Surgery, Gastroenterology and Oncology

Aim: Anastomotic leakage (AL) is a severe postoperative complication in colorectal surgery, but its preclinical diagnosis may improve outcomes and increase anastomotic salvage. This study aimed to assess the added value of serum biomarkers for early detection of colorectal AL.
Method: We performed a comprehensive literature review, and a qualitative and quantitative analysis of papers retrieved from MEDLINE, Embase, PubMed, Web of Science, Scopus and the Cochrane Library. We included all studies published before September 2021 assessing the serum biomarkers white blood cells (WBC), C-reactive protein (CRP), procalcitonin (PCT) and calprotectin (CLP) for the early diagnosis of AL.
Results: Fifteen studies that evaluated three different systemic biomarkers in the context of AL were identified, including 5150 patients. Diagnostic test accuracy was estimated for CRP and PCT. On postoperative day (POD) 5, the highest AUC (87.1%) and specificity (80.2%) values were estimated for CRP. Random-effects meta-analysis and total effect sizes estimation for the biomarkers CRP, PCT and WBC were performed according to POD. The concentration of serum biomarkers is significantly higher in patients presenting AL. Regarding the qualitative analysis, there was significant heterogeneity in the inclusion of different subcategories of the consensus definition of colorectal AL in each paper's definition.
Conclusion: The serum biomarkers CRP and PCT are moderate predictors for AL, showing a high heterogeneity among the studies. Combinations of these biomarkers might improve predictive accuracy, but more studies will be necessary to conduct a quality metaregression.

INTRODUCTION

Minimal access surgery and standardised recovery protocols have improved patient recovery after colorectal surgery. Regardless of these developments, anastomotic leakage (AL) remains a major complication after colorectal surgery, with a reported incidence ranging from 2 to 7% when surgery is performed by experienced surgeons (1-3), increasing up to 8 to 14% in low colorectal resections (4-6). Early diagnosis of AL is crucial to limit the clinical consequences of this complication, allowing its prompt treatment (4,5). AL contributes to possible patient morbidities, hospital re-admissions and overall healthcare costs. Furthermore, complications such as AL and reoperations are considered a quality indicator in colorectal surgery (6).
Although some risk factors have been identified and reported, it remains difficult to predict the development of AL in individual patients (7). Intraabdominal sepsis can be similar to physiological systemic inflammatory response syndrome (SIRS) to surgery, especially in the immediate postoperative period (8). This leads to a delay in clinical diagnosis, increasing the risk of patients being discharged before diagnosis and then readmitted with AL (7,8). Late detection of AL may lead to the development of sepsis, multiple organ dysfunction or death. Thus, early diagnosis of AL, at the asymptomatic stage, is of paramount importance. Several studies have suggested the use of serum biomarkers to ease the early detection of postoperative septic complications. In colorectal surgery, some biomarkers have been identified for detecting various stages of early ischaemia, inflammation and necrosis (9). Eosinopenia has been proposed as a biomarker that might help to identify several sepsis-related conditions, distinguished from other causes of SIRS (10). Serum C-reactive protein (CRP) has been shown to have a strong correlation with postoperative complications, including abdominal surgery (11,12). The usefulness of procalcitonin (PCT) has been highlighted as an earlier, more sensitive and more reliable biomarker of AL, even before symptoms appear. Moreover, PCT and CRP have been demonstrated to have a good negative predictive value for AL (13,14). Calprotectin (CLP) can be a biomarker for amplified inflammation early in major abdominal complications. There are currently few studies that have investigated CLP as a predictor for AL. Reisinger et al. showed that CLP is a better biomarker for detecting AL than CRP (15). However, data regarding the diagnostic accuracy of the combination of clinical and laboratory markers for the diagnosis of AL is still scarce. Further studies are needed to ascertain whether the addition of serum biomarkers can improve the early diagnosis of AL. This systematic review and metaanalysis aimed to assess the added value of the serum biomarkers CRP, PCT, CLP and white blood cells (WBC) for the early detection of AL after colorectal surgery.

METHOD

The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Transparent Reporting of Systematic Reviews and Meta-Analysis guideline (16), with PROSPERO registration number 161692.

Literature search

A comprehensive search was performed in MEDLINE, Embase, PubMed, Web of Science, Scopus and Cochrane databases, including the following controlled terms from MeSH: Eosinophils OR C-reactive protein OR Procalcitonin OR Calprotectin AND Colon OR Rectum OR Surgery OR Morbidity. Research articles published until 31st of August 2021, restricted to humans and written in English were considered and included in this study. Review articles were excluded. Additionally, references from the published literature that met the inclusion criteria were identified by searching relevant papers, systematic reviews, and meta-analyses manually. The results of all searches were combined to eliminate duplicate articles. The abstracts obtained by the search were used by two reviewers (N.R. and I.G.) independently to select suitable articles, after which the full-text versions were retrieved and independently reviewed for inclusion by the two reviewers.

Study selection

Studies were assessed for inclusion independently by two authors, and any disagreements over inclusion and exclusion were resolved by consensus. Studies were included if they met the following Population, Intervention, Comparison, Outcomes and Study (PICOS) criteria: (1) patients over the age of 18 years; (2) intervention included colorectal surgical procedure with resection and anastomosis, with or without a protective stoma, regardless of the pathology that motivated the procedure, as well as the elective or urgent character; (3) the comparison group was patients without AL; (4) outcomes assessed were AL rate, area under the receiver operating characteristic (ROC) curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV); (5) studies with different designs as presented in table S1 (Supplementary Material).

Table S1 - Design of the included studies
Randomised Controlled Trials
Cluster-Randomised Controlled Trials
Non-Randomised Cluster Controlled Trials
Controlled Before and After Studies
Interrupted Time Series
Before-After Study without a Control Group
Comparative Studies with Historical Controls

Data Extraction

Data were extracted by three authors (N.R., M.G., M.L.) and entered predefined tables. The primary outcome of interest was AL, defined as reported in the studies included. The measure of diagnostic accuracy, namely, ROC curve, AUC, sensitivity, specificity, PPV and NPV, were recorded in order to perform a diagnostic meta-analysis. Data reported in the text, graphs or figures of the studies were used to obtain the median or mean biomarker values on each postoperative day (POD) for the following patient groups: those with AL, any infectious complication, and no complications. Corresponding authors were contacted to obtain the necessary data when it was not made available from the article or supplementary material.

Quality assessment

Quality assessment of the studies was performed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 2 tool (17). The QUADAS 2 tool assessed the risk of bias and concerns about applicability in four key domains: patient selection, index test, reference standard, and flow of patients through the study and timing of tests, classifying them as low risk, unclear risk and high risk. The tool was tailored to suit the content of studies and the purpose of this review and applied independently by three authors (N.R., M.G., M.L.).

Data analysis and synthesis

To summarise and compare studies, where available, mean and standard deviation (SD) values for each biomarker in two groups of patients (AL and without AL) were directly pooled and analysed with standardised mean differences (SMDs), mean differences (MDs) and 95% confidence intervals (CIs) (18). Measures of diagnostic accuracy, including area under ROC, AUC, sensitivity, specificity, PPV and NPV, were recorded to enable a diagnostic meta-analysis to be performed. Study-specific estimates were pooled using randomeffect models. Two sets of meta-analyses were performed based on the biomarker, and POD.
The statistical heterogeneity among studies was assessed using the I2 index (19), thus reporting the percentage of variation in the global estimate that was attributable to heterogeneity (I2 = 25%: low; I2 = 50%: moderate; I2 = 75%: high).
Forest plots were created to illustrate the effects in the meta-analysis of the different studies and the global estimation. R (R Core Team, 2020) and RStudio (RStudio Team, 2020) were used to perform all analyses. The R package meta was used to conduct standard meta-analysis (20), and the R package mada was used for meta-analysis of diagnostic accuracy (21). Statistical significance was defined as a p value <0.05.
Qualitative methods were used to analyse the degree of conceptual agreement of the different AL definitions used in the included studies, based on a recently established consensus definition (22). Different conceptual categories of the consensus were considered, and each individual definition was split and whether each category was mentioned was recorded.

RESULTS

A PRISMA flowchart illustrating the selection of articles included in this systematic review is presented in fig. 1. Fifteen studies (12–14,23–34) met the defined inclusion criteria and had adequate data to be included in the meta-analysis.

Study characteristics

The characteristics of the fifteen included studies are summarised in table 1. All studies included patients undergoing both colonic and rectal surgery. Ten of the fifteen studies were prospective studies.

Risk of bias

The results from the QUADAS-2 assessment are shown in table 2. Eight studies (12,23–26,28,30,34) reported measuring CRP routinely during the postoperative period, whereas the other seven (13,14,27, 29,31–33) did not have CRP data available for all patients on each day. Only two studies (28,30) measured PCT daily in the postoperative period, and four studies (12,24,28,34) had WBC count data available daily after surgery. Only one study (29) reported blinding of surgeons to the results of CRP assays. The included studies had different definitions of AL (table 3) and not all patients had this complication diagnosed by the same reference standard.


Definition of anastomotic leakage

Definition of AL according to the included studies showed variations that are presented in table 3. Tables S2 to S3 (Supplementary Material) represent the results of the qualitative analysis performed. Considering the consensus-based recommendation for the definition of AL established in the study of van Helsdingen et al. (22), the different definitions presented in the selected studies were divided into three categories: clinical, radiological, and surgical findings. Regarding clinical criteria, only one study (31) covers all of the defined subcategories, and among these, drainage of faeces or other suspicious contents was considered in thirteen of the fifteen studies. Most studies did not include three of the four consensus clinical subcategories in the definition. In terms of radiological criteria, six studies integrate the subcategories "extravasation of contrast" and "abscess near anastomosis" in the definition. Six studies state that perianastomotic air is a suggestive sign of AL, and none of them considered the presence of intraperitoneal air as a diagnostic criterion. Finally, operative findings were considered in eleven studies, and each one mentioned up two subcategories: “signs of peritonitis” and “surgical evidence of dehiscence”. In selected studies, neither blind loop nor perianastomotic necrosis were considered as diagnostic criteria for AL. The AL rate in the included studies ranged from 2% (32) to 15% (29).

Diagnostic WBC accuracy for AL

The results of random-effects meta-analysis including two studies measuring WBC are shown in fig. S1 (Supplementary Material). Subgroups metaanalysis was performed according to POD 2 and 4, with low global heterogeneity (I2 = 0%; p = 0.82). The pooled average WBC level on each POD for patients with and without AL are shown in fig. S2 (Supplementary Material). A meta-analysis of the predictive value of WBC for AL was not possible due to the lack of available data in the selected studies.







Diagniostic CRP accuracy for AL

The results of random-effects meta-analysis considering the different studies measuring CRP are presented in fig. 2. Subgroups meta-analysis was performed according to POD 1 to 7, with a global heterogeneity statistic I2 values of 85% (p < 0.01), which is indicative of high between-study hetero-geneity, and a prediction interval that crosses the line of no effect. The comparison of pooled average CRP levels on each POD for patients with and without AL are presented in fig. 3.


Ten studies were selected in the subgroups metaanalysis of CRP accuracy for AL (POD 3 to 5), with a pooled prevalence of AL ranging from 5.9 to 7.7% (table 4). Pooled AUC values on POD 3 and 5 ranged from 77.9 to 87.1% and had similar diagnostic accuracy for AL (fig. S3 - Supplementary Material). The highest pooled sensitivity and specificity were found on POD 5 (79.4 and 80.2% respectively). At these three timepoints, pooled PPV and NPV ranged from 21.4 to 30.7%, and from 96.2 to 97.4%, respectively, showing low and moderate heterogeneity, except for POD 3. The positive likelihood ratio (LR) for CRP varied from 2.7 to 4.1, and the negative LR was between 0.30 and 0.36. The derived cut-offs on POD 3 and 5 were 150.7 ± 30.5 and 103.5 ± 35.9 mg/L, respectively.

Diagnostic PCT accuracy for AL

Random-effects meta-analysis for PCT are shown in fig. 4 with subgroups meta-analysis for POD 1 to 5. Global heterogeneity was moderate (I2 = 60%; p = 0.13) and the prediction interval crossed the line of no effect. The pooled average PCT level on each POD for patients with and without AL are shown in fig. S4 (Supplementary Material).


Five studies were selected in the subgroups metaanalysis of PCT accuracy for AL (POD 3 and 5), with a pooled prevalence of leakage that ranged from 6.5 to 7.8% (table 4). Pooled AUC values on POD 3 and 5 ranged from 79.3 to 83.1% and had similar diagnostic accuracy for AL (fig. S5 - Supplementary Material). The highest pooled sensitivity (80.7%) and specificity (84.9%) were found on POD 5. At these two time-points, PCT had a low pooled PPV between 26.9 and 36.1%, with moderate and high heterogeneity, and a high pooled NPV of 97.9% on POD 3, presenting low heterogeneity. The positive LR for PCT ranged between 3.9 and 5.86, and the negative LR ranged from 0.2 to 0.3. Derived cut-offs on POD 3 and 5 were 1.8 +-2.0 and 1.2 +-1.1 ng/mL, respectively.


DISCUSSION

Over the past 10 years, few systematic reviews and meta-analyses have evaluated the role of biomarkers in the early diagnosis of AL in colorectal surgery. Su'a et al. (35) analysed both peritoneal drain fluid and systemic biomarkers that are increased in the AL environment, finding an improvement in predictive accuracy when combining these biomarkers.
This systematic review and metaanalysis demonstrated that the diagnostic accuracy of CRP and PCT was similar on all days and showed higher values on POD 5, being superior for CRP with a value of 87.1%. Systemic biomarkers were moderate predictors of AL when assessed individually. Nevertheless, a combination of biomarkers could increase the predictive accuracy, but data meta-regression was not possible due to the small number of selected studies.
Singh et al (7) showed that serum CRP is a useful negative predictive test for detecting AL after colorectal surgery, but not a good positive predictor. In this study, the NPV of serum biomarkers was calculated and proved to be high and useful as a predictive indicator for AL exclusion. In fact, increased CRP and PCT may result from other clinical conditions, postoperative complications, and systemic inflammatory response. Hence, the clinical usefulness of biomarkers is based on the probability of ruling out an AL when a patient had a negative test (lower CRP and PCT level) on POD 3 and 5. In daily practice, this estimated high NPV is critical for ensuring safe early discharge.

The LR is a useful tool for clinical decision-making as these values are test-specific and independent of the prevalence and are more reliable as a single test for an individual patient. Therefore, LR provides relevant information applied to a variety of patient characteristics, as it can provide probabilities adjusted to each case, using information obtained from populations, institutions or surgeon's personal data. The usefulness of LR for AL detection reflects the ability to change a pre-test probability to a new post-test probability, considering the systemic biomarker measured, in relation to the estimated cut-off. In this study, the positive LR for PCT showed a good impact on the clinical decision, as a “rule-in” and “rule-out” test for AL. Moreover, LR calculated for CRP presented a moderate impact on the decision-making process, being relevant as a "rule-out" test.


In this random-effects meta-analysis, interstudy heterogeneity varied according to the biomarker measured, being high in the CRP studies. This important limitation can result from the differences in the patient population, study design and risk of bias. Five studies are retrospective, but only two of the prospective studies did not show investigation bias (blinded surgeons). Furthermore, not all biomarker assays were performed in a standardised manner for the same POD. The qualitative analysis detected inconsistencies in AL definitions, leading to a relevant verification bias. Both CRP and PCT had a prediction interval that crosses the line of no effect, reflecting the uncertainty expected in the summary effect if a new study is included in the meta-analysis. Only six studies measuring PCT were included, making the prediction interval particularly imprecise. The reduced number of studies assessing WBC and PCT did not support a meta-regression, which would be able to minimise the observed heterogeneity. A further limitation of the studies is that no analytic study was made between colonic and rectal procedures, which might also be responsible for different postoperative inflammatory reactions.
This review distinguishes itself from others that have been published previously. First, we only selected studies including a range of systemic biomarkers, mainly prospective, which can be useful in daily practice. However, rigorous inclusion criteria excluded the only eligible CLP study, and the scarce WBC studies available hampered relevant conclusions. Secondly, we decided not only to conduct a random-effects metaanalysis, but also to present and discuss the predictive interval, assuming its usefulness and potential drawbacks. Finally, a qualitative analysis of AL definitions in the selected studies was performed, based on the recommendation recently published (22), revealing remarkable conceptual heterogeneity.
The cost-effectiveness of these tests is a critical subject to be considered in further studies. Blood tests included in the postoperative routine are probably costeffective given the high cost of late treatment of AL. Furthermore, it is important to assess the combination of biomarkers to raise the accuracy of the test, as well as to define the best time to request them, considering the clinical approach. Our review and meta-analysis demonstrated that CRP and PCT are moderate predictors of AL in colorectal surgery. It is important for clinicians to be familiar with the role of biomarkers and their benefits. Despite a lack of evidence, it is interesting to note that some biomarkers have been used in clinical practice to predict AL. In this study, we found higher serum levels of systemic biomarkers in the group of patients presenting AL. However, these results should be interpreted with caution due to significant heterogeneity among the studies. Many questions remain regarding the usefulness of each biomarker both for early detection of AL and for assuring safe discharge of patients in this context, making their clinical application challenging.

Statement

Anastomotic leakage (AL) is a life-threatening condition after colorectal surgery. Its early detection is still challenging in clinical practice. This manuscript provides a quantitative analysis for some serum inflammatory biomarkers, suggesting their usefulness for the early detection of AL. Besides, a qualitative analysis of the definition of AL was performed.

Conflicts of interest

We declare no conflicts of interest.

Funding statement

No funding has been received by any author in relation to this article.

Ethical approval

No ethics committee or institutional review board approval.

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