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

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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.

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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

References

  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).

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  3. Rajkovic IA, Williams R. Abnormalities of neutrophil phagocytosis, intracellular killing and metabolic activity in alcoholic cirrhosis and hepatitis. Hepatology. 1986;6:252–262.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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).

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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).

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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 

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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.

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Authors and Affiliations

  1. Department of Gastroenterology, Skåne University Hospital, University of Lund, 22185, Lund, Sweden

    Konstantina Sargenti, Sara Bertilsson, Daniel Klintman & Evangelos Kalaitzakis

  2. Department of Haematology, Skåne University Hospital, University of Lund, Lund, Sweden

    Åsa Johansson

  3. Clinical Immunology and Transfusion Medicine, University and Regional Laboratories Region Skåne, Skåne University Hospital, 22185, Lund, Sweden

    Åsa Johansson

  4. Department of Microbiology, Sahlgrenska University Hospital, University of Gothenburg, 41345, Gothenburg, Sweden

    Inger Mattsby-Baltzer

  5. Digestive Disease Center, Copenhagen University Hospital/Herlev, University of Copenhagen, 2730, Copenhagen, Denmark

    Evangelos Kalaitzakis

Authors
  1. Konstantina Sargenti
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  2. Åsa Johansson
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  3. Sara Bertilsson
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  4. Inger Mattsby-Baltzer
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  5. Daniel Klintman
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  6. Evangelos Kalaitzakis
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Correspondence to Konstantina Sargenti.

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Sargenti, K., Johansson, Å., Bertilsson, S. et al. Dysfunction of Circulating Polymorphonuclear Leukocytes and Monocytes in Ambulatory Cirrhotics Predicts Patient Outcome. Dig Dis Sci 61, 2294–2302 (2016). https://doi.org/10.1007/s10620-016-4132-3

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  • DOI: https://doi.org/10.1007/s10620-016-4132-3

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