In this study, the RPR was demonstrated to be an independent predictor of 30-day all-cause mortality in patients with ARF. After confounders such as age, sex, race, laboratory test indices, comorbidities, disease severity scores (such as APACHE II and SOFA scores), and treatment regimens were corrected, ARF patients with high RPR values demonstrated significantly greater 30-day (HR: 1.28 [95% CI 1.15–1.42]; p < 0.001) and all-cause mortality rates. Additionally, RCS analysis revealed a significant nonlinear relationship between the RPR and 30-day all-cause mortality in ARF patients, with a steeply increasing trend in the mortality risk curve being observed when the RPR > 0.071, thus suggesting that the RPR may have a clear clinical cutoff value. In a previous study involving acute respiratory distress syndrome patients, Qin et al. [14] reported that the RPR was independently associated with 28-day all-cause mortality after correction for correlates in a multivariate model (HR: 2.74 [95% CI: 1.46–5.15]; p = 0.002). Moreover, Chen et al. [15] reported that the RPR was significantly associated with 28-day all-cause mortality (OR: 1.36 [95% CI: 1.01–1.84]; p = 0.042). These studies are consistent with the results of the present study. In the present study, the results revealed that the mortality rate of patients in the fourth quartile group of the RPR was significantly greater than that of the other three groups (p < 0.001); additionally, the all-cause mortality rate of patients with higher RPRs was significantly greater than that of patients with lower RPRs in the other three groups within 30 days after admission (log-rank test, p < 0.0001). The abovementioned results suggest the robustness of the RPR as an independent predictor of prognosis in patients with ARF. The RPR not only demonstrates good prognostic efficacy in patients with acute respiratory failure but also exhibits important clinical predictive value in other respiratory diseases.
The RPR is a simple biological index that is defined as the RDW divided by the platelet count. As a potential biomarker of the inflammatory response, the RPR has previously been regarded as a prognostic indicator in inflammation-related diseases. Specifically, Chen et al. described the RPR as an independent factor corresponding to hepatic fibrosis and cirrhosis in chronic hepatitis B patients and as a promising marker reflecting inflammation severity [12]. Similarly, Wang et al. demonstrated that the RPR was significantly associated with the histological severity of primary biliary cirrhosis (PBC) [16]. Moreover, Takeuchi et al. reported that an elevated RPR could be used as an auxiliary assessment tool to predict poor prognosis in patients with breast carcinoma [17]. Other studies have revealed that the RPR is a valuable predictive marker of mortality in acute pancreatitis, sepsis and acute myocardial infarction (AMI) patients [13, 17,18,19,20]. Furthermore, previous research has demonstrated that the RPR is more effective than the RDW or platelet count alone for predicting the prognosis of acute kidney injury, which is possibly due to the fact that the RPR comprehensively reflects the inflammatory load and metabolic state of patients [21]. To the best of our knowledge, no such association has yet been reported in patients with ARF. In this large public retrospective cohort analysis of MIMIC-IV datasets, we revealed for the first time that an elevated RPR is independently related to a significant increase in the risk of 30-day mortality in patients with ARF. Notably, the RCS analysis revealed a nonlinear correlation between the RPR and the risk of 30-day mortality in ARF patients. Subsequent subgroup analysis indicated no obvious interactions. Our findings are similar to those of observational studies of other diseases and have important clinical implications for the appropriate management of ARF patients.
The utility of the RPR as a prognostic predictor of ARF is associated with the biological functions of platelets and the RDW. The RDW is an easily obtainable parameter of the complete blood count test and routinely reflects the systemic inflammatory state and oxidative stress characteristics of patients (to a certain extent). Previous studies have demonstrated that the RDW is an independent predictor of both short-term and long-term mortality in ARF patients. For example, Zhang et al. reported that a high RDW at ICU admission was associated with an increased risk of 3-year mortality in patients with ARF [11]. Additionally, Shi et al. reported that an elevated RDW was associated with a higher 30-day mortality rate in ARF patients [22]. Several factors may partially explain the mechanism by which the RDW influences the prognosis of ARF in patients. Abnormal inflammatory reactions and oxidative stress inhibit erythrocyte maturation, induce increased production of new reticulocytes, reduce the survival rate of erythrocytes and cause the release of large premature red blood cells into the peripheral circulation, thereby resulting in an increase in the RDW [23, 24]. Additionally, systemic inflammation contributes to RDW elevation by changing the membrane glycoproteins and ion channels of RBCs, with consequent morphological alterations being elicited [25, 26]. Moreover, the RDW has been associated with elevated levels of several inflammatory markers, such as CRP and interleukins [27]. The platelet count represents another widely used complete blood count parameter and has historically been used as an important indicator of both the inflammatory process and hemostasis [28]. The relationship between the platelet count and poor prognosis of ARF in patients has attracted increasing attention. Both Xiao et al. and Zhou et al. emphasized a low platelet count as being a risk factor for mortality in ARF patients when the platelet count is detected within a certain range [29, 30]. Additionally, Lopez-Delgado et al. demonstrated that ARF patients with H1N1 influenza complicated with thrombocytopenia exhibited an increased risk of in-hospital mortality in a prospective observational study [31]. In general, numerous platelets are damaged by various toxins and inflammatory factors that are produced due to severe infection and/or acute inflammation, thus leading to dysfunction of the bone marrow microenvironment, insufficient production of thrombopoietin, suppression of stem cell/progenitor cell proliferation, and a decrease in the number of platelets [32,33,34,35,36].
Significant associations were observed in most of the subgroups, thus indicating the stability of the results. Additionally, the prognostic impact of the RPR was much greater in the subgroups of individuals younger than the age of 65 years, individuals of other races, and individuals with no malignancies, thus suggesting potential interactions between the RPR and these risk factors. Based on the findings of this study, it is recommended that specific RPR thresholds involving age, other races, and a lack of malignancy be integrated into risk stratification models of ARF; moreover, multidimensional intervention protocols including immunomodulatory therapy should be initiated in these specific groups of patients when their RPR levels exceed the 0.071 threshold. To the best of our knowledge, this is the first study to explore these interactions. However, the underlying mechanisms of these interactions remain unclear. Therefore, future studies should elucidate the molecular regulatory network of RPR abnormalities via multiomics techniques and conduct prospective cohort studies to validate the clinical value of targeted intervention strategies.
In this study, we observed that the RPR was significantly associated with mortality (HR = 2.15–2.27) in the unadjusted model (Model 1) and in the base-adjusted model (Model 2, adjusted for age, sex, and race). However, in the fully adjusted model (Model 5), which was further corrected for blood pressure parameters (including systolic, diastolic, and mean arterial pressure parameters), laboratory indices, and comorbidities, the effect value was attenuated (HR = 1.73). This attenuation may partly be due to the presence of multicollinearity with respect to the variables included in the model, such as the mean arterial pressure (MBP), which is essentially a derivative of the systolic (SBP) and diastolic (DBP) pressure parameters, as well as the scoring system, which includes vital signs and test results (in which the high degree of correlation may have diluted the independent effect of the RPR). Although we controlled for confounders by a stepwise adjustment strategy, the inherent correlation of such physiological parameters may still affect model stability.
Previous studies have demonstrated that the systemic immunoinflammatory index, platelet-lymphocyte ratio, and neutrophil-lymphocyte ratio are predictive of mortality in pneumosepsis patients in the intensive care unit [37]. Indices related to hemodynamic deterioration, such as the shock index and its derivatives, demonstrate an impact on the prognosis of ARF [38]. The combination of these indices with the RPR may enhance clinical decision-making.
The RPR is a conveniently accessible dual marker of inflammation and coagulation, and this study demonstrated its independent predictive value in the short- and medium-term prognostic assessment of ARF patients. Its nonlinear risk relationship and robust characteristics among different subgroups provide a theoretical basis for the establishment of RPR-based risk stratification models in clinical practice. Future studies could further explore the biological mechanisms of the RPR in respiratory diseases and provide guidance for individualized treatment decisions.
Limitations
This study explored the association between the RPR and the risk of death in ARF patients admitted to the ICU. Therefore, the novelty of this study is reflected in the establishment of a quantitative relationship between novel inflammatory indicators and the prognosis in critically ill patients. However, this study demonstrates several shortcomings. First, the parameter collection implemented in this study was limited to the baseline data collected at the time of the patient’s first admission to the ICU, and patients with multiple hospitalizations were not included; moreover, parameters that may exhibit dynamic changes during treatment were not incorporated, and this single time-point measurement may have weakened the strength of the observed temporal association between the index and prognosis. Second, the retrospective study design and single-center data source may have led to selection bias, and the limited sample size may have reduced the statistical power for rare clinical outcomes. Finally, although major confounders were corrected for via multivariate modeling, there may still be unmeasured residual confounders. Based on these limitations, a future multicenter, prospective cohort study with a large sample size should be conducted to obtain RPR trajectory data at multiple time points via a standardized dynamic monitoring protocol and to construct a composite predictive model in conjunction with other inflammation and organ function metrics. Such a study would further validate the external validity of the findings of the present study and the potential clinical translation of the RPR.