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Digestive Diseases and Sciences

, Volume 61, Issue 8, pp 2294–2302 | Cite as

Dysfunction of Circulating Polymorphonuclear Leukocytes and Monocytes in Ambulatory Cirrhotics Predicts Patient Outcome

  • Konstantina Sargenti
  • Åsa Johansson
  • Sara Bertilsson
  • Inger Mattsby-Baltzer
  • Daniel Klintman
  • Evangelos Kalaitzakis
Original Article

Abstract

Background

Cirrhosis represents a state of functional immune paresis with increased infection risk.

Aims

To investigate polymorphonuclear (PMN) leukocyte and monocyte function in ambulatory cirrhotics, and their potential relation with cirrhosis etiology or patient outcome.

Methods

Consecutive ambulatory cirrhotics without current or recent (<1 month) infection or acute decompensation were prospectively enrolled in 2013 and followed for a median time of 20 months until death, transplant or end of 2014. Oxidative burst and phagocytosis of circulating PMNs and monocytes were investigated at baseline and after in vitro Escherichia coli stimulation. Seventeen healthy blood donors served as controls. Baseline clinical and laboratory data as well as follow-up data on the development of cirrhosis complications, including acute-on-chronic liver failure (ACLF), and bacterial infections were collected.

Results

Sixty patients were included (70 % male, median age 63 years, 52 % with alcoholic cirrhosis). Compared to controls, cirrhotics showed increased resting and stimulated burst as well as reduced phagocytosis of PMNs, and increased stimulated monocyte burst (p < 0.05 for all). Alcoholic etiology was not related to PMN or monocyte dysfunction (p > 0.05 for all). In Cox regression analysis, increased stimulated monocyte and PMN burst were independent predictors of sepsis, severe sepsis and ACLF occurrence. Also, increased stimulated monocyte burst was associated with worse transplant-free survival (p < 0.05 for all).

Conclusions

Stimulated PMN and monocyte oxidative burst are increased in ambulatory cirrhotics without acute decompensation. In turn, these changes are associated to sepsis and ACLF occurrence.

Keywords

Liver cirrhosis Bacterial infection Polymorphonuclear leucocytes Monocytes Outcome 

Abbreviations

ACLF

Acute-on-chronic liver failure

ALD

Alcoholic liver disease

AUDIT

Alcohol use disorders identification test

AUROC

Area under the ROC curve

CI

Confidence interval

HR

Hazard ratio

MFI

Median fluorescence intensity

PMA

Phorbol-12-myristate-13-acetate

PMN

Polymorphonuclear leukocytes

ROC

Receiver operating characteristics

ROS

Reactive oxygen species

TNFα

Tumor necrosis alpha

Notes

Financial support

This study was supported by a grant from the Region Skåne (Government), the Swedish Society of Medicine, and the Royal Physiographic Society in Lund, Sweden. The work was independent of these grants.

Compliance with ethical standards

Conflict of interest

None.

Supplementary material

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References

  1. 1.
    Arvaniti V, D’Amico G, Fede G, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology. 2010;139:1246–1256. (1256 e1241–e1245).CrossRefPubMedGoogle Scholar
  2. 2.
    Jalan R, Fernandez J, Wiest R, et al. Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013. J Hepatol. 2014;60:1310–1324.CrossRefPubMedGoogle Scholar
  3. 3.
    Rajkovic IA, Williams R. Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Hepatology. 1986;6:252–262.CrossRefPubMedGoogle Scholar
  4. 4.
    Mookerjee RP, Stadlbauer V, Lidder S, et al. Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome. Hepatology. 2007;46:831–840.CrossRefPubMedGoogle Scholar
  5. 5.
    Taylor NJ, Manakkat Vijay GK, Abeles RD, et al. The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90-day and 1-year mortality. Aliment Pharmacol Ther. 2014;40:705–715.CrossRefPubMedGoogle Scholar
  6. 6.
    Fiuza C, Salcedo M, Clemente G, Tellado JM. In vivo neutrophil dysfunction in cirrhotic patients with advanced liver disease. J Infect Dis. 2000;182:526–533.CrossRefPubMedGoogle Scholar
  7. 7.
    Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R. Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J Hepatol. 2008;48:945–951.CrossRefPubMedGoogle Scholar
  8. 8.
    Tritto G, Bechlis Z, Stadlbauer V, et al. Evidence of neutrophil functional defect despite inflammation in stable cirrhosis. J Hepatol. 2011;55:574–581.CrossRefPubMedGoogle Scholar
  9. 9.
    Kirsch R, Woodburne VE, Shephard EG, Kirsch RE. Patients with stable uncomplicated cirrhosis have normal neutrophil function. J Gastroenterol Hepatol. 2000;15:1298–1306.CrossRefPubMedGoogle Scholar
  10. 10.
    Tazi KA, Quioc JJ, Saada V, Bezeaud A, Lebrec D, Moreau R. Upregulation of TNF-alpha production signaling pathways in monocytes from patients with advanced cirrhosis: possible role of Akt and IRAK-M. J Hepatol. 2006;45:280–289.CrossRefPubMedGoogle Scholar
  11. 11.
    Wasmuth HE, Kunz D, Yagmur E, et al. Patients with acute on chronic liver failure display “sepsis-like” immune paralysis. J Hepatol. 2005;42:195–201.CrossRefPubMedGoogle Scholar
  12. 12.
    Hassner A, Kletter Y, Shlag D, Yedvab M, Aronson M, Shibolet S. Impaired monocyte function in liver cirrhosis. Br Med J. 1981;282:1262–1263.CrossRefGoogle Scholar
  13. 13.
    Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction. 1993;88:791–804.CrossRefPubMedGoogle Scholar
  14. 14.
    Sargenti K, Prytz H, Strand A, Nilsson E, Kalaitzakis E. Healthcare-associated and nosocomial bacterial infections in cirrhosis: predictors and impact on outcome. Liver Int. 2015;35:391–400.CrossRefPubMedGoogle Scholar
  15. 15.
    Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144:1426–1437. (1437 e1421–e1429).CrossRefPubMedGoogle Scholar
  16. 16.
    Bruns T, Peter J, Hagel S, Herrmann A, Stallmach A. The augmented neutrophil respiratory burst in response to Escherichia coli is reduced in liver cirrhosis during infection. Clin Exp Immunol. 2011;164:346–356.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Levy R, Schlaeffer F, Keynan A, Nagauker O, Yaari A, Sikuler E. Increased neutrophil function induced by bile duct ligation in a rat model. Hepatology. 1993;17:908–914.CrossRefPubMedGoogle Scholar
  18. 18.
    Neugebauer H, Hartmann P, Krenn S, et al. Bacterial translocation increases phagocytic activity of polymorphonuclear leucocytes in portal hypertension: priming independent of liver cirrhosis. Liver Int. 2008;28:1149–1157.CrossRefPubMedGoogle Scholar
  19. 19.
    Manakkat Vijay GK, Taylor NJ, Shawcross DL. The quest for the elusive factors that underpin neutrophil dysfunction in cirrhosis goes on [Letter to Editor]. J Hepatol. 2012;56:1212–1213. (author reply 1213–1214).CrossRefPubMedGoogle Scholar
  20. 20.
    Maxwell WJ, Keating JJ, Hogan FP, Kennedy NP, Keeling PW. Prostaglandin E2 and leukotriene B4 synthesis by peripheral leucocytes in alcoholics. Gut. 1989;30:1270–1274.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cui W, Joshi NS, Liu Y, Meng H, Kleinstein SH, Kaech SM. TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation. J Immunol. 2014;192:4221–4232.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet. 2006;368:157–169.CrossRefPubMedGoogle Scholar
  23. 23.
    Antoniades CG, Berry PA, Davies ET, et al. Reduced monocyte HLA-DR expression: a novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure. Hepatology. 2006;44:34–43.CrossRefPubMedGoogle Scholar
  24. 24.
    Bernsmeier C, Pop OT, Singanayagam A, et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology. 2015;148:e614.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Konstantina Sargenti
    • 1
  • Åsa Johansson
    • 2
    • 3
  • Sara Bertilsson
    • 1
  • Inger Mattsby-Baltzer
    • 4
  • Daniel Klintman
    • 1
  • Evangelos Kalaitzakis
    • 1
    • 5
  1. 1.Department of Gastroenterology, Skåne University HospitalUniversity of LundLundSweden
  2. 2.Department of Haematology, Skåne University HospitalUniversity of LundLundSweden
  3. 3.Clinical Immunology and Transfusion Medicine, University and Regional Laboratories Region SkåneSkåne University HospitalLundSweden
  4. 4.Department of Microbiology, Sahlgrenska University HospitalUniversity of GothenburgGothenburgSweden
  5. 5.Digestive Disease Center, Copenhagen University Hospital/HerlevUniversity of CopenhagenCopenhagenDenmark

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