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

Table 1 Patient demographic and clinical characteristics

	Group 1, n = 277	Group 2, n = 94	Group 3, n = 25	P value
Age, mean ± SD	68.8 ± 11.3	72.2 ± 14.5	73.6 ± 13.6	0.02
Sex, n (%)				0.505
Male	161 (58.1)	59 (62.7)	17 (68.0)
Female	116 (41.9)	35 (37.3)	8 (32.0)
BMI, mean ± SD	26.8 ± 3.99	26.3 ± 4.05	26.0 ± 3.97	0.33
BMI, n (%)				0.33
17.5 < BMI < 25	95 (35.0)	32 (34.0)	12 (48.0)
25 ≤ BMI < 30	129 (46.0)	51 (54.0)	9 (36.0)
BMI ≥ 30	53 (19.0)	11 (12.0)	4 (16.0)
CCI, mean ± SD	5.12 ± 1.83	5.55 ± 2.38	6.04 ± 2.15	0.03
Prior abdominal surgery, n (%)	77 (27.8)	32 (34.0)	9 (36.0)	0.41
Immunosuppression, n (%)	10 (3.6)	5 (5.3)	0 (0)	0.45
Preoperative diagnosis malignant, n (%)	272 (98.2)	90 (95.7)	24 (96.0)	0.38
ASA score, n (%)				0.018
I–II	187 (67.5)	47 (50.0)	13 (45.8)
III–IV	90 (32.5)	47 (50.0)	12 (54.2)

Group 1: No complications; Group 2: Complications not related to colorectal anastomotic leakage (CAL); Group 3: CAL. BMI: Body mass index; CCI: Charlson Comorbidity Index; ASA: American Society of Anesthesiologists.

Table 2 Patients’ operative characteristics

	Group 1, n = 277	Group 2, n = 94	Group 3, n = 25	P value
Type of surgery, n (%)				0.071
Elective	238 (86.0)	72 (76.6)	19 (75.0)
Urgent	39 (14.0)	22 (23.4)	6 (25.0)
Surgical approach, n (%)				< 0.001
Open	25 (9.0)	15 (16.0)	2 (8.0)
Laparoscopic	238 (86.0)	72 (77.0)	15 (60.0)
Conversion	14 (5.0)	7 (7.4)	8 (32.0)
Procedure, n (%)				0.739
Right colectomy1	138 (49.8)	47 (50.0)	11 (44.0)
Left colectomy	17 (6.1)	7 (7.4)	1 (4.0)
Sigmoid/RS resection	55 (19.8)	15 (15.9)	4 (16.0)
Low anterior resection	48 (17.3)	16 (17.0)	8 (32.0)
Other	19 (6.8)	9 (9.6)	1 (4.0)
Level of anastomosis, n (%)				0.66
Ileocolic	150 (54.1)	50 (53.2)	11 (44.0)
Colocolic	23 (8.3)	5 (5.3)	1 (4.0)
≥ 6 cm from AV	67 (24.2)	25 (26.6)	10 (40.0)
< 6 cm from AV	37 (13.4)	14 (14.9)	3 (12.0)
Covering stoma, n (%)	23 (8.3)	8 (8.51)	2 (8.0)	0.99
Blood loss, mean ± SD, mL	51.6 ± 36.6	58.8 ± 47.7	104.0 ± 191.1	< 0.001
Intraoperative complications, n (%)	3 (1.1)	5 (5.3)	4 (16.0)	< 0.001
Operative time in min, mean ± SD	141.9 (48.3)	146.2 (50.0)	172.8 (57.2)	0.011

¹Included ileocecal resection/extended right-sided colectomy.

Group 1: No complications; Group 2: Complications not related to colorectal anastomotic leakage (CAL); Group 3: CAL. RS: Rectosigmoid; AV: Anal verge.

Table 3 Ninety-day postoperative morbidity and mortality

	Patients, n (%)	Length of hospital stay in d, mean ± SD
With complications	119 (30.0)	16.4 ± 9.91
With no complications	277 (70)	7.4 ± 2.10
Noninfectious complications	49 (41.2)	14.2 ± 6.93
Infectious complications
Surgical wound	36 (30.3)	14.6 ± 8.34
Respiratory tract	10 (8.4)	16.1 ± 7.22
Urinary tract	11 (9.2)	16.2 ± 6.00
Anastomotic leakage classification
Minor	7 (28)	28.0 ± 17.00
Major	18 (72)	22.4 ± 12.88
Postoperative mortality	3 (0.8)	NA

NA: Not applicable.

Table 4 Short-term outcomes by group

	Group 1, n = 277	Group 2, n = 94	Group 3, n = 25	P value
LOHS in d				< 0.001
mean ± SD	7.4 ± 2.1	14.3 ± 7.4	24.0 ± 14.0
Median	7	13	21
90-d morbidity, n (%)				< 0.001
Clavien-Dindo I	NA	64 (68.1)	0 (0)
Clavien-Dindo II		14 (14.9)	4 (16.0)
Clavien-Dindo III		8 (8.5)	16 (64.0)
Clavien-Dindo IV		8 (8.5)	5 (20.0)
Readmission, n (%)	15 (5.4)	6 (6.4)	5 (20.0)	0.019
Reoperation, n (%)	4 (1.1)	3 (3.2)	3 (12.0)	0.005
90-d mortality, n (%)	0 (0)	0 (0)	3 (12.0)	< 0.001

Group 1: No complications; Group 2: Complications not related to colorectal anastomotic leakage (CAL); Group 3: CAL. LOHS: Length of hospital stay; NA: Not applicable.

Table 5 Intraoperative and postoperative details of patients with colorectal anastomotic leakage (minor vs major)

	Minor CAL, n = 7	Major CAL, n = 18	P value
Type of anastomosis, n (%)			0.52
Intrabdominal	3 (42.8)	9 (50.0)
Pelvic	4 (57.2)	9 (50.0)
Covering stoma, n (%)	1 (14.3)	1 (5.6)	0.47
Abdominal pain
POD3	1.86	1.94	0.08
POD4	1.57	2.13	0.04
POD5	1.86	1.92	0.03
Clinical condition
POD3	1	1.25	0.07
POD4	1.14	1.47	0.13
POD5	1.29	1.58	0.02
CRP levels in mg/L
POD3	178.35	221.02	0.28
POD4	146.30	226.01	0.13
POD5	107.64	251.45	0.01
CLP levels in μg/mL
POD3	2.75	12.99	< 0.001
POD4	3.34	10.60	0.01
POD5	2.52	10.96	0.004
CAL diagnosis in d, median	8	5.5	0.07
Diagnostic method, n (%)			0.12
Clinical	0 (0)	7 (38.9)
Abdominopelvic CT	7 (100)	11 (61.1)
CAL management, n (%)			< 0.001
Drainage	NA	2 (11.1)
Reoperation		16 (88.9)
LOHS in d, mean ± SD	28.0 ± 17.0	22.4 ± 12.9	0.38

CAL: Colorectal anastomotic leakage; POD: Postoperative day; CRP: C-reactive protein; CLP: Calprotectin; CT: Computed tomography; LOHS: Length of hospital stay; NA: Not applicable.

Table 6 Summary of the predictive performance of the studied plasma biomarkers

	AUROC	Cut-off value	SS	SP	NPV	PPV	PLR	NLR
WBC in g/L
POD3	0.57	9.75	0.46	0.75	0.95	0.11	1.84	0.72
POD4	0.60	8.25	0.52	0.68	0.96	0.10	1.64	0.70
POD5	0.62	7.55	0.56	0.62	0.95	0.09	1.48	0.71
ECC in cells/μL
POD3	0.59	150	0.50	0.59	0.95	0.08	1.23	0.84
POD4	0.54	150	0.33	0.71	0.94	0.07	1.14	0.94
POD5	0.70	250	0.89	0.43	0.98	0.10	1.55	0.26
CRP in mg/L
POD3	0.76	175.90	0.64	0.83	0.97	0.20	3.77	0.44
POD4	0.76	152.40	0.62	0.89	0.97	0.27	5.40	0.43
POD5	0.81	96.80	0.78	0.78	0.98	0.19	3.48	0.29
PCT in ng/mL
POD3	0.57	0.19	0.68	0.47	0.96	0.08	1.28	0.68
POD4	0.50	0.31	0.38	0.76	0.95	0.10	1.56	0.82
POD5	0.61	0.39	0.44	0.79	0.96	0.12	2.10	0.71
CLP in μg/mL
POD3	0.78	6.57	0.71	0.72	0.97	0.15	2.55	0.40
POD4	0.67	8.34	0.56	0.86	0.97	0.21	3.89	0.51
POD5	0.65	6.98	0.58	0.80	0.97	0.16	2.84	0.52

AUROC: Area under the receiver operating characteristic curve; SS: Sensitivity; SP: Specificity; NPV: Negative predictive value; PPV: Positive predictive value; PLR: Positive likelihood ratio; NLR: Negative likelihood ratio; WBC: White blood cell count; POD: Postoperative day; ECC: Eosinophil cell count; CRP: C-reactive protein; PCT: Procalcitonin; CLP: Calprotectin.

Table 7 Area under the receiver operating characteristic curve of pairwise combination of biomarkers on postoperative day 3

	CLP	PCT	CRP	ECC
PCT	0.76
CRP	0.82	0.72
ECC	0.77	0.52	0.72
WBC	0.74	0.53	0.72	0.54

CLP: Calprotectin; PCT: Procalcitonin; CRP: C-reactive protein; ECC: Eosinophil cell count; WBC: White blood cell count.

Table 8 Area under the receiver operating characteristic curve of pairwise combination of biomarkers on postoperative day 5

	CLP	PCT	CRP	ECC
PCT	0.60
CRP	0.78	0.79
ECC	0.61	0.63	0.81
WBC	0.57	0.60	0.78	0.67

CLP: Calprotectin; PCT: Procalcitonin; CRP: C-reactive protein; ECC: Eosinophil cell count; WBC: White blood cell count.