Diagnostic value of C-reactive protein and procalcitonin for postoperative pancreatic fistula following pancreatoduodenectomy: a systematic review and meta-analysis

Introduction

Pancreaticoduodenectomy (PD) is one of the standard surgical methods used to treat ampullary malignant tumors such as carcinoma of the pancreatic head, carcinoma of the lower common bile duct, and carcinoma of the duodenal papilla (1,2). However, postoperative complications still greatly affect patient recovery, presenting an urgent problem for hepatobiliary and pancreatic surgeons. Pancreatic fistula (PF) is a common and potentially severe complication after PD (3,4). Soft pancreas is an independent risk factor for PF after PD. The main pancreatic duct of soft pancreas is often thin, which makes it difficult to operate and the suture is not firm during PD, thus increasing the risk of PF after PD (2).

Relevant literature shows that the incidence of PF after PD is as high as 30% (5). Furthermore, the occurrence of PF after PD usually leads to other complications (6,7). Both grade B and grade C PF are defined as clinical postoperative pancreatic fistula (POPF) (8). Grade B PF is usually accompanied by abdominal hemorrhage and abdominal infection, while the more severe grade C PF is usually accompanied by organ failure or further complications leading to death. In addition, the occurrence of a POPF will extend the patient’s postoperative hospital stay, affect their postoperative healing, and increase the financial and mental burden placed upon them (9,10).

POPF is a serious postoperative complication, and reducing the incidence of POPF is one of the most effective means to reducing further complications after PD (11). Although there have been a large number of studies on the risk factors of POPF after PD, there is still much controversy, and it is difficult to determine all the clinical variables and related risk factors (12,13). Markers for POPF include procalcitonin (PCT), C-reactive protein (CRP), drain amylase, serum lipase, serum amylase, and white blood cells (WBCs) (14-20). The difficulty arises from the sheer number of factors related to POPF, making it impossible to resolve in a single study.

At present, other systematic reviews have studied the diagnostic value of drain amylase and WBC in predicting POPF after PD (21-24), but there are few systematic reviews on the diagnostic value of CRP and PCT in such cases. CRP is a sensitive marker for judging tissue damage and inflammation. PCT is a marker with high specificity to determine bacterial infection. The purpose of this study is to evaluate the diagnostic value of CRP and PCT in predicting POPF after PD by meta-analysis. We present the following article in accordance with the PRISMA-DTA reporting checklist (available at https://dx.doi.org/10.21037/gs-21-658).

Methods

Literature search strategy

Electronic databases, including PubMed, Excerpta Medica (EMBASE), the Web of Science (WOS), and the China National Knowledge Infrastructure (CNKI) were systematically searched from inception to July 2021 for the following keywords: (I) C-reactive protein (CRP); (II) procalcitonin (PCT); (III) postoperative pancreatic fistula (POPF); and (IV) pancreatoduodenectomy (PD). To broaden the search, numerous combinations of words and strings were applied with the Boolean operators “AND” and “OR”. There were no restrictions on the language of publication in document retrieval. To identify additional eligible studies, we reviewed reference lists from eligible trials and relevant reviews and guidelines. Disagreements were resolved through consensus between the two reviewers.

POPF definition

POPF is defined as any measurable excretion volume with an amylase content greater than three times the upper limit of normal serum, and classified as follows (25):

• Grade A: a temporary fistula with no clinical impact; patient can take orally, and clinical condition is good;
• Grade B: patient receives partial or total parenteral or enteral nutrition support, and usually requires continuous drainage for 3 weeks;
• Grade C: clinical management of fistula changes significantly or deviates from the normal clinical pathway, and radiation intervention or reoperation is required.

In our study, grade B and grade C were defined as clinical POPF.

Study selection

In selecting studies for inclusion in this meta-analysis, we applied the following criteria:

• Study is about patients with PD;
• Study focuses on the value of CRP and/or PCT in the diagnosis of POPF after PD;
• Study directly or indirectly provides the following data: true positive (TP), false positive (FP), false negative (FN) and true negative (TN);
• Study is available in full text.

The exclusion criteria agreed upon were as follows:

• Study does not meet the inclusion criteria;
• Relevant results are not reported or cannot be used;
• Only review or abstract is available, or study is a duplicate publication.

Data extraction and quality assessment

The data extracted from the selected studies included: year of publication, country of origin, sample size, patient age, POPF prevalence, reference standard, and tested variables. The validity of the eligible studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool (QUADAS-2) in the RevMan software suite (version 5.4). Data extraction and quality assessment were performed independently by two reviewers, and disagreements were resolved by consensus.

Statistical analysis

The meta-analysis in our study was performed using RevMan 5.4 (The Cochrane Collaboration, Oxford, UK) and STATA 14.0 (STATA Corp., College Station, TX, USA). We evaluated the degree of statistical heterogeneity and inconsistency by using the Chi 2 and I² statistics. The random-effect model was applied if heterogeneity was observed, while the fixed-effect model was applied in the absence of between-study heterogeneity. In the meta-analysis of diagnostic test accuracy, the threshold effect is one of the important reasons for the heterogeneity. Therefore, if there is a threshold effect, the best way to merge data is to fit the summary receiver operating characteristic (SROC) curve and calculate the area under the SROC curve (AUC) when performing a Meta-analysis to merge effect values. In this study, we all use SROC curve and AUC to judge the diagnostic value. Sensitivity analysis was conducted by eliminating individual studies one by one, and Deeks’ funnel plot was used to identify publication bias when the number of articles included exceeded 10. P>0.05 was considered indicative of no significant publication bias.

Results

Search process

A total of 1,322 potentially relevant articles from electronic databases were retrieved after the literature search. By preliminary screening of the titles and abstracts, we excluded 1,160 documents, which did not meet the inclusion criteria. After full-text screening, a further 142 articles were excluded. Thus, 20 studies met the criteria for inclusion in the present meta-analysis (26-45). The process of literature retrieval is shown in Figure 1.

Figure 1 Flow diagram of study selection in the systematic review and meta-analysis.

Characteristics of included studies

The baseline characteristics of the studies included in the meta-analysis are shown in Table 1. This study includes ten prospective cohort studies and ten retrospective cohort studies consisting of 4,076 patients. All articles were published from 2013 to 2021. POPF prevalence ranged from 7.5% to 26%. All studies adopted the standard of the International Study Group of Pancreatic Surgery (ISGPS) as the reference standard for POPF.

Results of quality assessment

As shown in Figure 2, the QUADAS-2 tool was used to assess the quality of the selected studies, among which two showed a high risk of index test bias, and two others showed a high risk of flow and timing bias. A summary of the risk of bias assessment for each study is shown in Figure 2B.

Figure 2 Overall assessment of risk of bias. (A) Proportion of studies with low, high, or unclear risk of bias; (B) risk of bias summary.

Results of diagnostic accuracy

Given the significant changes in PCT and CRP after PD and the likelihood of different diagnostic values on different postoperative days (PODs), we carried out a subgroup analysis according to POD.

Diagnostic accuracy of CRP

Table 2 shows the results of the meta-analysis of the diagnostic accuracy of CRP in predicting POPF after PD, presented separately for POD 1–5. The highest sensitivity was found on POD 4 (0.85; 95% CI: 0.78–0.91); the highest specificity occurred on POD 3 (0.74; 95% CI: 0.60–0.84); and the highest diagnostic odds ratio (DOR) was found on POD 4 (13; 95% CI: 4–41). Regarding sensitivity and specificity, the highest AUC was also found on POD 4 (0.86; 95% CI: 0.83–0.89). Figure 3 shows the AUC on POD 1–5.

Figure 3 ROC curve plots for the diagnostic accuracy of CRP levels on POD 1–5 for POPF. ROC, receiver operating characteristic; CRP, C-reactive protein; POD, postoperative day; POPF, postoperative pancreatic fistula.

Diagnostic accuracy of PCT

Table 3 shows the results of the meta-analysis of the diagnostic accuracy of PCT in predicting POPF after PD, presented separately for POD 1, 3 and 5, as no study chose to display the diagnostic accuracy of PCT on POD 4, and only 1 study provided data for POD 2, making it impossible to conduct a pooled analysis of POD 2 and POD 4. The results show that the highest sensitivity was found on POD 1 (0.84; 95% CI: 0.72–0.91) and POD 5 (0.84; 95% CI: 0.71–0.92); the highest specificity occurred on POD 3 (0.77; 95% CI: 0.61–0.87); and the highest DOR was found on POD 5 (15; 95% CI: 5–44). Regarding sensitivity and specificity, the highest AUC was also found on POD 5 (0.87; 95% CI: 0.84–0.90). Figure 4 shows the AUC on POD 1, 3 and 5.

Figure 4 ROC curve plots for the diagnostic accuracy of PCT levels on POD 1, 3, 5 for POPF. ROC, receiver operating characteristic; PCT, procalcitonin; POD, postoperative day; POPF, postoperative pancreatic fistula; SROC, summary receiver operating characteristic.

Sensitivity analysis

We conducted a sensitivity analysis by excluding the selected studies one by one and observing whether the results obtained changed significantly. No noticeable changes were observed, indicating that these studies are relatively stable.

Publication bias

We evaluated the publication bias of the selected studies using Deeks’ funnel plot asymmetry test for the diagnostic value of CRP on POD 3. The P value was 0.70, which indicates that no significant publication bias exists in this meta-analysis (Figure 5).

Figure 5 Deeks’ funnel plot asymmetry test for the evaluation of publication bias.

Discussion

POPF is a severe complication of PD, with a high rate of morbidity. The clinically relevant POPF is often accompanied by abdominal cavity infection. Abdominal cavity infection is not only related to POPF, but may also be an important inducing and aggravating factor for the occurrence and development of POPF, but the exact correlation between abdominal cavity infection and POPF is not clear (7).

Current literature shows that many factors determine the risk of developing a PF after PD, including gender, body mass index, diabetes, pancreatic texture, pancreatic duct diameter, intraoperative blood loss, pathological type, anastomosis, neoadjuvant therapy, somatostatin analogues and drainage tube placement (46,47). Based on the above risk factors, several risk prediction scoring systems for POPF have been established, such as the National Cancer Center Hospital (NCCH) POPF prediction scoring system, the Fistula Risk Score (FRS), and the measurement of amylase in postoperative drainage fluid (48,49).

To find a simple and accurate method for assessing POPF, early screening and effective preventive measures for high-risk patients have been the focus of pancreatic surgeons. The detection of blood indexes with high sensitivity and specificity is one of the most reliable predictors of POPF (50). Therefore, clarifying the correlation between early postoperative biochemical sensitive indexes and POPF is of significant clinical value.

Several markers, such as drain amylase, serum lipase, serum amylase and WBC, have been proposed as predictors for POPF (11,17,20,51). Yang et al. (52) found that a value of drain fluid amylase on POD 1 over 1,300 U/L indicated a risk factor for PF, with a pooled sensitivity and specificity of 81% and 87%, respectively. Liu et al. (53) concluded that the drain/plasma pancreatic amylase value on POD 1 was a useful predictive test for overall POPF and clinical POPF with high sensitivity (92%) and specificity (77%) scores. The present meta-analysis aimed to assess the accuracy of CRP and PCT in the prediction of POPF. To date, there have been few studies to assess the pooled performance of CRP and PCT for POPF after PD.

It was found that both CRP and PCT are effective in helping to diagnose POPF and have a high AUC. They could therefore be used as a routine means for diagnosing POPF. Regarding the AUC value: an AUC of 0.5–0.7 suggests low diagnostic accuracy; AUC of 0.7–0.9 suggests medium diagnostic accuracy; and AUC >0.9 suggests high diagnostic accuracy. Our study showed that the AUC of CRP on POD 3–5 was greater than 0.80, especially the AUC of CRP on POD 4, which had a value of 0.86, with a sensitivity and specificity of 0.85 and 0.69, respectively, illustrating the positive diagnostic value of CRP for POPF. The AUC of PCT on POD 5 also showed high diagnostic accuracy for POPF with a value of 0.87, and a sensitivity and specificity of 0.84 and 0.74, respectively.

Several limitations should be noted. The ISGPF published two slightly different versions of POPF in 2005 and 2016 (54,55). Most of the studies included in this meta-analysis adopted the 2005 version, although some adopted the 2016 version, which may impact the results. Secondly, there were differences in the cutoff values of CRP and PCT in each study, which will have a certain impact on the final sensitivity and specificity and consequently affect the results of the AUC. Thirdly, the number of studies on the diagnosis of POPF by PCT was small, and more studies are needed to confirm its accuracy.

In conclusion, CRP and PCT have a high diagnostic value in predicting POPF, especially the CRP levels on POD 4 and PCT levels on POD 5. Given the study’s limitations, more randomized controlled trials should be implemented to provide further unbiased evidence.

Acknowledgments

Funding: This work was supported by research grants from the science and technology plan project for research and development in Chengde (No. 201804A039).

Footnote

Reporting Checklist: The authors have completed the PRISMA-DTA reporting checklist. Available at https://dx.doi.org/10.21037/gs-21-658

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/gs-21-658). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Roberts)