Previous studies have shown that N/LPR is a good indicator to evaluate systemic inflammatory diseases, because it can comprehensively reflect the aspects of inflammation, coagulation, and immunity[11, 12, 15].The predictive value of N/LPR was first determined by Koo et al. in a retrospective study of 1099 patients who underwent cardiovascular surgeries . The results revealed that N/LPR can be used as an indicator to evaluate inflammatory status of acute kidney injury (AKI) and mortality in patients after high-risk cardiovascular surgeries, and that the predictive accuracy of N/LPR is better than that of NLR or platelet count. A retrospective analysis by Liu et al. also confirmed the clinical value of N/LPR in reflecting inflammatory response, immune function and coagulation dysfunction of sepsis patients. N/LPR not only has better predictive value than NLR, but also can effectively predict 28-day mortality in sepsis patients admitted to ICU. Therefore, after comprehensive consideration of the pathogenesis of ARDS involving a complex interplay of multiple aspects of inflammatory response imbalance, abnormal coagulation function, and uncontrolled immune regulation, we thought to investigate the clinical value of N/LPR in ARDS patients and determine the optimal cutoff value for N/LPR to predict28-day mortality. Our results showed that non-survivors had significantly higher NLR and N/LPR values than survivors (P < 0.05). Although logistic regression analyses revealed that both NLR and N/LPR were independent predictors, ROC curve analysis further indicated that N/LPR was better than NLR for predicting 28-day mortality in ARDS (AUC:0.785 vs. 0.679). Furthermore, survival analyses confirmed that ARDS patients with high N/LPR or NLR values had higher mortality and lower survival months than patients with low N/LPR or NLR values (P < 0.05). Our results clearly revealed that ARDS patients with high N/LPR or NLR are associated with a higher risk of death, and that N/LPR has a better clinical value than NLR in predicting the 28-day mortality in ARDS patients.
The pathogenesis of ARDS is very complex, mainly manifested as an imbalance between inflammation and coagulation [16, 17].NLR is known to be a sensitive indicator that can reflect systemic inflammatory response, and has been shown to useful in assessing the prognosis of various inflammatory disease, such as sepsis , rheumatoid arthritis , and coronary artery disease , as well as the recent epidemic of coronavirus disease 2019 (COVID-19)[22, 23]. In this study, the elevated NLR value was found to be significantly associated with the prognosis of ARDS. This association may be due to the imbalance of inflammation and immune cell-mediated inflammatory cascades. In ARDS patients, the balance between pro-inflammatory and anti-inflammatory mechanisms is disrupted, leading to an inflammatory waterfall effect and creating a vicious circle[24, 25]. The NLR is ratio between the neutrophil counts and lymphocyte counts measured in peripheral blood. Neutrophils, key immune cells in the ARDS inflammatory microenvironment, increase in number with the intensification of systemic inflammatory response. Lymphocytes, important immune cells in protecting pulmonary microvascular endothelial cells, are negatively associated with increased inflammatory risk. Therefore, changes in NLR values reflect not only aspects of acute and chronic inflammation (neutrophil counts), but also aspects of adaptive immunity (lymphocyte counts)[24, 26, 27]. In this study, non-survivors had significantly higher neutrophil counts than survivors (P < 0.05). Furthermore, although not statistically significant, there was a trend which indicated that the lymphocyte counts of non-survivors was lower than that of survivors. Importantly, non-survivors had significantly higher NLR values than survivors (P < 0.05), which is consistent with the previous study by Wang et al.. Taken together, these suggest that NLR, an indicator of inflammatory status, can be used as a predictor for evaluating the 28-day mortality in ARDS.
Although our findings reveal the predictive potential of NLR for 28-day mortality, NLR can only reflect aspects of inflammatory response and immune status, ignoring the role of coagulation abnormalities in ARDS patients. In the recent study by Wu et al., coagulation dysfunction was identified as a risk factor associated with the development of ARDS and subsequent progression to death in patients with COVID-19 pneumonia. Coagulation dysfunction in patients with ARDS is mainly due to the exposure of tissue factor (TF) and interaction with neutrophil elastase, resulting in the activation of coagulation cascade[10, 30]. In the prospective study by Ozolina et al., patients who developed ARDS had significantly higher plasma TF concentrations than patients who did not develop ARDS. For COVID-19 patients at a high risk of developing ARDS, neutrophil elastase inhibitors showed promising therapeutic in reducing the development and progression of ARDS. In the pro-inflammatory state, the imbalance between coagulation and anticoagulation and protein C-mediated impairment of endogenous anticoagulation can further exacerbate the inflammatory response. Furthermore, a study investigating the relationship between protein C and acute lung injury (ALI) showed that ALI patients with low levels of plasma protein C were associated with higher mortality .
Platelets and coagulation mutually influence each other, and their close interplay contributes to the balance of hemostasis and bleeding. Therefore, the association between platelets and ARDS may be due to the extensive cross talk between coagulation and inflammation[30, 36, 37]: platelets interact with neutrophils to form platelet–neutrophil complexes, which recruit more neutrophils, trigger endothelial and immune cell activation, and finally the development of ARDS. In our study, non-survivors had significantly lower platelet counts than survivors, suggesting that low platelet counts are associated with poor prognosis in ARDS. This finding is also supported by several studies showing that platelet count is an independent predictor of mortality in ARDS patients[31, 33, 36].Furthermore, our findings are consistent with the study by Wang et al.that thrombocytopenia accelerate the progression of ARDS and increase mortality in critically ill patients.
There were several limitations in this study. First, this study is a single-center study in China, and the conclusion may only applicable to similar populations. Therefore, the applicability of N/LPR to other populations or races need to be further explored. The second limitation is the small sample size. This limits our further exploration of other potential confounding factors that may affect the prognosis of ARDS. Future large-scale prospective studies should be conducted to overcome the current disadvantages of this study and to further confirm the clinical application of N/LPR predictor for 28-day mortality in ARDS patients.