Usefulness of serum C-reactive protein and calprotectin for the early detection of colorectal anastomotic leakage: A prospective observational study

Abstract

Background: Colorectal anastomotic leakage (CAL) is one of the most dreaded complications after colorectal surgery, with an incidence that can be as high as 27%. This event is associated with increased morbidity and mortality; therefore, its early diagnosis is crucial to reduce clinical consequences and costs. Some biomarkers have been suggested as laboratory tools for the diagnosis of CAL.

Aim: To assess the usefulness of plasma C-reactive protein (CRP) and calprotectin (CLP) as early predictors of CAL.

Methods: A prospective monocentric observational study was conducted including patients who underwent colorectal resection with anastomosis, from March 2017 to August 2019. Patients were divided into three groups: G1 - no complications; G2 - complications not related to CAL; and G3 - CAL. Five biomarkers were measured and analyzed in the first 5 postoperative days (PODs), namely white blood cell (WBC) count, eosinophil cell count (ECC), CRP, CLP, and procalcitonin (PCT). Clinical criteria, such as abdominal pain and clinical condition, were also assessed. The correlation between biomarkers and CAL was evaluated. Receiver operating characteristic (ROC) curve analysis was used to compare the accuracy of these biomarkers as predictors of CAL, and the area under the ROC curve (AUROC), specificity, sensitivity, positive predictive value, and negative predictive value (NPV) during this period were estimated.

Results: In total, 25 of 396 patients developed CAL (6.3%), and the mean time for this diagnosis was 9.0 ± 6.8 d. Some operative characteristics, such as surgical approach, blood loss, intraoperative complications, and duration of the procedure, were notably related to the development of CAL. The length of hospital stay was markedly higher in the group that developed CAL compared with the group with complications other than CAL and the group with no complications (median of 21 d vs 13 d and 7 d respectively; P < 0.001). For abdominal pain, the best predictive performance was on POD4 and POD5, with the largest AUROC of 0.84 on POD4. Worsening of the clinical condition was associated with the diagnosis of CAL, presenting a higher predictive effect on POD5, with an AUROC of 0.9. WBC and ECC showed better predictive effects on POD5 (AUROC = 0.62 and 0.7, respectively). Those markers also presented a high NPV (94%-98%). PCT had the best predictive effect on POD5 (AUROC = 0.61), although it presented low accuracy. However, this biomarker revealed a high NPV on POD3, POD4, and POD5 (96%, 95%, and 96%, respectively). The mean CRP value on POD5 was significantly higher in the group that developed CAL compared with the group without complications (195.5 ± 139.9 mg/L vs 59.5 ± 43.4 mg/L; P < 0.00001). On POD5, CRP had a NPV of 98%. The mean CLP value on POD3 was significantly higher in G3 compared with G1 (5.26 ± 3.58 μg/mL vs 11.52 ± 6.81 μg/mL; P < 0.00005). On POD3, the combination of CLP and CRP values showed a high diagnostic accuracy (AUROC = 0.82), providing a 5.2 d reduction in the time to CAL diagnosis.

Conclusion: CRP and CLP are moderate predictors of CAL. However, the combination of these biomarkers presents an increased diagnostic accuracy, potentially decreasing the time to CAL diagnosis.

Keywords: Anastomotic leakage; Biomarkers; C-reactive protein; Calprotectin; Colorectal; Surgery.

Figure 1

Flow diagram of patients according to the study protocol. POD1: Postoperative day 1.

Figure 2

Distribution of rates of abdominal pain (A) and clinical condition (B). G1: No complications; G2: Complications not related to colorectal anastomotic leakage; G3: CAL. POD: Postoperative day.

Figure 3

Area under the receiver operating characteristic curve of colorectal anastomotic leakage for clinical criteria. A: Abdominal pain from postoperative day 1 to postoperative day 5; B: Clinical condition from postoperative day 1 to postoperative day 5. POD: Postoperative day.

Figure 4

C-reactive protein (A) and calprotectin (B) levels. Values are the mean ± SE. G1: No complications; G2: Complications not related to colorectal anastomotic leakage; G3: CAL; ▲: P statistically significant (P < 0.05).

Figure 5

Area under the receiver operating characteristic curve of colorectal anastomotic leakage. A: For C-reactive protein from postoperative day 1 to postoperative day 5; B: For calprotectin from postoperative day 1 to postoperative day 5; C: For calprotectin from postoperative day 3 to postoperative day 5; D: For C-reactive protein from postoperative day 3 to postoperative day 5. Left: All leaks; Right: Major leaks; POD: Postoperative day.