Severity of early diagnosed organ/space surgical site infection in elective gastrointestinal and hepatopancreatobiliary surgery

Abstract Background Organ/space surgical site infection (SSI) is a significant clinical problem. The postdiagnosis course of organ/space SSIs and the impact of its early diagnosis on clinical outcomes are yet to be clarified. Thus, we aimed to investigate the association between the timing of diagnosis and the clinical outcome of organ/space SSI. Methods This retrospective, single‐center cohort study evaluated patients who underwent elective gastrointestinal or hepatopancreatobiliary surgery between 2016 and 2020. Clinical outcomes were compared between the early group (ie, SSI diagnosed until postoperative day [POD] 4) and normal‐late group (ie, SSI diagnosed after POD 5). The primary outcome was the final C‐reactive protein (CRP) level within 14 d after organ/space SSI diagnosis. Results In total, 110 patients were evaluated. The median time of diagnosis was 7 d postoperatively (interquartile range, 5–9 d postoperatively). Compared with the normal‐late group, the early group included a higher proportion of patients with Clavien–Dindo grade ≥IIIb (8/21 vs 11/89, P = .01), higher final CRP value within 14 d after SSI diagnosis (mean, 4.49 mg/dL vs 2.27 mg/dL, P = .01), longer postoperative length of hospitalization (median, 45.0 d vs 33.0 d; P = .028), and worse 1‐y overall survival rate (74.8% vs 89.3%, P = .08). Conclusion Early diagnosed organ/space SSI are originally severe and may therefore be detected earlier. Importantly, early diagnosed organ/space SSI is likely to be severe and refractory.

treatment are speculated to improve the outcomes of organ/space SSI, but diagnosis in the early postoperative period is challenging. 3 A previous study reported that an anastomotic leak in colorectal surgery was diagnosed within a mean of 8.8 d postoperatively. 4 Delayed diagnosis is mainly attributed to the fact that organ/ space SSIs become apparent only after the development of clinical symptoms. 5 Flooden et al suggested that more severe leakages cause symptoms earlier, whereas less severe leakages take longer to develop symptoms. 6 In addition, Morks et al reported that early anastomotic leakage is associated with a higher probability of relaparotomy than late anastomotic leakage. 7 Many predictive models using postoperative inflammatory markers have been developed for the early detection of organ/space SSIs. 8 However, no study to date has evaluated the postdiagnosis course of organ/space SSIs that could actually be diagnosed early.
Thus, this study aimed to investigate the association between the timing of diagnosis and clinical outcome of organ/space SSI in patients who have undergone either elective gastrointestinal (GI) or hepatopancreatobiliary (HPB) surgery. In particular, we focused on daily changes in C-reactive protein (CRP) levels after diagnosis and subsequent treatment of organ/space SSIs.

| Study design
This retrospective, observational, single-center study was con- The need for informed consent was waived owing to the retrospective nature of the study.

| Patient selection
The study included patients who underwent elective gastrointestinal and hepatopancreatobiliary surgery with general anesthesia between January 1, 2016, and December 31, 2020. Patients who underwent liver transplant, hernia repair, and abdominal surgery not involving the GI tract or biliary system (eg, adhesive small bowel surgery without intestinal resection, abdominal irrigation for generalized peritonitis, and laparotomy hemostasis) were excluded. Liver transplant was excluded due to the heterogeneous nature of the surgery. In addition, we excluded patients in whom only ileostomy or colostomy was performed because these surgeries have no risk of organ/space SSI. Finally, we also excluded emergency cases because they have a significantly different mechanism of postoperative intraabdominal infection.
Surgical procedures were classified according to the Japan Nosocomial Infections Surveillance (JANIS) 10 surgical classification criteria (Table S1). For patients who underwent simultaneous multiorgan surgeries, only the primary procedure was recorded as the surgical procedure.

| Statistical analysis
Univariate analysis was performed to examine the background differences between organ/space SSIs diagnosed until POD 4 (early diagnosis group) and after POD 5 (normal-late diagnosis group).
There were several reasons for adopting this division. First, in our previous study the median diagnosis date of organ/space SSI was POD 6 (interquartile range, 4-9 d). 8 Second, postoperative laboratory tests are likely to be performed on odd days in our hospital.
Considering the division by odd-numbered days, we thought it was appropriate to set POD 1-4 as the cutoff to define the early diagnosis group.
Continuous variables were presented as the means and standard deviations (SDs) and analyzed using a t-test. Meanwhile, categorical variables were presented as frequencies and proportions and analyzed using Fisher's exact test. Length of hospitalization and duration of operation were expressed as median and interquartile range and was analyzed using the Mann-Whitney U test. As a supplement, the date of diagnosis by type of organ/space SSI, the date of diagnosis by type of surgical procedure, and final laboratory test date by the date of diagnosis were expressed as median and interquartile range and were analyzed using the Kruskal-Wallis test. Further, organ/space SSI diagnosis date was divided into 2 d and plotted the transition of WCC and CRP for 14 d after the start of organ/space SSI treatment. The reason for dividing by 2 d was that postoperative laboratory tests are likely to be performed on odd days in our hospital. In addition, a local regression line generated using the locally estimated scatterplot smoothing method with 95% confidence interval (CI) was added. 15 The 1-y overall survival rate was determined by generating Kaplan-Meier survival curves and then comparing these between the two groups using the log-rank test and the Cox proportional hazard model. The hazard ratio (HR) with a 95% CI was estimated.
All statistical analyses were performed using R statistical software v. 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). All P-values were two-tailed, and statistical significance was set at P < .05.
The median date of diagnosis by type of surgical procedure is shown in Figure S2 and there were no significant differences among procedure types (P = .83).
In total, 21 patients (19.1%) and 89 patients (80.9%) were categorized into the early and normal-late diagnosis groups, respectively. The results of univariate analysis are shown in Tables 2 and 3. Postdiagnosis changes in CRP and WCC were followed for 14 d. Figure S3, the median final laboratory test date was above day 13 in all five groups (POD 1-2, POD 3-4, POD 5-6, POD 7-8, and POD9-). The mean final CRP and WCC values within 14 d tended to increase with an earlier diagnosis date ( Figure 2). The final CRP value was significantly higher in the early diagnosis group than in the normal-late group (mean, 4.49 mg/dL vs 2.27 mg/dL; P = .01, Table 3). The average CRP and WCC values tended to be higher 14 d after diagnosis in the early diagnosis group (Figure 3). Figure 4.

The 1-y Kaplan-Meier survival curve is shown in
Overall, 14 events occurred in our cohort, five events in the early group, and nine events in the normal-late group. The cause of death is shown in

| DISCUSS ION
The postdiagnosis course of organ/space SSIs and the impact of its early diagnosis on clinical outcomes are yet to be clarified. In this study, the median time between surgery and diagnosis was 7 d (interquartile range, 5-9 d). Compared with the normal-late diagnosis group, the early diagnosis group had a longer median postoperative length of hospitalization, a higher proportion of patients with Clavien-Dindo grade ≥IIIb complications, higher final CRP value within 14 d after organ/space SSI diagnosis, and worse overall survival rate. These findings suggest that early diagnosed organ/space SSI cases were originally severe and may, therefore, be detected earlier.
The most important clinical implication of this study is that physicians should be aware that early diagnosed organ/space SSI is likely to be severe and refractory. The early diagnosed group had a worse overall survival rate than did the normal-late group (74.8% vs 89.3%, P = .08). Given that these patients showed prominent clinical manifestations from the early postoperative period, organ/space SSI may have been detected early. Notably, considering the expanded use of Another clinical implication of this study is that the normal or latediagnosed organ/space SSI cases are less likely to become severe. We processed Japan nosocomial infections surveillance (JANIS) data in 2020 (available at: https://janis.mhlw.go.jp/engli sh/index.asp. Accessed August 31, 2021).
JANIS is the national survey in Japan, in which 2418 hospitals participated. Surgical procedures are classified according to JANIS surgical classification criteria (See Table S1).
*JANIS does not separate elective and emergency cases for organ/space SSI. We compared the incidence of organ/space SSI including both types of surgery in Table S4. Continuous variables were analyzed by Welch's t-test, and categorical variables were analyzed by Fisher's exact test. Duration of operation was expressed in median and interquartile range, and was analyzed by Mann-Whitney U test.

F I G U R E 1
Surgical procedures are classified according to Japan nosocomial infections surveillance (JANIS) surgical classification criteria (See Table S1). findings support that prolonged CRP elevation is an important indicator of severity, and thus, it is reasonable to evaluate CRP levels.
Additionally, we also investigated the trends in WCC, and the early diagnosed group showed a bimodal curve. The delayed second peak occurred around day 8 after diagnosis, implying severe SSI in the early diagnosis group.
Unlike previous studies that used a combination of primary outcomes, such as in-hospital mortality, cardiovascular complications, incisional SSI, and postoperative remote infections (eg, pneumonia, postoperative urinary tract infections), [22][23][24][25] our study focused on organ/space SSI, which is another strength of the present study.
When a composite outcome is adopted, it is sometimes difficult to make a clinical interpretation because of the diverse treatment.
There are also several options for the management of organ/space SSI; these include antibiotics, bowel rest, percutaneous drainage, and relaparotomy. Further, we focused on organ/space SSIs, due to their severity. Finally, our study has the advantage of accurate observation of organ/space SSI patients owing to its single-center setting.
However, this study also had some limitations. In this study, Clavien-Dindo Grade V was defined as death caused by organ/space SSI during the same hospitalization stay.
Surgical procedures are classified according to Japan nosocomial infections surveillance (JANIS) surgical classification criteria (See Table S1). hospitals, we decided to use the CDC definitions for all types of resection organs. 11 The incidence of organ/space SSI in this study was comparable to that of the national survey in 2020.
Unfortunately, JANIS does not separate elective and emergency cases for organ/space SSI; therefore, we compared the incidence of organ/space SSI without excluding emergency cases (Table S4).
However, in our previous study based on the same SSI criteria, the median time between surgery and the diagnosis of organ/space SSI was 6 d (interquartile range, 4-9 d), 8 which is not highly different from the 7 d (interquartile range, 5-9 d) in this study. These results show that there is no significant difference between our hospital and other facilities in Japan.