The Procalcitonin Combined with C-Reactive Protein/Albumin Ratio as a Predictor of Mortality in Patients After Lung Transplantation

The Procalcitonin (PCT) and C-reactive protein (CRP)/albumin ratio have recently been used to predict early prognosis for intensive care unit (ICU) patients and patients undergoing major surgery. But there were few clinical studies in patients after lung transplantation (LTX). The purpose of this study was to identify the association between PCT combined with CRP/albumin ratio and 30-day mortality and predict the accuracy of PCT combined with CRP/albumin ratio for 30-day mortality in patients after LTX. From January 1, 2016 to December 1, 2020, the clinical data of 77 patients undergoing LTX who died within 30 days were retrospectively collected, we randomly collected 87 patients survived more than 30 days after LTX. ROC curve was used to evaluate the prognostic value of PCT combined with CRP/albumin in predicting mortality at 30 days after ICU admission, Cox proportional hazard model analysis was used to identify risk factors, subgroup analyses was conducted. Postoperative PCT, CRP, albumin, CRP/albumin ratio, atrial fibrillation, primary graft dysfunction (PGD) grade, the hours of postoperative mechanical ventilation (MV) and length of ICU stay between survivor and non-survivor had a significant difference. On Cox proportional hazard regression analysis, both PCT [HR 1.02 (1.00–1.05), P = 0.037] and CRP/albumin ratio [HR 1.438 (1.26–1.65), P < 0.001] were independent predictors of 30-day mortality. In all patients after LTX, the area under the curve (AUC) of PCT combined with CRP/albumin ratio for predicting 30-day mortality was 0.76 (95% CI 0.69–0.83). In subgroup analysis, the AUC of PCT combined with CRP/albumin ratio for predicting 30-day mortality was 0.83 (95% CI 0.75–0.91) in patients undergoing LTX for interstitial pulmonary fibrosis (IPF). The PCT combined with CRP/albumin ratio could be a predictor of the outcomes in patients undergoing LTX. The predictive efficacy was better in patients undergoing LTX for IPF.


Introduction
Lung transplantation (LTX) is now an alternative treatment for many end-stage lung disease patients [1]. With the development of LTX, early postoperative survival is improving, but there is still some gaps than other solid organ transplant patients [2]. There is a need to predict the prognosis of patients after LTX to determine the direction of treatment. Many biomarkers are used for the prediction of prognosis in patients after LTX [3]. A simple and accessible parameter is needed to confirm treatment response and predict mortality in patients after LTX. Procalcitonin (PCT) is primarily used as aids in diagnosis bacterial infections and to guide antimicrobial therapy [4]. Furthermore, several studies have evaluated PCT as a marker for predicting graft outcome and survival, showing that high PCT levels predict poor outcomes in heart, liver, renal and lung transplant recipients without clinical signs of infection [5][6][7]. High C-reactive protein (CRP) levels have been shown to be associated with various conditions, including severe sepsis, heart failure, cerebral disease, and other inflammatory diseases [8]. Furthermore, CRP has been used as a prognostic marker in the critical care setting [9]. Albumin levels can provide nutritional status. Malnutrition is usually correlated with immune dysfunction, inflammatory procedures, and wound healing delay or failure that directly increases the incidence of postoperative complications [10]. The CRP/albumin ratio, a combination of markers for systemic inflammation and nutritional status, has been extensively studied as an independent prognostic marker in patients with infection, malignancy, and other diseases [11]. However, there are relatively few studies in patients after LTX. Patients after LTX have severe lung disease and generally poor nutritional status before surgery [12] and experience Ischemia-reperfusion injury and surgical trauma during surgery, primary graft dysfunction (PGD) occurs within 72 h after transplant. The highest grade of PGD, grade 3, increased 90-day and 1-year mortality compared to absent or lower grades of PGD [13]. These factors may influence the prognostic effectiveness of PCT and CRP/ albumin ratio. This study intends to further investigate the predictive value of postoperative PCT, CRP/albumin ratio and PCT combined with CRP/albumin ratio in the 30-day mortality of patients after LTX.

Data Extraction
All patients included were classified as survivors or nonsurvivors based on post-LTX survival status. Groups were compared for the following baseline characteristics: age, sex, primary disease, smoking history, hypertension, diabetes, coronary heart disease, pulmonary hypertension; hemoglobin, platelets, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and serum creatinine within 48 h before surgery; application of intraoperative extracorporeal membrane oxygenation (ECMO), type of transplant operation, operation time; PCT, lactic acid (Lac), CRP and albumin 24 h postoperatively. We compared the complications during postoperative intensive care unit (ICU) hospitalization in the surviving and non-surviving groups, atrial fibrillation and PGD grade at 72 h after surgery, atrial fibrillation was defined by electrocardiogram (ECG), The PGD grade was determined using the International Society for Heart and Lung Transplantation consensus definition [14]. The primary outcome were as follows: survival at 30 days after lung transplantation. The secondary outcome included the hours of postoperative mechanical ventilation (MV) and length of ICU stay.

The Procedure for Collecting Data and How It Was Protected
During normal clinical care, all parameters were regularly gathered into a database. Checking was done manually. Data was collected on a safe hospital computer and was deidentified and stored.

Statistical Analysis
Categorical variables were presented as absolute frequency and percentage, and continuous variables were presented as mean ± standard deviation. The clinical characteristics of the two groups, survivors and non-survivors, were compared using the Pearson's chi-squared test or Fisher's exact test for categorical variables, and the Student's t-test for continuous variables. The Cox proportional hazard regression analysis was used to evaluate the association between variables and mortality. The effect of PCT, CRP/albumin ratio, atrial fibrillation, and PGD was evaluated using Cox proportional hazard models, with an adjusted P-value < 0.05 considered statistically significant. Hazard ratios (HRs) and 95% CIs were calculated. Analysis of the receiver operating characteristic (ROC) curves and the area under the ROC curves (AUC) were performed to evaluate PCT, CRP/albumin and PCT combined with CRP/albumin ratio as predictive values for mortality in patients after LTX. In addition, we compared the ROC curves between all patients after LTX and patients undergoing LTX for interstitial pulmonary fibrosis (IPF). A P-values < 0.05 were considered statistically significant. All statistical analyses were performed with IBM SPSS software version 25.0

Patient Characteristics
incomplete clinical data. In the survival group, 3 patients were younger than 18 years old. Finally, 164 patients were included in the analysis and data on laboratory result were accurately recorded for all admitted patients. All enrolled 164 patients were divided into two groups: survivors and non-survivors. Table 1 compares the basic features and postoperative condition. There were no significant differences in age, sex, primary disease, smoking, hypertension, diabetes, coronary heart disease, pulmonary hypertension, Hb, platelets, ALT, AST, serum creatinine, intraoperative ECMO application, transplant type, operation time and Lac (P > 0.05), and there were significant differences in PCT, CRP, albumin, CRP/albumin ratio, atrial fibrillation, PGD grade, the hours of postoperative MV and length of ICU stay.

The Prognosis Factors and Mortality
Univariate and multivariate Cox regression analysis affecting survival after LTX (

Subgroup Analysis
Patients who underwent LTX for IPF were divided into two groups: survivors and non-survivors.

ROC Curve Analysis of Patients Who Underwent LTX for IPF
In predicting 30-day mortality, ROC curve comparisons showed that the AUROC of PCT + CRP/albumin ratio (0.830) was the highest among predictors (Table 5, Fig. 2), followed by CRP/albumin ratio (0.762) and PCT (0.753), Moreover, the PCT + CRP/albumin ratio was with the highest specificity (91.8%) and positive predictive value (PPV) (88.9%), which highlighted the prediction performance of PCT + CRP/ALB.

Discussion
An easily available parameter is needed to predict the early survival of patients after LTX to better identify high-risk patients to increase the attention and initial management of these patients, ultimately clinicians achieve the goal of further reducing the early mortality of high-risk patients after LTX. In this study, PCT, CRP/albumin and PCT combined with CRP/albumin were selected to predict the 30-day survival of patients after LTX, and the results showed that both  PCT is mainly produced in the liver by macrophages and neuroendocrine cells [15]. Studies have shown plasma PCT levels rise after liver transplantation, peaking on day 1 and gradually decreasing over the next 7 days [16]. We also found that a significant increase in PCT after LTX, with PCT of 1.97 ng/ml in the survival group and 3.5 ng/ml in the non-survival group (P = 0.007). Mechanism for increasing the level of the PCT after LTX is related to graft hypoxia and use of intraoperative ECMO. Possible explanations include (1) Ischemia-reperfusion injury increases inflammatory factors (e.g., IL-6, IL-8, and IL-10). (2) On the one hand, the use of ECMO causes the destruction of cells and leads to the release of cytokines, on the other hand, it may cause a decrease in renal blood flow, leading to a decrease in renal   clearance of PCT. Other study found that PCT = 2 ng/ml within 24 h was used as a cut-off value, The AUC for predicting mortality was 0.74 (95% CI 0.61-0.88). Moreover, the occurrence of grade 3 PGD at 72 h could be excluded at PCT < 2 ng/ml, and the PCT rate for predicting ICU mortality at 24 h was better than that at 48 h and 72 h [17]. In our study, the cut-off value of PCT = 2.81 at 24 h predicted survival at 30 days after LTX, The AUC for predicting 30-day mortality was 0.62 (95% CI 0.54-0.71). The immunosuppressants used in this research center have no effect on the catabolism of PCT, All patients initially received a tripledrug regimen including cal-cineurin inhibitors (cyclosporine or tacrolimus), antimetabo-lites (mycophenolate mofetil or mycophenolate sodium), and corticosteroids. CRP is an acute-phase protein synthesized by the liver, and its levels reflect the degree of inflammation [18]. On the one hand, LTX surgery causes tissue damage [19]. On the other hand, LTX leads to the occurrence of lung ischemia-reperfusion injury. The acute non-infectious inflammatory reaction caused by LTX leads to lung dysfunction, high expression of a variety of cytokines, release of inflammatory mediators, damage to vascular endothelial and alveolar epithelial cells, aggravate inflammation and induce inflammatory waterfall effect [20]. Therefore, as an inflammatory indicator, CRP has a certain correlation with the occurrence of PGD, which makes it possible to predict the early survival of LTX [21]. Albumin acts as the body's major serum-binding protein and has a multitude of important physiological functions including maintenance of colloidal osmotic pressure and the binding of a wide variety of compounds [22]. Studies have shown that LTX recipients have a high incidence of nutritional risk and malnutrition, which seriously affects their early prognosis [23]. Hypoalbuminaemia is an independent risk factor for death after LTX [24]. CRP/albumin ratio may reflect both inflammation and nutrition status, and has been used to predict 30-day mortality in critically ill patients, severity of multiple organ dysfunction, and 90-day mortality in patients with sepsis [25][26][27]. Studies have shown that CRP/albumin ratio values at 24 h and 48 h postoperatively are predictive of postoperative complications [9]. Its diagnostic accuracy is higher than that of CRP and albumin alone [28]. Patients with a CRP/ albumin ratio of > 2.0 on the third day after abdominal surgery have a higher incidence of postoperative complications [29]. In this review, the use of a CRP/albumin ratio = 1.68 as a cut-off at 24 h predicted survival at 30 days after LTX. The AUC for predicting 30-day mortality was 0.74 (95% CI 0.67-0.82). The predictive power of the CRP/albumin ratio was significantly higher than that of PCT and slightly lower than that of PCT combined CRP/albumin ratio [AUG = 0.76 (95% CI 0.69-0.83)].
Repeated abnormal repair after alveolar epithelial injury occurs in patients with IPF during the development of the disease, resulting in the production of a large number of fibrotic factors [30]. Cell analysis often shows an increase in neutrophils or eosinophils, and other factors lead to the release of pro-inflammatory cytokines [31]. It was speculated that the prognosis of this group of patients was more strongly correlated with the level of inflammation, and IPF accounted for the largest proportion of the primary disease. In subgroup analysis. The predictive power of PCT was significantly improved, and it was concluded that the cut-off value of PCT = 3.55 at 24 h predicted survival at 30 days after LTX, The AUC for predicting 30-day mortality was 0.75 (95% CI 0.66-0.85). There was no significant change in the predictive power of CRP/albumin ratio. The predictive performance of PCT combined with CRP/albumin ratio was significantly improved. The AUC for predicting 30-day mortality was 0.83 (95% CI 0.75-0.91), and significantly higher than PCT and CRP/albumin ratio alone. In patients undergoing LTX for IPF, PCT + CRP/albumin ratio was more effective in predicting 30-day mortality after surgery.
The results of our study had the potential to improve clinical practice. PCT and CRP/albumin ratio were an independent risk factor affecting survival. When patients with IPF after LTx had PCT > 3.55 ng/ml and CRP/albumin > 1.68, suggesting a poor prognosis, the clinician needed to find the cause of the elevated indicator and take treatment measures to intervene. However, further research was needed to confirm whether this intervention is effective.
Our study had several limitations. First, this study is a single-center study, the adaptability in other centers is unknown. Second, PCT and CRP/albumin levels may also be influenced by other factors that are not discussed in this study. Third, the changes in PCT and CRP/albumin ratios over time were not continuously monitored. Fourth, the postoperative albumin level may not really reflect a patient's nutritional status to some extent, It may be affected by supplementation during surgery and treatment. But we want to communicate to anesthesiologists, intensive care physicians, and surgeons a way to explore early outcomes in patients after LTx using traditional prognostic indicators, and hope that future multicenter and prospective experiments will confirm these findings.

Conclusion
In summary, our findings further suggest that PCT, CRP/ albumin ratio, atrial fibrillation, and PGD were an independent risk factor for death after LTX, postoperative PCT + CRP/albumin ratio had predictive value on the 30-day survival of patients after LTX, in patients undergoing LTX for IPF, PCT + CRP/albumin ratio was more effective in predicting 30-day mortality after surgery.