International Journal of Colorectal Disease

https://doi.org/10.1007/s00384-019-03481-1

ORIGINAL ARTICLE

Compare risk factors associated with postoperative infectious

complication in Crohn’s disease with and without preoperative
infliximab therapy: a cohort study
Shasha Tang 1 & Xue Dong 2 & Wei Liu 1 & Weilin Qi 1 & Lingna Ye 3 & Xiaoyan Yang 1 & Qian Cao 3 & Xiaolong Ge 1 & Wei Zhou 1

Accepted: 28 November 2019

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Purposes The incidence of postoperative complication is higher in Crohn’s disease (CD) compared with other intestinal disease.
There is less published data yet on the comparison of risk factors to predict postoperative complications in CD exposed and
unexposed to previous infliximab therapy. Also the relationship between infliximab and postoperative infectious complications is
still controversial. Our aim is to compare the risk factors to predict infectious complications in CD with and without preoperative
infliximab and to clarify relationship between infliximab and infectious complications.
Methods This retrospective study included 390 patients from June 2014 to June 2018. Postoperative complications were
compared in patients with and without preoperative infliximab. Univariate and multivariable analyses were performed to identify
risk factors.
Results Eighty-five patients received infliximab within 8 weeks of surgery. A total of 129 patients had postoperative complica-
tions, with 35 receiving infliximab. No significant differences of whole postoperative complications were found in CD with and
without infliximab (p = 0.073). However, patients receiving infliximab suffered more infectious complications (p = 0.010).
Preoperative infliximab was confirmed to be an independent risk factor in infectious complications (p = 0.042). Multivariate
analysis suggested that increased erythrocyte sedimentation rate (ESR) was an independent risk factor for infectious complica-
tions in patients receiving preoperative infliximab (p = 0.022), and increased C-reactive protein was an independent risk factor in
patients not receiving preoperative infliximab (p = 0.019).
Conclusions Preoperative use of infliximab ≤ 8 weeks was independently associated with infectious complications in CD. Risk
factors were different in predicting postoperative complications in CD with and without infliximab, and preoperative ESR and C-
reactive protein were risk factors, respectively.

Keywords Infliximab . Crohn’s disease . Infectious complications . Risk factors

Introduction
Shasha Tang and Xue Dong contributed equally to this work.
Crohn’s disease (CD) is characterized by a transmural
* Xiaolong Ge inflammatory disease of the intestinal mucosa, and it hap-
gxlmed@zju.edu.cn pens in any segment of the digestive tract discontinuously
* Wei Zhou [1]. Although there are various therapies including immu-
zhouweisrrs@zju.edu.cn nosuppressive and biologic treatments recently, CD still
requires surgical resection somewhat due to the failure
1
Department of General Surgery, Sir Run Run Shaw Hospital, School of medical therapy [2]. It is reported that almost 30% of
of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang,
China CD patients require surgical resection after 5 years of
2 diagnosis, and 70% of CD patients will undergo CD-
Department of Radiology, Sir Run Run Shaw Hospital, School of
Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, China related surgery during their whole life [3]. Unfortunately,
3 surgery is not considered to be curative for CD, and in-
Department of Gastroenterology, Sir Run Run Shaw Hospital,
School of Medicine, Zhejiang University, testinal failure or short bowel syndrome results from ex-
Hangzhou 310016, Zhejiang, China tensive small bowel resection or multiple surgeries [4]. So

the treatment strategy should ideally be made by gastro-
enterologists and surgeons in order to protect limited
intestine.
Preoperative optimization in CD plays a pivotal role in
minimal bowel resection, and appropriate planning of medical
therapy for CD patients profits surgical outcome. The tumor
necrosis factor-α (TNF-α) is one of the important pro-
inflammatory cytokines in the inflamed intestinal mucosa of
CD patients [5]. Thus, the TNF-α monoclonal antibodies like
infliximab (IFX) and adalimuab have been widely used for
induction and maintenance treatment in moderate to severe
CD patients [6]. With the advantage of anti-TNF agents, the
inflammatory burden is reduced and mucosal healing is
achieved in active CD, which could contribute to reduce bow-
el damage and resection.
However, the emergence of IFX is considered as a
double-edged sword in surgery. Due to its inhibitory effect
on the immune system, the risk of postoperative complica-
tions is thought to be increased [7]. A study by Syed et al.
[5] showed that the use of IFX therapy before surgery in
CD patients was an independent risk factor for infectious
and surgical complications. Jouvin et al. [3] also reported
that preoperative IFX treatment could increase overall
postoperative morbidity and septic complications indepen-
dently. On the opposite, Xu et al. [7] found there was no
association between preoperative IFX and postoperative
complications of CD in a meta-analysis of research.
Kotze et al. [8] draw the consistent conclusion that IFX
therapy appeared safe in elective intestinal resections for
CD. Thus, the influence of IFX on postoperative compli-
cations is controversial.
Our study analyzed a large cohort of CD patients in
Inflammatory Bowel Disease center of out hospital to com-
pare the rate of postoperative complications, especially the
infectious complications, in CD patients treated with and
without IFX. We also tried to evaluate the predictors for com-
plications of patients exposed or unexposed to IFX, as there is
less published data yet on the topic.
Materials and methods
Patients
This study was a retrospective review of 390 CD patients
undergoing surgical resection from June 2014 to
June 2018 at IBD Center, a teaching hospital of Zhejiang
University. All the data of CD patients were collected from
patients’ medical charts in the IBD database. All CD pa-
tients were diagnosed depended on accepted criteria [9].
This study was approved by the Ethics Committee of our
hospital.
Int J Colorectal Dis
Inclusion and exclusion criteria
CD patients with intestinal resection due to failure of medical
therapy or developed complications (structuring, penetrating,
or malignancy) were included in this study [9]. CD patients
exposed to preoperative infliximab were defined as a docu-
mented dose of IFX less than 8 weeks before surgery. Those
without a surgical bowel resection and those with incomplete
laboratory data were excluded. Patients with emergency sur-
gery were also excluded.
Data collection
Baseline characteristics included age, body mass index
(BMI), sex, comorbidity, smoking, medication, and
Montreal classification and disease severity (defined as
remission stage, CDAI < 150; mild disease activity, 150
< CDAI < 220; moderate disease, 220 < CDAI < 450; sev-
er disease, CDAI > 450). Intraoperative data included op-
eration time, surgical approach (open vs laparoscopy),
stoma creation, estimated blood loss, and operative time.
Laboratory data included white blood count (WBC), red
blood count (RBC), hematocrit (HCT), hemoglobin (HB),
albumin (ALB), C-reactive protein (CRP), erythrocyte
sedimentation rate (ESR), platelet (PLT), and lymphocyte.
Preoperative enteral nutrition therapy was defined as daily
intake of enteral nutrition of 25–30 kcal/kg of body
weight for least 4 weeks before surgery by nasogastric
tube. Preoperative steroid use was defined as corticoste-
roids within 30 days before surgery. In addition, the dos-
age of thiopurines (1.0–1.5 mg/kg for 6-MP and 2.0–
2.5 mg/kg for azathioprine) and infliximab (5 mg/kg,) is
managed based on weight of patients. However, the dose
of methotrexate is 25 mg per week by intramuscularly or
subcutaneously.
Definition of outcomes
The primary outcome of this study was to evaluate com-
plications associating with risk factors in CD exposed
with and without IFX. Postoperative complications were
defined as those occurring within 30 days from the date of
operation including discharge based on the Clavien-Dindo
system [10]. Mild complications included grades I to II,
and major complications included grades III to IV. The
infectious complications were defined as any wound in-
fection, abdomino-pelvic abscess, peritonitis, sepsis,
pneumonia, and other major infection [5]. SSIs were de-
fined as any infection of the superficial or deep tissues or
the organ/space affected by surgery, and which occurs
within 30 days of surgery when no prosthesis has been
implanted according to WHO recommendations [11]. The
second outcomes included infectious complications,
Int J Colorectal Dis

Table 1 Patients’ characteristics

and comparison of cohorts at the Variable Overall (n = 390) IFX (n = 85) No IFX (n = 305) P value
time of surgery
Male 251 (64.4) 56 (65.9) 195 (63.9) 0.740
Comorbidities
Cardiovascular 0 0 0 –
Diabetes mellitus 26 (6.7) 5 (5.9) 21 (6.9) 0.743
Pulmonary 3 (0.8) 1 (1.2) 2 (0.7) 0.523
Hypertension 39 (10.0) 9 (10.6) 30 (9.8) 0.838
Age at surgery* 36.3 ± 12.6 31.5 ± 10.7 37.7 ± 12.8 < 0.001
Disease duration* 50.6 ± 51.5 59.7 ± 45.9 48.0 ± 52.8 0.066
Surgical history 144 (36.9) 38 (44.7) 106 (34.8) 0.093
Current smoker 65 (16.7) 13 (15.3) 52 (17.0) 0.701
Medication history
5-ASA 223 (57.2) 52 (61.2) 171 (56.1) 0.400
Corticosteroids 120 (30.8) 35 (41.2) 85 (27.9) 0.019
Azathioprine 186 (47.7) 54 (63.5) 132 (43.3) 0.001
Methotrexate 45 (11.5) 23 (27.1) 22 (7.2) < 0.001
Antibiotics 33 (8.5) 6 (7.1) 27 (8.9) 0.599
Others 22 (5.6) 5 (5.9) 17 (5.6) 0.913
Disease severity(CDAI score)
Mild (150 < CDAI < 220) 111 (28.5) 17 (20.0) 94 (30.8) 0.001
Moderate (220 < CDAI < 450) 224 (57.4) 50 (58.8) 174 (57.1) 0.002
Severe (CDAI > 450) 55 (14.1) 18 (21.2) 37 (12.1) 0.582
Preoperative enteral nutrition 123 (31.5) 16 (18.8) 107 (35.1) 0.004
Age (≤ 16) 5 (1.3) 2 (2.4) 3 (0.1) 0.655
Age (17–40) 256 (65.6) 67 (78.8) 189 (62.0) 0.004
Age (> 40) 129 (33.1) 16 (18.8) 113 (37.0) 0.002
L1 (ileal) 168 (43.1) 37 (43.5) 131 (43.0) 0.924
L2 (colonic) 32 (8.2) 12 (14.1) 20 (6.6) 0.025
L3 (ilecolonic) 168 (43.1) 32 (37.6) 136 (44.6) 0.253
L4 (upper gastrointestinal) 39 (10.0) 8 (9.4) 31 (10.2) 0.838
B1 (failure of medical therapy) 20 (5.1) 5 (5.9) 15 (4.9) 0.937
B2 (stricturing) 265 (67.9) 56 (65.9) 209 (68.5) 0.644
B3 (penetrating) 154 (39.5) 33 (38.8) 121 (39.7) 0.887
Perianal disease 127 (32.6) 47 (55.3) 80 (26.2) < 0.001

CDAI Crohn’s Disease Activity Index, IFX, infliximab

*Values are expressed as mean ± SD; other values are expressed as n (%)

length of postoperative hospital stay, and surgical site in-
fections (SSIs). The relationship between IFX and com-
plications was also assessed. The relationship between
IFX and complications was also assessed.
Statistical analysis
All of the statistical analyses were conducted using SPSS
21.0 (Armonk, NY: IBM Corp). Continuous data was pre-
sented as the mean ± SD or median (range), whereas cate-
gorical data were presented as number (%). The continuous
variables were analyzed by the Student t test or Mann-
Whitney U test depending on the normality of the data dis-
tribution, and the categorical variables were analyzed by the
Pearson χ2 test or the Fisher exact test, as appropriate.
Significant associations on univariate analyses (p < 0.05)
were evaluated, and then the multivariate logistic regression
analysis was used to identify independent predictors of in-
fectious complications. The receiver operating characteris-
tic curve analysis was used to assess the predictive accuracy
of predictors. P value < 0.05 was considered to be statisti-
cally significant.
 Int J Colorectal Dis

Table 2 Preoperative surgical

characteristics and operative Variable Overall (n = 390) IFX (n = 85) No IFX (n = 305) P value
details of CD patients with and
without IFX White blood count 6.1 ± 2.9 5.7 ± 2.8 6.2 ± 2.9 0.195
Red blood count 4.3 ± 0.6 4.2 ± 0.7 4.3 ± 0.6 0.507
Hematocrit 36.1 ± 5.2 36.5 ± 5.7 35.9 ± 5.1 0.366
Hemoglobin 12.1 ± 6.0 13.4 ± 12.4 11.8 ± 1.8 0.025
Albumin 36.0 ± 5.3 36.4 ± 5.5 35.9 ± 5.3 0.440
C-reactive protein 15.7 ± 34.8 13.7 ± 32.4 16.3 ± 35.5 0.539
Erythrocyte sedimentation rate 18.1 ± 16.0 18.4 ± 16.7 17.9 ± 15.8 0.814
Lymphocyte 1.2 ± 0.5 1.3 ± 0.6 1.1 ± 0.5 0.087
BMI 18.9 ± 2.9 18.7 ± 3.2 18.9 ± 2.8 0.548
Laparoscopic surgery* 233 (59.7) 52 (61.2) 181 (59.3) 0.761
Conversion* 83 (21.3) 9 (10.6) 74 (24.3) 0.006
Creation of a stoma* 106 (27.2) 27 (31.8) 79 (25.9) 0.283
Estimated blood loss 146.4 ± 128.1 75.4 ± 89.6 131.1 ± 111.4 0.092
Operative time 209.2 ± 64.6 183.6 ± 61.1 209.6 ± 63.0 0.354

IFX infliximab, BMI body mass index, CD Crohn’s disease

*Values are expressed as n (%); other values are expressed as mean ± SD/SE

Results levels of HB, significantly (13.4 ± 12.4 vs 11.8 ± 1.8,

Study population and baseline characteristic
Totally, 390 CD patients were enrolled in this study
(men:women = 251:139), of which the mean age at sur-
gery was 36.3 ± 12.6 years old. The mean disease duration
before surgery was 50.6 ± 51.5 months, and 144 (36.9%)
had surgical history. Among 390 enrolled patients, 123
(31.5%) were treated with preoperative enteral nutrition.
The Montreal classification of enrolled patients was
shown in Table 1. For medication history, 85 (21.8%)
received IFX within 8 weeks before surgery, and a num-
ber of patients that received 5-ASA, corticosteroids, aza-
thioprine, methotrexate, and antibiotics were 223 (57.2%),
120 (30.8%), 186 (47.7%), 45 (11.5%), and 33 (8.5%),
respectively. Age at surgery, medication history, preoper-
ative enteral nutrition, location of disease, and perianal
disease were significantly different between patients treat-
ed with and without IFX, as shown in Table 1. Patients
receiving IFX were younger than control when at surgery
(p < 0.001). Patients receiving IFX were more likely to be
diagnosed as colonic disease and accompanying perianal
disease (p < 0.05).
Preoperative surgical characteristics and operative
details
There were no significant differences between patients
treated with and without IFX therapy in WBC, RBC,
HCT, ALB, CRP, ESR, and lymphocyte as shown in
Table 2. However, patients receiving IFX had higher
p = 0.025). For surgical information, although the percent-
age of laparoscopic surgery was similar between patients
treated with and without IFX (61.2% vs 59.3%, p =
0.761), the incidence of conversion in patients receiving
IFX was lower than that in patients without IFX (10.6%
vs 24.3%, p = 0.006). More operative details were pre-
sented in Table 2.
Comparison of postoperative complications in CD
patients with and without preoperative IFX
Totally, 261 (66.9%) patients recovered uneventfully, and
129 (33.1%) had postoperative complications, with 35
(41.2%) CD patients receiving IFX and 94 (30.8%) with-
out IFX treatment. No significant difference of postoper-
ative complications was found in CD patients treated with
and without IFX (p = 0.073). However, according to
Clavien-Dindo classification, the incidence of mild com-
plications was higher in patients receiving IFX than not
receiving IFX before surgery (38.8% vs 23.9%, p =
0.006). There was no significant difference in major com-
plications between these two groups (22.4% vs 20.0%,
p = 0.635). In addition, CD patients receiving preoperative
IFX suffered more infectious complications which was
defined before (25.9% vs 14.1%, p = 0.010). By further
analysis, it was found that there were significantly differ-
ences in wound infection and surgical site infection in
patients treated with and without IFX (15.3% vs 7.9%,
p = 0.039; 28.2% vs 16.4%, p = 0.014). More details about
complications were shown in Table 3.
Int J Colorectal Dis

Table 3 Postoperative
complications of CD patients with Variable Overall (n = 390) IFX (n = 85) No IFX (n = 305) P value
and without IFX undergoing
abdominal surgery Postoperative length of stay* 18.1 ± 18.2 12.4 ± 10.5 17.0 ± 16.4 0.141
Overall 129 (33.1) 35 (41.2) 94 (30.8) 0.073
Grade I
Ileus 7 (1.8) 3 (3.5) 4 (1.3) 0.368
Fever > 38.5 °C after surgery 30 (7.7) 9 (10.6) 21 (6.9) 0.257
Diarrhea 8 (2.1) 1 (1.2) 7 (2.3) 0.833
Grade II
Postoperative blood transfusions > 2 U 9 (2.3) 4 (4.7) 5 (1.6) 0.209
Wound infection 37 (9.5) 13 (15.3) 24 (7.9) 0.039
Early postoperative bowel obstruction 13 (3.3) 3 (3.5) 10 (3.3) 0.909
Line sepsis 2 (0.5) 0 2 (0.7) 0.611
Grade III
Abdomino-pelvic collection 7 (1.8) 1 (1.2) 6 (2.0) 0.981
Lymphatic leakage 1 (0.3) 0 1 (0.3) 0.782
Pleural effusion 3 (0.8) 0 3 (1.0) 0.477
Gastrointestinal bleeding 16 (4.1) 4 (4.7) 12 (3.9) 0.994
Intra-abdominal bleeding 2 (0.5) 0 2 (0.7) 0.611
Stoma complications 11 (2.8) 4 (4.7) 7 (2.3) 0.414
Intra-abdominal abscess 8 (2.1) 2 (2.4) 6 (2.0) 0.824
Anastomotic leakage 23 (5.9) 5 (5.9) 18 (5.9) 0.995
Grade IV
Septic shock 6 (1.5) 2 (2.4) 4 (1.3) 0.848
Sepsis 3 (0.8) 1 (1.2) 2 (0.7) 0.523
Grade V
Surgical site infection 74 (19.0) 24 (28.2) 50 (16.4) 0.014
Incisional SSI 39 (10.0) 15 (17.6) 24 (7.9) 0.008
Organ/space SSI 35 (9.0) 9 (10.6) 26 (8.5) 0.556
Mild complications 106 (27.2) 33 (38.8) 73 (23.9) 0.006
Major complications 80 (20.5) 19 (22.4) 61 (20.0) 0.635
Infectious complication 65 (16.7) 22 (25.9) 43 (14.1) 0.010

IFX infliximab, SSI surgical site infection, CD Crohn’s disease

*Values are expressed as mean ± SD; other values are expressed as n (%)

Analysis of possible risk factors for infectious
complications in CD patients with and
without preoperative IFX
In this cohort of CD patients, univariate analysis showed
that stricturing disease, penetrating disease, WBC level,
ALB level, CRP level, laparoscopic surgery, stoma crea-
tion, estimated blood loss, operative time, and preopera-
tive IFX were associated with infectious complications. In
CD patients receiving preoperative IFX, univariate analy-
sis showed that stricturing disease, penetrating disease,
ESR level, and laparoscopic surgery were associated with
infectious complications. In CD patients treated without
preoperative IFX, univariate analysis showed that WBC
level, ALB level, CRP level, laparoscopic surgery, con-
version, stoma creation, estimated blood loss, operative
time, and preoperative EN were associated with infectious
complications. Multivariate analysis revealed that laparo-
scopic surgery (OR = 0.398, 95% CI 0.203–0.782, P =
0.008), operative time (OR = 2.105, 95% CI 1.046–
4.238, P = 0.037), and preoperative IFX (OR = 1.951,
95% CI 1.025–3.713, P = 0.042) were independent factors
associated with infectious complications in the overall
group of CD patients. However, multivariate analysis sug-
gested that ESR level was an independent risk factor as-
sociated with infectious complications in patients receiv-
ing preoperative IFX (OR = 3.562, 95% CI 1.198–10.595,
P = 0.022), and CRP level was an independent risk factor
in patients not receiving preoperative IFX (OR = 2.637,
95% CI 1.174–5.923, P = 0.019). Different risk factors
were found in CD patients treated with and without pre-
operative IFX in our study as shown in Tables 4 and 5.
Table 4 Univariate analysis of infectious complications in CD patients

With IFX Without IFX All

Variable Infectious No infectious P Infectious No infectious P value Infectious No infectious P value

complications complications (n = 63) value complications complications (n = 262) complications complications (n = 325)
(n = 22) (n = 43) (n = 65)

Male 11 (50.0) 45 (71.4) 0.068 27 (62.8) 168 (64.1) 0.866 38 (58.5) 213 (65.5) 0.277
Disease severity (CDAI score)
Mild 4(18.2) 13 (20.6) 0.214 11 (25.6) 83(31.7) 0.325 15(23.1) 96(29.5) 0.311
(150 < CDAI <
220)
Moderate 10(45.4) 40 (63.5) 0.072 23(53.5) 151(57.6) 0.517 33(50.8) 191(58.8) 0.605
(220 < CDAI <
450)
Severe (CDAI > 450) 8(36.4) 10(15.9) 0.510 9(20.9) 28(10.7) 0.207 17(26.1) 38(11.7) 0.193
Disease duration* 66.9 ± 45.1 57.1 ± 46.2 0.393 58.4 ± 48.6 46.4 ± 53.3 0.167 61.3 ± 47.3 48.4 ± 52.1 0.067
Surgical history 12 (54.5) 26 (41.3) 0.281 18 (41.9) 88 (33.6) 0.291 30 (46.2) 114 (35.1) 0.298
Current smoker 4 (18.2) 9 (14.3) 0.926 6 (14.0) 46 (17.6) 0.560 10 (15.4) 55 (16.9) 0.761
Medication history
5-ASA 14 (63.6) 38 (60.3) 0.783 28 (65.1) 143 (54.6) 0.197 42 (64.6) 181 (55.7) 0.184
Corticosteroids 8 (36.4) 27 (42.9) 0.594 15 (34.9) 70 (26.7) 0.268 23 (35.4) 97 (29.8) 0.377
Azathioprine 14 (63.6) 40 (63.5) 0.990 17 (39.5) 115 (43.9) 0.593 31 (47.7) 155 (47.7) 0.555
Methotrexate 8 (36.4) 15 (23.8) 0.254 3 (7.0) 19 (7.3) 0.948 11 (16.9) 34 (10.5) 0.137
Antibiotics 2 (9.1) 4 (6.3) 0.666 2 (4.7) 25 (9.5) 0.449 4 (6.2) 29 (8.9) 0.464
Others 1 (4.5) 4 (6.3) 0.757 1 (2.3) 16 (6.1) 0.520 2 (3.1) 20 (6.2) 0.492
Age (≤ 16) 2 (9.1) 0 0.065 0 3 (1.1) 0.633 2 (3.1) 3 (0.9) 0.195
Age (17–40) 18 (81.8) 49 (77.8) 0.923 28 (65.1) 161 (61.5) 0.646 46 (70.8) 210 (64.6) 0.340
Age (> 40) 2 (9.1) 14 (22.2) 0.298 15 (34.9) 98 (37.4) 0.751 17 (26.2) 112 (34.5) 0.194
L1 (ileal) 7 (31.8) 30 (47.6) 0.198 18 (41.9) 113 (43.1) 0.876 25 (38.5) 143 (44.0) 0.410
L2 (colonic) 6 (27.3) 6 (9.5) 0.089 2 (4.7) 18 (6.9) 0.832 8 (12.3) 24 (7.4) 0.187
L3 (ilecolonic) 9 (40.9) 23 (36.5) 0.714 20 (46.5) 116 (44.3) 0.784 29 (44.6) 139 (42.8) 0.784
L4 (upper 2 (9.1) 6 (9.5) 0.952 3 (7.0) 28 (10.7) 0.636 5 (7.7) 34 (10.5) 0.497
gastrointestinal)
B1 (failure of medical 1 (4.5) 4 (6.3) 0.757 0 15 (5.7) 0.219 1 (1.5) 19 (5.8) 0.259
therapy)
B2 (stricturing) 10 (45.5) 46 (73.0) 0.019 27 (62.8) 182 (69.5) 0.382 37 (56.9) 228 (70.2) 0.037
B3 (penetrating) 13 (59.1) 20 (31.7) 0.023 20 (46.5) 101 (38.5) 0.323 33 (50.8) 121 (37.2) 0.042
Perianal disease 11 (50.0) 36 (57.1) 0.562 12 (27.9) 68 (26.0) 0.787 23 (35.4) 104 (32.0) 0.595
White blood count* 6.3 ± 2.8 5.5 ± 2.8 0.258 7.0 ± 4.2 6.0 ± 2.6 0.049 6.7 ± 3.8 5.9 ± 2.7 0.036
Red blood count* 4.2 ± 0.6 4.2 ± 0.7 0.932 4.1 ± 0.6 4.3 ± 0.6 0.184 4.2 ± 0.6 4.3 ± 0.7 0.283
Int J Colorectal Dis
Table 4 (continued)

With IFX Without IFX All

Variable Infectious No infectious P Infectious No infectious P value Infectious No infectious P value

Int J Colorectal Dis

complications complications (n = 63) value complications complications (n = 262) complications complications (n = 325)
(n = 22) (n = 43) (n = 65)

Hematocrit* 36.5 ± 4.8 36.6 ± 6.2 0.940 34.9 ± 5.2 36.1 ± 5.0 0.158 35.4 ± 5.1 36.2 ± 5.3 0.308
Hemoglobin* 12.1 ± 1.6 13.9 ± 14.4 0.581 11.4 ± 2.0 11.8 ± 1.8 0.204 11.7 ± 1.9 12.2 ± 6.6 0.520
Albumin* 35.8 ± 4.7 36.6 ± 5.7 0.563 34.0 ± 5.7 36.2 ± 5.2 0.013 34.6 ± 5.4 36.3 ± 5.2 0.023
C-reactive protein* 23.2 ± 53.4 10.4 ± 20.4 0.110 40.4 ± 73.0 12.4 ± 22.3 < 0.001 34.6 ± 67.1 11.8 ± 20.8 < 0.001
ESR* 25.3 ± 21.7 15.9 ± 13.8 0.022 19.5 ± 15.4 17.7 ± 15.9 0.490 21.5 ± 17.9 17.3 ± 15.5 0.057
Lymphocyte* 1.3 ± 0.7 1.2 ± 0.6 0.565 1.0 ± 0.5 1.2 ± 0.5 0.076 1.1 ± 0.6 1.2 ± 0.5 0.422
BMI* 18.0 ± 1.9 19.0 ± 3.5 0.199 18.4 ± 2.5 19.0 ± 2.8 0.210 18.3 ± 2.3 19.0 ± 3.0 0.062
PLT* 240.9 ± 78.0 259.3 ± 87.3 0.385 253.1 ± 90.4 258.5 ± 91.9 0.720 249.0 ± 86.0 258.3 ± 91.3 0.450
Laparoscopic surgery 9 (40.9) 43 (68.3) 0.023 12 (27.9) 169 (64.5) < 0.001 21 (32.3) 212 (65.2) < 0.001
Conversion 1 (4.5) 8 (12.7) 0.504 18 (41.9) 56 (21.4) 0.004 19 (29.2) 64 (19.7) 0.086
Creation of a stoma 10 (45.5) 17 (27.0) 0.109 17 (39.5) 62 (23.7) 0.028 27 (41.5) 79 (24.3) 0.004
Estimated blood loss* 114.1 ± 104.0 70.7 ± 90.1 0.065 103.5 ± 103.3 60.8 ± 55.2 < 0.001 107.1 ± 102.8 62.7 ± 63.4 < 0.001
Operative time* 199.9 ± 57.7 179.9 ± 67.2 0.217 221.0 ± 67.7 187.1 ± 55.4 < 0.001 213.8 ± 64.8 185.7 ± 57.8 < 0.001
Preoperative EN 6 (27.3) 10 (15.9) 0.389 9 (20.9) 98 (37.4) 0.036 15 (23.1) 108 (33.2) 0.108
Age at surgery* 29.5 ± 9.7 32.2 ± 11.0 0.312 37.4 ± 13.8 37.7 ± 12.7 0.902 34.8 ± 13.1 36.6 ± 12.5 0.273
Preoperative IFX – – – – – – 22 (33.8) 63 (19.4) 0.010

IFX infliximab, CD, Crohn’s disease, ESR erythrocyte sedimentation rate, BMI body mass index, PLT platelet, EN enteral nutrition
*Values are expressed as mean ± SD; other values are expressed as n (%)
 Int J Colorectal Dis

Table 5 Multivariate analysis of risk factors for infectious complication in CD patients

With IFX Without IFX All

Variable P OR 95% CI Variable P OR 95% CI Variable P OR 95% CI

value value value

Montreal B WBC 0.535 1.287 0.580–2.855 WBC 0.194 1.480 0.819–2.675

B2 0.331 0.497 0.122–2.034 ALB 0.145 1.717 0.829–3.554 ALB 0.564 0.841 0.466–1.516
B3 0.477 1.640 0.420–6.407 CRP 0.019 2.637 1.174–5.923 CRP 0.351 0.758 0.423–1.357
ESR 0.022 3.562 1.198–10.595 Creation of a 0.390 0.700 0.311–1.576 Creation of a 0.634 1.167 0.619–2.201
stoma stoma
Laparoscopic 0.113 0.411 0.136–1.236 Laparoscopic 0.016 0.292 0.107–0.793 Laparoscopic 0.008 0.398 0.203–0.782
surgery surgery surgery
Conversion 0.865 0.926 0.383–2.240 Estimated blood 0.276 1.437 0.749–2.758
loss
Estimated blood 0.807 1.112 0.474–2.612 Operative time 0.037 2.105 1.046–4.238
loss
Operative time 0.081 2.347 0.901–6.109 Montreal B
Preoperative EN 0.075 0.466 0.201–1.080 B2 0.638 0.835 0.394–1.771
B3 0.936 0.969 0.455–2.067
Anti-TNF 0.042 1.951 1.025–3.713

ESR erythrocyte sedimentation rate, WBC white blood count, ALB albumin, CRP C-reactive protein, IFX infliximab

Compare the predictive accuracy of preoperative
factors for infectious complications in CD patients
treated with and without preoperative IFX
Finally, we determined the predictive accuracy of ESR and
CRP for infectious complications after surgery in patients re-
ceiving and not receiving preoperative IFX. As shown in
Fig. 1, the receiver operating characteristic curve analysis
showed that in patients with IFX, the cutoff value of ESR
for infectious complication prediction was 19.5, with a AUC
of 0.606, sensitivity of 0.545, specificity of 0.730, positive
predictive value of 42.9%, and negative predictive value of
82.1%, The Youden index was 0.275. In patients without IFX,
the cutoff value of CRP was 5.0, with AUC of 0.637, sensi-
tivity of 0.767, specificity of 0.534, positive predictive value
of 21.3%, negative predictive value of 93.3%, and Youden
index was 0.301.
Discussion
The emergence of anti-TNF agents brings great changes in the
management of CD patients. The majority of moderate to
severe CD patients will be induced and maintained remission
successfully by anti-TNF agents. However, the anti-TNF
agents might also result in some troubles to patients who suf-
fering surgery, especially postoperative complications and in-
fectious complications. The results of previous study about
anti-TNF agents are conflicted. In the current study, we found
IFX therapy within 8 weeks of surgery could be associated
with surgical outcomes, especially infectious complications.
Additionally, this study revealed that the potential predictors
of infectious complications in CD patients treated with and
without IFX were quite different, which indicated surgeon
should focus on different risk factors to predict outcomes in
these situations.
There were various studies focusing on the association be-
tween IFX agents and surgical outcomes. They draw different
conclusions from these studies. Some suggested IFX could
lead to higher infectious complications, and others found that
there was no association between IFX and complications [3, 5,
12–14]. In term of these studies, the time from the last dose of
the IFX before surgery was different. Some studies assessed
the influence of IFX on patients exposed to them within
12 weeks of surgery, and some studies included patients ex-
posed to medications within 8 weeks of surgery. Actually, it
was found that after intravenous infusion, the half-life of IFX
was 8–10 days, and the levels of IFX declined in exponential
between 8 and 12 weeks after treating with standard doses in
CD patients [12, 15, 16]. In our study, we included patients
exposed to IFX within 8 weeks of surgery, and we found use
of IFX therapy less than 8 weeks before surgical resection was
independently associated with higher incidence of infectious
complications. Our results were in accordance with some
studies before [3, 5]. Recently, Xu et al. [7] conducted a
meta-analysis about the influence of preoperative IFX on post-
operative complications, and they concluded that there was no
association between them. However, they also found that the
duration of IFX exposure in studies was quite different and
one of their limitations was time since last IFX exposure [7].
In addition, we did not find out the significant association
between other complications and preoperative IFX. For
Int J Colorectal Dis

Fig. 1 a ROC curve showing a

ESR levels before surgery
predictive of postoperative
infectious complications in CD
patients with IFX. b ROC curve
showing CRP levels before
surgery predictive of
postoperative infectious
complications in CD patients
without IFX

ESR CRP
Cutoff point 19.5 5
AUC 0.606 0.637
Sensitivity 54.5% 76.7%
Specificity 73.0% 53.4%
Positive predictive value 42.9% 21.3%
Negative predictive value 82.1% 93.3%

example, preoperative IFX therapy did not contribute to the
major complications and postoperative length of stay. So some
differences of methodology in studies including dosage of
IFX, last time of IFX treatment, endpoints of study, and others
may contribute to the controversy regarding the influences of
IFX in complications.
Postoperative complications are major challenges in CD pa-
tients undergoing surgical resections. Therefore, it is need to find
out easy and reliable markers to predict infectious complications.
In the last study, we have found that early postoperative decrease
of serum albumin predicted complications in patients undergoing
colorectal resection including CD [17]. Zuo et al. [18] suggested
that changes in CRP before surgery could predict postoperative
intra-abdominal septic complications in CD patients. BMI was
also demonstrated to be a practical preoperative nutritional index
to predict infectious complications in CD patients with intestinal
resection [19]. However, there is little information in comparison
of risk factors to predict infectious complications between CD
patients treated with and without preoperative IFX. To the best of
our knowledge, the present study is the first to compare the
difference of risk predictors in infectious complications in CD.
Our study demonstrated that CRP level was an independent risk
factor to predict infectious complications in CD patients without
preoperative IFX therapy, and ESR level was an independent risk
factor in CD patients with preoperative IFX. The different phe-
nomenon might result from the function of anti-TNF therapy.
CRP is considered to be an acute-phase reactant, and when it
is stimulated by cytokine (like TNF-α, interleukin-6), the hepa-
tocytes produce and release more CRP [20]. Thus, CD patients
receiving IFX treatment always have lower level of CRP. The
CRP levels is associated with anti-TNF therapy. Boyle et al.
found CRP levels over 12 mg/L exhibited a high specificity to
identify CD patients with a concentration of IFX less than 3 μg/
mL [21]. Thus, once CD patients receive IFX therapy before
surgery, they will have lower CRP level or normal level.
Clinically, we even find some patients have surgical indication
with normal CRP level. So does preoperative CRP level could
still predict outcomes or is it necessary to find some other factors
to predict infectious complications? In our study, the multivariate
logistic regression analysis showed that preoperative ESR level
but not CRP was associated with infectious complications in CD
patients receiving IFX therapy. In fact, ESR is one of the most
widely used indicators of inflammation just as CRP [22].
Preoperative ESR and CRP are demonstrated to be associated
with an increased risk of systemic inflammatory response syn-
drome after surgery [23]. ESR is considered to reflect plasma
acute-phase protein concentrations indirectly, and it is not only
affected by the size, shape, and number of erythrocytes, but also
by other plasma constituents including serum immunoglobulins
[24]. What’s more, the concentration of plasma fibrinogen deter-
mines the level of ESR resulting from acute inflammation.
Because the plasma fibrinogen causes greater cohesion of eryth-
rocytes, it leads to agglutination, rouleaux formation, and faster
Int J Colorectal Dis
rate of sedimentation [25]. In some patients with rheumatoid
arthritis, it was observed that the ESR was elevated in the face
of a normal CRP during treatment [26]. Barnes et al. [24] also
found the discordance between ESR and CRP in children with
IBD treated by azathioprine or 6-mercaptopurine, and the ESR
was elevated with normal CRP level. Therefore, with treatments
of immunosuppressants and biological, the inflammatory cyto-
kines might be inhibited which result to normal CRP levels, but
ESR might still be elevated which represents subclinical inflam-
mation even during periods of clinical remission [1]. In clinic, we
observed that in some patients that have surgical resection with
preoperative IFX therapy, they still had complications such as
stricture or penetrating lesions that required surgery in normal
CRP level due to IFX. So surgeons are advised to be aware of
preoperative ESR level for CD patients receiving IFX with nor-
mal CRP.
However, there are still more patients who had moderate to
severe disease activity that did not use IFX prior to intestinal
surgery, which could affect the reliability of results in the study.
We consider that these patients may have taken IFX in the dis-
ease initiation subsequently secondary nonresponse to it.
Simultaneously, there is another possibility that patients with
penetrating behavior are not allowed to use IFX treatment in
the early stages of the disease. In addition, it may be due to
economic problems and serious condition requiring timely sur-
gery followed receiving top-down treatment.
The current study has several limitations. Firstly, this is a
retrospective observational analysis, and there remain some
residual confounding factors. Secondly, dosage of IFX and
serum drug levels (pharmacokinetic) are not available in this
study, and this might affect the relationship between IFX and
surgical outcomes. Last but not least, a multi-center prospec-
tive observational study is really warranted.
Conclusion
In summary, the present study showed that risk factors asso-
ciated with infectious complications following surgical resec-
tions in CD patients treated with and without infliximab ther-
apy preoperatively were different. Our study indicated that
preoperative ESR and CRP level could predict infectious
complications in CD patients with and without IFX therapy,
respectively. In addition, preoperative use of IFX within
8 weeks of surgery could increase infectious complications
in CD patients.
Acknowledgements The authors gratefully acknowledge all of the inves-
tigators for their contributions to the trial.
Authors’ contributions Xiaolong Ge and Wei Zhou contributed to the
study conception and design; Shasha Tang and Xue Dong contributed
to the acquisition of data; Wei Liu, Weilin Qi, Lingna Ye, and Xiaoyan
Yang contributed to the analysis and interpretation of data; Shasha Tang
Int J Colorectal Dis
and Xue Dong contributed to the drafting of manuscript; Qian Cao,
Xaiolong Ge, and Wei Zhou contributed to the critical revision.
Source of funding This study is supported by grants from the National
Natural Science Foundation of China (81800474), the Zhejiang Natural
Science Foundation (LY18H030006), and the Zhejiang Province
Education Department Foundation (Y201738056).
Compliance with ethical standards
The institutional review board of Sir Run Run Shaw Hospital approved
the project.
Conflict of interest The authors declare that they have no conflict of
interests.
References
1. Torres J, Mehandru S, Colombel JF et al (2017) Crohn’s disease.
Lancet 389(10080):1741–1755
2. Masaki T, Kishiki T, Kojima K, Asou N, Beniya A, Matsuoka H
(2018) Recent trends (2016-2017) in the treatment of inflammatory
bowel disease. Ann Gastroenterol Surg 2(4):282–288
3. Jouvin I, Lefevre JH, Creavin B, Pitel S, Chafai N, Tiret E,
Beaugerie L, Parc Y, Saint-Antoine IBD Network (2018)
Postoperative morbidity risks following ileocolic resection for
Crohn’s disease treated with anti-TNF alpha therapy: a retrospec-
tive study of 360 patients. Inflamm Bowel Dis 24(2):422–432
4. Limketkai BN, Parian AM, Shah ND, Colombel JF (2016) Short
bowel syndrome and intestinal failure in Crohn’s disease. Inflamm
Bowel Dis 22(5):1209–1218
5. Syed A, Cross RK, Flasar MH (2013) Anti-tumor necrosis factor
therapy is associated with infections after abdominal surgery in
Crohn’s disease patients. Am J Gastroenterol 108(4):583–593
6. Kaymak T, Moriconi F, Niess JH, Beglinger C, Hruz P (2018) Low
discontinuation rate of infliximab treatment in steroid-dependent/
refractory Crohn’s disease patients. Inflamm Intest Dis 2(3):171–
179
7. Xu Y, Yang L, An P et al (2018) Meta-analysis: the influence of
preoperative infliximab use on postoperative complications of
Crohn’s disease. Inflamm Bowel Dis 25(2):261–269
8. Kotze PG, Saab MP, Saab B, da Silva Kotze LM, Olandoski M,
Pinheiro LV, Martinez CA, Ayrizono ML, Magro DO, Coy CS
(2017) Tumor necrosis factor alpha inhibitors did not influence
postoperative morbidity after elective surgical resections in
Crohn’s disease. Dig Dis Sci 62(2):456–464
9. Gomollon F, Dignass A, Annese V et al (2017) 3rd European
Evidence-based Consensus on the Diagnosis and Management of
Crohn’s Disease 2016: part 1: diagnosis and medical management.
J Crohns Colitis 11(1):3–25
10. Dindo D, Demartines N, Clavien PA (2004) Classification of sur-
gical complications: a new proposal with evaluation in a cohort of
6336 patients and results of a survey. Ann Surg 240(2):205–213
11. Allegranzi B, Bischoff P, de Jonge S, Kubilay NZ, Zayed B, Gomes
SM, Abbas M, Atema JJ, Gans S, van Rijen M, Boermeester MA,
Egger M, Kluytmans J, Pittet D, Solomkin JS, WHO Guidelines
Development Group (2016) New WHO recommendations on pre-
operative measures for surgical site infection prevention: an
evidence-based global perspective. Lancet Infect Dis 16(12):
e276–e287
12. Shwaartz C, Fields AC, Sobrero M, Cohen BD, Divino CM (2016)
Effect of anti-TNF agents on postoperative outcomes in
inflammatory bowel disease patients: a single institution experi-
ence. J Gastrointest Surg 20(9):1636–1642
13. Kunitake H, Hodin R, Shellito PC et al (2008) Perioperative treat-
ment with infliximab in patients with Crohn’s disease and ulcerative
colitis is not associated with an increased rate of postoperative com-
plications. J Gastrointest Surg 12(10):1730–1736 discussion 1736-
7
14. Billioud V, Ford AC, Tedesco ED, Colombel JF, Roblin X, Peyrin-
Biroulet L (2013) Preoperative use of anti-TNF therapy and post-
operative complications in inflammatory bowel diseases: a meta-
analysis. J Crohns Colitis 7(11):853–867
15. Sandborn WJ, Hanauer SB (1999) Antitumor necrosis factor ther-
apy for inflammatory bowel disease: a review of agents, pharma-
cology, clinical results, and safety. Inflamm Bowel Dis 5(2):119–
133
16. Cornillie F, Shealy D, D’Haens G, Geboes K, van Assche G,
Ceuppens J, Wagner C, Schaible T, Plevy SE, Targan SR,
Rutgeerts P (2001) Infliximab induces potent anti-inflammatory
and local immunomodulatory activity but no systemic immune
suppression in patients with Crohn’s disease. Aliment Pharmacol
Ther 15(4):463–473
17. Ge X, Dai X, Ding C et al (2017) Early postoperative decrease of
serum albumin predicts surgical outcome in patients undergoing
colorectal resection. Dis Colon Rectum 60(3):326–334
18. Zuo L, Li Y, Wang H, Zhu W, Zhang W, Gong J, Li N, Li J (2015) A
practical predictive index for intra-abdominal septic complications
after primary anastomosis for Crohn’s disease: change in C-reactive
protein level before surgery. Dis Colon Rectum 58(8):775–781
19. Zhu Y, Zhou W, Qi W, Liu W, Chen M, Zhu H, Xiang J, Xie Q,
Chen P (2017) Body mass index is a practical preoperative nutri-
tional index for postoperative infectious complications after intesti-
nal resection in patients with Crohn’s disease. Medicine (Baltimore)
96(23):e7113
20. Magro F, Rodrigues-Pinto E, Santos-Antunes J et al (2014) High C-
reactive protein in Crohn’s disease patients predicts nonresponse to
infliximab treatment. J Crohns Colitis 8(2):129–136
21. Boyle MP, Moss AC, O’Toole AM, Vaughn B, Cheifetz AS (2017)
C-reactive protein as a predictor of low trough infliximab concen-
trations in patients who lose response to infliximab. J Dig Dis
18(12):678–683
22. Hyams JS, Mandel F, Ferry GD, Gryboski JD, Kibort PM,
Kirschner BS, Griffiths AM, Katz AJ, Boyle JT (1992)
Relationship of common laboratory parameters to the activity of
Crohn’s disease in children. J Pediatr Gastroenterol Nutr 14(2):
216–222
23. Ganesan V, Brown RD, Jimenez JA et al (2017) C-reactive protein
and erythrocyte sedimentation rate predict systemic inflammatory
response syndrome after percutaneous nephrolithotomy. J Endourol
31(7):638–644
24. Barnes BH, Borowitz SM, Saulsbury FT, Hellems M, Sutphen JL
(2004) Discordant erythrocyte sedimentation rate and C-reactive
protein in children with inflammatory bowel disease taking azathi-
oprine or 6-mercaptopurine. J Pediatr Gastroenterol Nutr 38(5):
509–512
25. Zlonis M (1993) The mystique of the erythrocyte sedimentation
rate. A reappraisal of one of the oldest laboratory tests still in use.
Clin Lab Med 13(4):787–800
26. Amos RS, Constable TJ, Crockson RA et al (1977) Rheumatoid
arthritis: relation of serum C-reactive protein and erythrocyte sedi-
mentation rates to radiographic changes. Br Med J 1(6055):195–
197
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