Langenbeck's Archives of Surgery

, Volume 403, Issue 2, pp 235–244 | Cite as

Utility of C-reactive protein as predictive biomarker of anastomotic leak after minimally invasive esophagectomy

  • Emanuele Asti
  • Gianluca Bonitta
  • Matteo Melloni
  • Stefania Tornese
  • Pamela Milito
  • Andrea Sironi
  • Elena Costa
  • Luigi Bonavina



Early detection of anastomotic leakage after esophagectomy has the potential to reduce morbidity and mortality. Prompt suspicion of leak may help to exclude patients from fast-track protocols, thereby avoiding early oral feeding and early hospital discharge which could aggravate the prognosis of a clinically occult leak.

Patients and methods

Observational retrospective cohort study. Patients with diagnosis of esophageal cancer who underwent elective minimally invasive esophagectomy were included. The following data were collected: age, gender, BMI, comorbidities, ASA score, tumor histology, TNM staging, use of neo-adjuvant therapy, type of operation, operative time, morbidity, and 90-day mortality. A panel of biomarkers including C-reactive protein (CRP), procalcitonin (PCT), white blood cells (WBC), and percentage of neutrophils (PN) were measured at baseline and on postoperative days 3, 5, and 7.


Two hundred forty-three patients operated between 2012 and 2017 were included in the study. Anastomotic leakage occurred in 29 patients. There was a statistical association over time between anastomotic leakage and CRP (p < 0.001), PCT (p < 0.001), WBC (p = 0.019), and PN (p = 0.007). The cut-off value of CRP on POD 5 was 8.3 mg/dL, AUC = 0.818, negative LR = 0.176.


Increased serum CRP, PCT, WBC, and PN after minimally invasive esophagectomy are associated with anastomotic leakage. A CRP value lower than 8.3 mg/dL, combined with reassuring clinical and radiological signs, may be useful to exclude leakage on postoperative day 5.


Esophagus Esophagectomy Anastomotic leakage C-reactive protein 



This work was supported by AIRES (Associazione Italiana Ricerca Esofago).

Authors’ contribution

Authorship EA, GB, MM, ST, PM, AS, EC, and LB participated in the acquisition, analysis, or interpretation of data for the work and drafting or revising it critically for important intellectual content; gave final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity in any part of the work are appropriately investigated and resolved.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

423_2018_1663_MOESM1_ESM.docx (19 kb)
ESM 1 (DOCX 19 kb)


  1. 1.
    Schmidt HM, Gisbertz SS, Moons J, Rouvelas I, Kauppi J, Brown A, Asti E, Luyer M, Lagarde SM, Berlth F, Philippron A, Bruns C, Hölscher A, Schneider PM, Raptis DA, Henegouwen MIB, Nafteux P, Nilsson M, Räsanen J, Palazzo F, Rosato E, Mercer S, Bonavina L, Nieuwenhuijzen G, Wijnhoven BPL, Schröder W, Pattyn P, Grimminger PP, Gutschow CA (2017) Defining benchmarks for transthoracic esophagectomy. A multicenter analysis of total minimally invasive esophagectomy in low risk patients. Ann Surg 266(5):814–821. CrossRefPubMedGoogle Scholar
  2. 2.
    Low DE, Alderson D, Cecconello I, Chang A, Darling GE, Benoit D’Journo X et al (2015) International consensus on standardization of data collection for complications associated with esophagectomy. Ann Surg 262:286–294CrossRefPubMedGoogle Scholar
  3. 3.
    Kassis ES, Kosinski AS, Jr RP, Koppes KE, Donahue JM, Daniel VC (2013) Predictors of anastomotic leak after esophagectomy: an analysis of the society of thoracic surgeons general thoracic database. Ann Thorac Surg 96:1919–1926CrossRefPubMedGoogle Scholar
  4. 4.
    Bonavina L, Scolari F, Aiolfi A, Bonitta G, Sironi A, Saino G, Asti E (2016) Early outcome of thoracoscopic and hybrid esophagectomy: propensity-matched comparative analysis. Surgery 159:1073–1081CrossRefPubMedGoogle Scholar
  5. 5.
    Biere SS, van Berge Henegouwen MI, Bonavina L, Rosman C, Roig Garcia J, Gisbertz SS, van der Peet DL, Cuesta MA (2017) Predictive factors for post-operative respiratory infections after esophagectomy for esophageal cancer: outcome of randomized trial. J Thorac Dis 9:S861–S867CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Straatman J, Harmsen AM, Cuesta MA, Berkhof J, Jansma EP, Van der Peet DL (2015) Predictive value of C-reactive protein for major complications after major abdominal surgery: a systematic review and pooled-analysis. PLoS One 10:e0132995CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Adamina M, Steffen T, Tarantino I, Beutner U, Schmied BM, Warschkow R (2015) Meta-analysis of the predictive value of C-reactive protein for infectious complications in abdominal surgery. Br J Surg 102:590–598CrossRefPubMedGoogle Scholar
  8. 8.
    Hoeboer SH, Groeneveld AB, Engels N, Van Genderen M, Wijnhoven BPL, Van Bommel J (2015) Rising C-reactive protein and procalcitonin levels precede early complications after esophagectomy. J Gastrointest Surg 19:613–624CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Miki Y, Toyokawa T, Kubo N, Tamura T, Sakurai K, Tanaka H, Muguruma K, Yashiro M, Hirakawa K, Ohira M (2017) C-reactive protein indicates early stage of postoperative infectious complications in patients following minimally invasive esophagectomy. World J Surg 41:796–803CrossRefPubMedGoogle Scholar
  10. 10.
    Park JK, Kim JJ, Moon SW (2017) C-reactive protein for the early prediction of anastomotic leak after esophagectomy in both neo-adjuvant and non-neoadjuvant therapy case: a propensity score matching analysis. J Thorac Dis 9(10):3963–3702Google Scholar
  11. 11.
    Findlay JM, Tilson RC, Harikrishnan A, Sgromo B, Marshall REK, Maynard ND, Gillies RS, Middleton MR (2015) Attempted validation of the Nun score and inflammatory markers as predictors of esophageal anastomotic leak and major complications. Dis Esophagus 28:626–633CrossRefPubMedGoogle Scholar
  12. 12.
    Bonavina L, Asti E, Sironi A, Bernardi D, Aiolfi A (2017) Hybrid and total minimally invasive esophagectomy: how I do it. J Thorac Dis 9:S761–S772CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Fitzmaurice GM, Laird NM, Ware JH (2011) Applied longitudinal analysis. Wiley, HobokenGoogle Scholar
  15. 15.
    Youden WJ (1950) Index for rating diagnostic tests. Cancer 3:32–35CrossRefPubMedGoogle Scholar
  16. 16.
    Agresti A, Coull BA (1998) Approximate is better than “exact” for interval estimation of binomial proportions. Am Stat 52:119–126Google Scholar
  17. 17.
    Simel DL, Samsa GP, Matchar DB (1991) Likelihood ratios with confidence: sample size estimation for diagnostic test studies. J Clin Epidemiol 44:763–770CrossRefPubMedGoogle Scholar
  18. 18.
    Šimundić AM (2009) Measures of diagnostic accuracy: basic definitions. EJIFCC 19:203–211PubMedPubMedCentralGoogle Scholar
  19. 19.
    Sloane P, Slatt L, Ebell NH, Smith MA, Power DV, Viera AJ (2012) Essentials of family medicine, 6th edn. Walters Kluwer. Health, PhiladelphiaGoogle Scholar
  20. 20.
    R Core Team Development (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  21. 21.
    Singh PP, Zeng IS, Srinivasa S, Lemanu DP, Connolly AB, Hill AG (2014) Systematic review and meta-analysis of use of serum C-reactive protein levels to predict anastomotic leak after colorectal surgery. Br J Surg 101:339–346CrossRefPubMedGoogle Scholar
  22. 22.
    Motoyama S, Miura M, Hinai Y, Maruyama K, Usami S, Nakatsu T, Saito H, Minamiya Y, Suzuki T, Ogawa JI (2009) C-reactive protein 1059G>C genetic polymorphism influences serum C-reactive protein levels after esophagectomy in patients with thoracic esophageal cancer. J Am Coll Surg 209:477–483CrossRefPubMedGoogle Scholar
  23. 23.
    Frees EW (2006) Longitudinal and panel data: analysis and applications in the social sciences. J Am Stat Assoc 101(March):402–402.

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biomedical Sciences for Health, Division of General Surgery, IRCCS Policlinico San DonatoUniversity of MilanSan Donato Milanese (Milano)Italy

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