Acute respiratory distress syndrome (ARDS) has a high mortality rate worldwide; thus, identifying death risk factors related to ARDS is critical for risk stratification in patients with ARDS. In the present study, we conducted a single-center retrospective cohort analysis. Out of 278 patients with ARDS admitted from January 2016 to June 2022, 226 were included in this study. The patients were classified based on whether they were alive or dead during hospitalization. Their demographic and laboratory data and results were analyzed by performing a standard statistical analysis. Patients in the death group were older, with worse respiratory functions and blood biochemistry than those in the non-death group. Moreover, statistically significant differences were observed in the levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) between the two groups. Multivariate stepwise logistic regression analysis showed that the VEGF/PEDF ratio was strongly associated with the risk of death. The area under the curve of the VEGF/PEDF ratio was 0.829 (95% confidence interval: 0.772–0.885; P < 0.001), sensitivity was 86.3%, and specificity was 68.0%. Therefore, a VEGF/PEDF ratio is positively correlated with the risk of death in patients with ARDS. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are acute injuries to pulmonary capillary endothelial cells and alveolar epithelial cells caused by severe infection and shock1,2. The key clinical manifestations of ARDS are progressive hypoxemia and respiratory distress; the global prevalence of ARDS in intensive care units is about 10%; however, it can increase to 23% in ventilated patients3. High morbidity, mortality, and treatment costs are associated with ARDS4. Currently, ARDS pathogenesis is yet to be fully elucidated; however, most researchers believe that important factors that lead to ALI, followed by ARDS progression are rapid lung inflammation and alveolar endothelial and epithelial cell damage, causing excessive or uncontrolled inflammation in the body via several activation pathways, and eventually leading to multiple organ failure and even death5,6. Hence, identifying more death risk factors is crucial for determining the clinical prognosis of patients with ARDS and reducing the ARDS mortality rate. Vascular endothelial growth factor (VEGF), a member of the platelet-derived growth factor family, plays a significant role in ARDS pathogenesis by regulating vascular permeability and inflammation. VEGF binds to its receptors (VEGFR1 and VEGFR2) on endothelial cells, leading to phosphorylation events that increase vascular permeability, contribute to alveolar-capillary barrier dysfunction, and promote pulmonary edema formation7. VEGF also recruits and activates neutrophils, intensifying lung inflammation by releasing pro-inflammatory cytokines and reactive oxygen species (ROS)8,9. However, the diagnostic value of VEGF levels in ARDS prognosis remains unclear. Conversely, pigment epithelium-derived factor (PEDF), a 50-kD small secreting glycoprotein belonging to a non-inhibitory serpin family group, exhibits diverse biological activities. PEDF has anti-angiogenic and anti-inflammatory properties, mediated through its interaction with VEGF and its capacity to inhibit neutrophil activation and endothelial cell proliferation10. Many studies showed that PEDF was present in many tissues, such as adipose and lung tissues11. PEDF participates in multiple physiological and pathological processes. It inhibited ovalbumin-induced airway inflammation in mice12. Conversely, it might be involved in promoting chronic obstructive pulmonary disease (COPD) development by exhibiting proinflammatory functions13. To date, sufficient research is not available to explore the role of PEDF in lung diseases. The imbalance between VEGF and PEDF levels is involved in the occurrence of various lung diseases, such as lung cancer14, pulmonary fibrosis15and COPD13. However, the role of VEGF and PEDF levels in predicting in-hospital mortality in patients with ARDS remains unclear. In the present study, we aimed to investigate whether a VEGF/PEDF ratio is significant in predicting the death of patients with ARDS. This study showed the following two key findings: (1) Patients with ARDS who died during hospitalization showed higher VEGF levels and lower PEDF levels in serum and (2) The VEGF/PEDF ratio possesses a good predictive value for the in-hospital mortality of patients with ARDS. This single-center, retrospective study was approved by the Ethics Committee of the Affiliated Hospital of Xuzhou Medical University (XYFY2022-KL135-02). And all methods were performed in accordance with the relevant guidelines and regulations. This study was conducted according to the tenets of the Declaration of Helsinki. The requirement for informed consent was waived by the ethics committee of the Affiliated Hospital of Xuzhou Medical University (Xuzhou, Jiangsu, China) due to the retrospective nature of the study. From January 2016 to June 2022, 278 patients with ARDS were admitted to the Affiliated Hospital of Xuzhou Medical University, and they met the 2012 ARDS Berlin diagnostic criteria16. Considering that psychiatric disorders such as delirium exacerbate the risk of death in ARDS patients and that acute illnesses, surgery or tumors may affect the expression levels of VEGF or PEDF. Patients were excluded if they had a history of mental illness, malignant tumors, or stroke, acute myocardial infarction, and post-surgical status within one month. Laboratory data included only serological observations obtained on the day of patient admission, which included routine blood examinations, biochemical analysis, determining the levels of D-dimer, cardiac troponin T, B-type natriuretic peptide, and blood coagulation factors, and arterial blood gas analysis. A 60-day all-cause-mortality follow-up was performed on all patients with ARDS. Blood samples were obtained from the residual blood samples of the patients after arterial blood gas analysis. VEGF and PEDF levels were detected using quantitative ELISA kits (Shanghai Renjie Biotechnology Co., Ltd. Shanghai, China) per the manufacturer’s protocol. The study protocol was reviewed by the hospital Ethics Committee. Patient characteristics, including demographics such as age and sex, blood pressure, heart rate at the time of admission, a medical history of diseases, including hypertension, diabetes mellitus, and chronic obstructive pulmonary disease, and smoking and drinking statuses, were collected and analyzed. Continuous variables were expressed as the mean ± standard deviation. The χ2 test was performed for the categorical comparison of demographic variables between different groups, whereas the Student’s t-test and/or non-parametric test were used for a continuous comparison. Skewness continuous variables were analyzed using median and interquartile range (IQR) and compared using the Mann–Whitney U test. A logistic regression model was used to evaluate factors affecting the mortality of patients with ARDS. The α-value < 0.05 on both sides was considered statistically significant. All statistical analyses were performed using SPSS 25.0 (SPSS, Inc., Chicago, IL, USA). From January 2016 to July 2022, a total of 278 patients with ARDS were enrolled at our center. We excluded patients whose laboratory values were missing and who had a history of mental illness or malignant tumor or had a stroke, acute myocardial infarction, or post-surgical status within the past 1 month (Fig. 1). We analyzed 226 patients with ARDS, of whom 153 survived and 73 died. We categorized all ARDS patients into two groups based on whether they died or lived. The patient demographics were similar between the surviving and expiring patient groups, except for their age (P = 0.037). In addition, compared to the non-death group, patients in the death group exhibited significantly worse clinical scores and physiological parameters. Specifically, they had higher APACHE II, SOFA, and LIS scores, alongside increased heart rate and PEEP. Conversely, the death group showed lower mean blood pressure (MBP), body temperature, and oxygenation index (OI) values. Detailed comparisons are presented in Table 1. Flow chart of the selected population in this study. Table 1 Demographics and characteristics of death and non-death ARDS patients. COPD = chronic obstructive pulmonary disease; MBP = mean blood pressure; sofa: sequential organ failure assessment; LIS: lung injury score; PEEP = positive end-expiratory pressure; OI = oxygenation index (PaO /FiO ). *Statistically significant values. As shown in Table 2, laboratory results revealed significant differences between patients who died and those who survived. In the death group, VEGF levels were elevated (median, IQR: 113.9 [74.3–153.5] pg/mL vs. 97.5 [53.4–141.6] pg/mL, P = 0.007), while PEDF expression was decreased (40.3 [27.8–53.7] pg/mL vs. 48.6 [33.4–63.7] pg/mL, P < 0.001), resulting in a higher VEGF/PEDF ratio (2.87 [2.25–3.49] vs. 2.00 [1.38–2.62], P < 0.001). Moreover, inflammatory markers such as CRP (93 [60–126] mg/L vs. 37 [2–72] mg/L, P < 0.001) and IL-6 (25.1 [14.6–35.6] pg/mL vs. 20.9 [7.5–30.3] pg/mL, P = 0.021) were markedly higher, alongside increased LDH, Lac, ALT, and AST levels. Conversely, the death group exhibited lower albumin (25 [18–32] g/L vs. 31 [8–53] g/L, P = 0.046), platelet counts (147 [33–258] vs. 195 [80–310], P = 0.004), and hemoglobin levels (91 [65–117] g/L vs. 99 [74–124] g/L, P = 0.030). Table 2 Laboratory test results of the death and non-death ARDS patients. WBC, white blood cell; CRP, C-reactive protein; cTnT, troponin T; BNP, B-type natriuretic peptide; LDH, lactate dehydrogenase; Lac, lactic acid; BUN, urea nitrogen; ALT, alanine transaminase; AST, aspartate transaminase; IL-6, interleukin-6. *Statistically significant values. Multivariate analysis indicated that the APACHE II score (OR: 1.255, 95% CI: 1.075–1.465, P = 0.004), CRP (OR: 1.037, 95% CI: 1.020–1.055, P < 0.001), LDH (OR: 1.003, 95% CI: 1.000–1.006, P = 0.022), IL-6 (OR: 1.045, 95% CI: 1.004–1.086, P = 0.029), and VEGF/PEDF (OR: 7.655, 95% CI: 4.375–12.950, P = 0.001) were significant (Table 3). Table 3 Multivariate analysis for the independent predictors of death in ARDS patients. *Statistically significant values. The ROC curve is depicted in Fig. 2. Based on these results, the AUC of the VEGF/PEDF receiver operating characteristic (ROC) curve was 0.829 (95% CI: 0.772–0.885; P < 0.001), the sensitivity was 86.3%, and the specificity was 68.0% (Fig. 2). ROC curve and area under the curve (AUC) for VEGF (AUC: 0.622), PEDF (AUC: 0.655), and VEGF/PEDF (AUC: 0.829, cut-off: 2.225, 95% CI: 0.772–0.885, log rank P < 0.001, 86.3% sensitivity, and 68.0% specificity) to predict death. In this study, based on a large cohort of patients with ARDS, we reported a correlation between a VEGF/PEDF ratio and in-hospital mortality. The in-patient mortality rate for ARDS was 32.3%. Patients who died showed higher VEGF and lower PEDF serum levels at the time of admission. However, only VEGF or PEDF levels could not help predict mortality in patients with ARDS satisfactorily. Further, we showed that the VEGF/PEDF ratio possessed a better predictive value for ARDS. ARDS is caused by excessive and uncontrolled inflammation triggered by neutrophil activation and damage due to oxygen-free radicals. Inflammation changes the permeability of pulmonary microvessels and the morphology and functions of pulmonary microvascular endothelial cells17. Moreover, inflammation causes albumin leakage in blood vessel tissues, leading to hypoxemia3. In this process, VEGF acts as a regulator of vascular permeability and increases the proliferation and migration of endothelial cells. Moreover, anti-VEGF therapy is effective in treating ARDS18. However, in a study, opposite results were obtained on the basis of the analysis of lung tissue homogenates and bronchoalveolar lavage fluid from patients with ARDS19. In patients with ARDS with high mortality, pulmonary VEGF levels are low20. VEGF levels change dynamically, and depend on the timing of the test. ARDS disease course is long, and VEGF levels may be different in different stages21. We found that patients with ARDS who died showed higher VEGF levels on the day of admission than those who survived; however, the predictive value of VEGF levels in these patients was not ideal (the AUC of the VEGF ROC curve was 0.622). Evidence from animal models of lung injury suggests that VEGF levels usually increase in the early stages of inflammation, followed by a gradual decrease15. The present serological examination data included observations from the first examination of patients on the day of admission, and probably, most patients were still in the early stage of ARDS, which might be an important reason for the higher VEGF levels. In contrast to the biological functions of VEGF, PEDF is one of the strongest inhibitors of angiogenesis15. Growing evidence shows that PEDF acts as an endogenous anti-inflammatory factor and a vascular barrier protective factor22. However, the role of PEDF in ALI/ARDS is uncertain. Tissue hypoxia can affect PEDF levels23, which may be an essential reason for the lower PEDF levels in patients with ARDS who died in the present study; these patients showed lower oxygenation indices. Similar to VEGF levels, only PEDF levels could not satisfactorily reflect the severity of ARDS in the patients (the AUC of the PEDF ROC curve was 0.655). Nevertheless, the VEGF/PEDF ratio could well-predict the risk of death in patients with ARDS (the AUC value was 0.829). Our recent research found that the expression of PEDF was decreased during LPS-induced acute lung injury in rats. PEDF is an anti-inflammatory factor, which can inhibit apoptosis of lung epithelial cells and reducing LPS-induced ALI in rats24. Studies have shown that VEGF levels in tissues affect PEDF levels, and a VEGF/PEDF ratio may more accurately reflect the degree of hypoxia in tissues or damage to microvascular structures. ARDS is often accompanied by acute hypoxemia and may develop disseminated intravascular coagulation (DIC), which impedes microcirculatory blood flow and leads to localized tissue hypoxia. Due to individual variability, a single indicator such as VEGF or PEDF alone may not accurately reflect the extent of local tissue hypoxia. Therefore, the VEGF/PEDF ratio may serve as a more reliable marker. Therefore, a VEGF/PEDF ratio is a potential indicator in determining the severity of ARDS in patients. For patients with high VEGF/PEDF values on the day of admission, clinical decisions may need to be made with caution. The present study has the following limitations: (1) To exclude errors caused by dynamic evolution, we included serological examination results on the day of admission in the study. Furthermore, considering that patients with ARDS receive various therapeutic interventions, including antimicrobials and steroids, VEGF and PEDF levels were not continuously monitored. (2) The relationship between VEGF and PEDF levels and the degree of lung endothelial barrier damage was not quantified owing to the limitations of existing techniques, diseases that accompany ARDS, such as sepsis, can affect VEGF and PEDF levels. (3) The sample size of the present study was relatively small; we also did not provide detailed statistics on the treatment strategies of each patient after admission (such as mechanical ventilation duration and medication use). Therefore, a larger and multicenter prospective study should be conducted to evaluate the relationship between the preoperative VEGF/PEDF ratio and ARDS-related clinical events. In conclusion, a VEGF/PEDF ratio can help advance the classification of patients with ARDS at death risk. The VEGF/PEDF ratio of patients with ARDS can indicate the severity of the disease as well as prognosis. Therefore, rapid, simple, and low-cost VEGF/PEDF level detection can be an effective monitoring parameter for determining the risk of in-hospital death in patients with ARDS.…Read more by Yuting, Jingtian, Feng, Shenzhen, Ningning, Liang, Shoujie, Shanghai Pulmonary Hospital, China, Qifeng, Luo, Technology, First Affiliated Hospital of Southern University of Science, The Affiliated Hospital of Xuzhou Medical University, Chen, Shanghai, Department of Emergency Medicine, Lei, Department of Critical Medicine, Xu, Xichun, Shen, Shenzhen People’s Hospital, Tongji University School of Medicine, Second Clinical Medicine College of Jinan University, Qin, Xuzhou, Department of Thoracic Surgery
