLR and mortality
There was a statistically significant increase in mortality depending on the increasing NLR quartile—first quartile: 6 (10.7%), second quartile: 11 (19.6%), third quartile: 23 (41.1%), and fourth quartile: 30 (53.6%), P < 0.001 (Table 2). In the Cox regression model, we found increasing quartile of NLR had a statistical association with 28-day mortality (Table 3). After multivariable analysis, NLR values remained independently associated with the 28-day mortality. The difference in mortality between quartile of NLR was also independent of the Berlin classification (Fig. 2). The increasing quartile of NLR was related to increasing ICU mortality and hospital mortality, which were consistent with it in the 28-day mortality (Table 4). There was a stepwise increasing baseline NLR according to the Berlin classification from mild-to-severe ARDS (mild 14.15, IQR: 8.47–23.51; moderate 16.55, IQR: 9.07–23.92; severe: 20.44, IQR: 11.03–34.13, P = 0.006). In patients who meet the sepsis criteria at ICU admission (n = 66), there was a statistically significant difference in the 28-day mortality with increasing quartile of NLR—first quartile: 2 (11.8%), second quartile: 4 (22.2%), third quartile: 11 (64.7%), and fourth quartile: 7 (50%), P = 0.004. The results also showed there were associations between NLR and the risk of death at 28 days (adjusted HR: first quartile, reference group; second quartile = 1.432, 95% CI, 0.251–8.166, P = 0.686; third quartile = 8.423, 95% CI, 1.707–41.562, P = 0.009; fourth quartile = 3.494, 95% CI, 0.705–17.309, P = 0.125). Similar trends were observed for ICU mortality and hospital mortality.
A cutoff value of 20.34 (specificity: 0.734, sensitivity: 0.7) was identified to predict ICU mortality according to ROC curve and AUC was 0.747 (95% CI, 0.679–0.815, P < 0.001) (Fig. 3). The AUC for APACHE II score was 0.673 (95% CI, 0.597–0.750, P < 0.001). The AUC for Berlin classification was 0.671 (95% CI, 0.594–0.749, P < 0.001). When combined NLR, Berlin classification, and APACHE II score, the AUC increased to 0.793 (95% CI, 0.731–0.855, P < 0.001). When the patients were stratified by the NLR quartile, the Kaplan–Meier curve showed the highest NLR values quartile associated with the highest mortality, whereas the lowest NLR values quartile showed highest survival possibility (P < 0.001; Fig. 4A). When we used the cutoff point to stratify patients into high NLR values group (n = 90, 40.2%) and low NLR values group (n = 134, 59.8%), a similar tendency was observed; there was a significant higher mortality in high NLR values group compared with low NLR group (P < 0.001; Fig. 4B).
In this study, we found there was an association between NLR at ICU admission and the clinical outcomes in patients with ARDS. The primary outcome was NLR was an independent risk factor for predicting 28-day mortality in ARDS patients. The secondary outcomes were NLR was related to ICU mortality and hospital mortality. In addition, we also found there was an association between baseline NLR and the severity of ARDS according to the Berlin classification.
Previous studies have described increased NLR was associated with mortality in various diseases ranged from solid tumors to cardiovascular diseases and other inflammatory-related diseases (14–16, 21). For example, NLR has been recognized as an additional prognostic factor with a strong association with death in end-stage liver disease patients with cirrhosis (22). In addition, NLR has been investigated in critical care medicine and may prove to be a prognostic biomarker. In a cohort study of patients with liver failure, Moreau et al. (23) found there was a relationship between NLR and mortality in acute-on-chronic liver failure patients admitted to the ICU, and they found a significant increase in mortality depending on the NLR quartile, the same trend was also presented in our study. Furthermore, in an observational cohort study of 5,763 patients, Salciccioli et al. (24) reported that increased NLR was independently associated with a greater risk of mortality in unselected critically ill patients and they also found there was a stepwise increase in mortality with increasing quartiles of NLR. In a recent study, Sung et al. (18) investigated the relationship between the NLR and mortality in cohort of 1,728 patients with severe sepsis or septic shock and the patients were categorized into five groups based on the quintile of NLR. However, their results showed that both low and the high NLRs were associated with increased 28-day mortality and the persistently low and high NLRs were significant risk factors when considering the changes in NLR during the first 2 days. Another prospective observational study of septic shock reported low NLR measured at admission had a significantly association with early death, whereas an increased NLR during the first 5 days had an association with late death (25). They explained the overly strong immune response with a cytokine storm may lead to early death and dysregulation may cause a complex state, persistent inflammation may result in multiple organ dysfunction and impaired adaptive immune response. A study of sepsis shock reported low circulating neutrophils were related to mortality, the researchers provided it may due to ineffective innate immune response in patients with low circulating neutrophils and the neutrophil adhesion to the vascular endothelium may contribute to low circulating neutrophil count (26). In our study, the results displayed a significantly increase mortality with increasing quartile of baseline NLR. The main reasons for this difference may be the insufficient number of patients with low NLR in our study and part of patients included had a diagnosis as sepsis combined with ARDS, which may suggest there was a more serious inflammation in patients in our study. Compared with other studies of NLR in noncritically patients, our results displayed a significantly higher median NLR, which is consistent with the illness severity and elevated inflammation in ARDS patients; another reason may be the patients included in our study were most of moderate and severe degree according to Berlin classification. Furthermore, previous studies described critically ill cancer patients with ARDS have demonstrated a relationship between neutropenia and mortality (27), and it is hypothesized patients with neutropenia were associated with an increased risk of infectious and various acute, noninfectious conditions (28). In our study, the patients were divided into four groups, and the results showed there was no significantly difference in mortality between the first and second quartile but the top two quartiles. The reason might be part of patients included in the first quartile of initial NLR showed neutropenia, which is a risk factor for bacterial infection and subsequent severe sepsis could result in high mortality. Our results showed high NLR value is not just a more severe form of ARDS and definitely not captures the same severity as the Berlin classification, which is primarily based on the oxygenation (PaO2/FiO2). Thus, there is added value of the NLR to the Berlin classification in the prediction of mortality. In addition, the NLR was significantly higher in nonsurvivors from the day admitted to ICU and still remained higher until day 5 despite the considerable experience of treatment, the persistently high NLR might represent patients that have an ongoing severe inflammatory process due to disease progression.
Systemic inflammation is associated with the development and progression of ARDS (29); previous studies have reported increased levels of inflammatory biomarkers were associated with poor outcomes in ARDS (30, 31). NLR may serve as an inflammatory biomarker based primarily on the ability to indicate the response to systemic inflammatory stress with neutrophils rising and lymphocytes apoptosis (32, 33). A study of patients with trauma and systemic inflammatory response syndrome showed lymphopenia was associated with high mortality, the lymphocytes were important in the regulation of an appropriate inflammatory response, and low circulating lymphocytes may perpetuate a harmful inflammatory status (34, 35). High NLR in patients was associated with high levels of inflammation; de Jager et al. (36) showed that NLR-predicted bacteremia was better than conventional inflammation markers such as C-reactive protein, white blood cell count, and neutrophil count. A recent study showed that NLR and other inflammatory factors such as lymphopenia and plasma calprotectin were independent predictors of increased all-cause mortality in moderate-to-severe chronic obstructive pulmonary disease in stable phase and not in treatment with systemic glucocorticoids (37). Thus, we supposed increased NLR values could predict the poor outcome in ARDS patients on the evidence of the association between NLR-related inflammation and disease severity.
We observed that NLR was a prognostic factor for mortality in ARDS independent of APACHE II score and Berlin classification. As APACHE II score and Berlin classification were also identified as prognostic factors, we attempted to combine NLR with APACHE II score and Berlin classification, and we found it could improve the effect than using any of them alone, as shown by the ROC curves analysis. Thus, a model could helpfully help clinicians to stratify the prognosis of ARDS patients.
Several limitations in our study must be acknowledged. First, it was a single-center and retrospective observational study, subject selection bias could not be avoided, and the causal relationship between NLR and mortality could not be drawn. Therefore, our findings need be confirmed in a prospective multicenter study. Second, our sample size was limited, the findings about the association between low NLR value and mortality may be shifted due to the insufficient number of patients with low NLR in our study, so a large population study is needed. Third, NLR value is influenced by comorbidities and medications that affect the neutrophil and lymphocyte count. We could not determine whether these patients had both ARDS and the associated noninfectious condition at ICU admission, and we did not have the full data about all the details of the treatments patients have received due to the retrospective design.
We found high NLR was associated with poor outcome in critically ill patients with ARDS. NLR was an independent risk factor for predicting 28-day mortality in ARDS patients, and the same results were found in ICU mortality and hospital mortality. There was an association between baseline NLR and the severity of ARDS according to the Berlin classification. The NLR therefore seems to be a prognostic biomarker of outcomes in critically ill patients with ARDS. Further studies, especially large sample prospective studies, are needed to confirm these findings and elucidate the underlying mechanism in exploring the role of NLR in ARDS patients.
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Keywords:© 2019 by the Shock Society
Acute lung injury; acute respiratory failure; intensive care unit; lymphopenia; neutrophils; prognostic