Invited Editorials
Editorial: neutrophil dysfunction in patients with cirrhosis S. K. Asrani* & P. S. Kamath† *Baylor University Medical Center, Dallas, TX, USA. † Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA. E-mail: [email protected] doi:10.1111/apt.12915
Development of infection and sepsis may represent the penultimate stage in the natural history of decompensated cirrhosis.1 Infected cirrhotics have a fourfold higher mortality that non-infected cirrhotics, with a significant risk of mortality at 1 month (30%) and at 1 year (63%).1 Describing risk factors for development of infection in this vulnerable population is paramount. Recent attention has focused on the inflammatory response to infection among cirrhotics.2–5 A duality exists, where cirrhosis-induced immune dysfunction coexists with a state of persistent activation of immune system cells.3 Specifically, neutrophil function in cirrhotics is impaired, with an increase in resting oxidative burst (OB), and a defect in phagocytosis and killing, despite increased circulating pro inflammatory cytokines.3, 6 Although neutrophils may be functionally normal in stable disease, infection may lead to expression of an impaired phenotype. End organ damage may be a function of not only the intense inflammatory response, but also a reduced capacity of the host to endure the effects of the inflammatory response.3 Taylor et al. describe the importance of neutrophil dysfunction among persons with advanced liver disease.7 In this prospective study, 62 patients with either stable cirrhosis or acute–on-chronic liver failure (ACLF) were compared to 11 controls without evidence of liver disease. Neutrophil phagocytic activity (NPA, per cent of neutrophils undergoing phagocytosis) among persons with cirrhosis and ACLF was much lower, as compared with controls, and decreased with increasing severity of liver disease. Neutrophil phagocytic activity was lower in certain subsets of cirrhotics: cirrhotics with refractory ascites on beta blockers, those without alcohol consumption and subjects with elevated ammonia. Lower NPA was associated with an increased risk of either baseline or subsequent development of infection. Increased resting OB (percentage of phagocytic cells producing reactive oxygen species), but not Escherichia coli, stimulated burst (potentially due to depletion of response), was associated with worsening liver disease, increased levels of plasma cytokines and worse survival within 90 days.5 986
The authors are to be commended for trying to establish separate phenotypes of cirrhotics that are at even higher risk of complications based on patterns of OB and NPA. However, several questions still remain. Neutrophil dysfunction is a cornerstone of sepsis. Whether cirrhotics with neutrophil dysfunction have different patterns as compared to a control group of septic patients without presence of underlying liver disease is unknown. Whether the presence of liver disease inherently induces a state of immune dysfunction above and beyond the overwhelming stress of sepsis is also unclear. Given the small number of patients, potential co-factors such as advanced age, receipt of active treatment or prophylactic antibiotics, variable response to subtypes of infection (bacterial vs. fungal, multidrug resistant, nosocomial or community acquired), impact of baseline immunosuppressants (e.g. steroids) are harder to assess.2, 8 Provocative associations between beta blocker use and impaired neutrophil function in a selected subset, and the putative interaction with elevated ammonia (and its implication) need to be explored further in larger studies.5, 9
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. 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: 1246–56, 1256 e1-5. 2. Sipeki N, Antal-Szalmas P, Lakatos PL, et al. Immune dysfunction in cirrhosis. World J Gastroenterol 2014; 20: 2564–77. 3. 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: 1310–24. 4. Bruns T, Zimmermann HW, Stallmach A. Risk factors and outcome of bacterial infections in cirrhosis. World J Gastroenterol 2014; 20: 2542–54. 5. Bruns T, Peter J, Hagel S, et al. The augmented neutrophil respiratory burst in response to Escherichia coli is reduced in liver cirrhosis during infection. Clin Exp Immunol 2011; 164: 346–56. 6. Tritto G, Bechlis Z, Stadlbauer V, et al. Evidence of neutrophil functional defect despite inflammation in stable cirrhosis. J Hepatol 2011; 55: 574–81. 7. 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: 705–15. 8. 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– 40. 9. Manakkat Vijay GK, Taylor NJ, Shawcross DL. The quest for the elusive factors that underpin neutrophil dysfunction in cirrhosis goes on. J Hepatol 2012; 56: 1212–3; author reply 1213–4. Aliment Pharmacol Ther 2014; 40: 982-989 ª 2014 John Wiley & Sons Ltd
Editorial: neutrophil dysfunction in patients with cirrhosis S. K. Asrani* & P. S. Kamath† *Baylor University Medical Center, Dallas, TX, USA. † Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA. E-mail: [email protected] doi:10.1111/apt.12915
Development of infection and sepsis may represent the penultimate stage in the natural history of decompensated cirrhosis.1 Infected cirrhotics have a fourfold higher mortality that non-infected cirrhotics, with a significant risk of mortality at 1 month (30%) and at 1 year (63%).1 Describing risk factors for development of infection in this vulnerable population is paramount. Recent attention has focused on the inflammatory response to infection among cirrhotics.2–5 A duality exists, where cirrhosis-induced immune dysfunction coexists with a state of persistent activation of immune system cells.3 Specifically, neutrophil function in cirrhotics is impaired, with an increase in resting oxidative burst (OB), and a defect in phagocytosis and killing, despite increased circulating pro inflammatory cytokines.3, 6 Although neutrophils may be functionally normal in stable disease, infection may lead to expression of an impaired phenotype. End organ damage may be a function of not only the intense inflammatory response, but also a reduced capacity of the host to endure the effects of the inflammatory response.3 Taylor et al. describe the importance of neutrophil dysfunction among persons with advanced liver disease.7 In this prospective study, 62 patients with either stable cirrhosis or acute–on-chronic liver failure (ACLF) were compared to 11 controls without evidence of liver disease. Neutrophil phagocytic activity (NPA, per cent of neutrophils undergoing phagocytosis) among persons with cirrhosis and ACLF was much lower, as compared with controls, and decreased with increasing severity of liver disease. Neutrophil phagocytic activity was lower in certain subsets of cirrhotics: cirrhotics with refractory ascites on beta blockers, those without alcohol consumption and subjects with elevated ammonia. Lower NPA was associated with an increased risk of either baseline or subsequent development of infection. Increased resting OB (percentage of phagocytic cells producing reactive oxygen species), but not Escherichia coli, stimulated burst (potentially due to depletion of response), was associated with worsening liver disease, increased levels of plasma cytokines and worse survival within 90 days.5 986
The authors are to be commended for trying to establish separate phenotypes of cirrhotics that are at even higher risk of complications based on patterns of OB and NPA. However, several questions still remain. Neutrophil dysfunction is a cornerstone of sepsis. Whether cirrhotics with neutrophil dysfunction have different patterns as compared to a control group of septic patients without presence of underlying liver disease is unknown. Whether the presence of liver disease inherently induces a state of immune dysfunction above and beyond the overwhelming stress of sepsis is also unclear. Given the small number of patients, potential co-factors such as advanced age, receipt of active treatment or prophylactic antibiotics, variable response to subtypes of infection (bacterial vs. fungal, multidrug resistant, nosocomial or community acquired), impact of baseline immunosuppressants (e.g. steroids) are harder to assess.2, 8 Provocative associations between beta blocker use and impaired neutrophil function in a selected subset, and the putative interaction with elevated ammonia (and its implication) need to be explored further in larger studies.5, 9
ACKNOWLEDGEMENT Declaration of personal and funding interests: None. 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: 1246–56, 1256 e1-5. 2. Sipeki N, Antal-Szalmas P, Lakatos PL, et al. Immune dysfunction in cirrhosis. World J Gastroenterol 2014; 20: 2564–77. 3. 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: 1310–24. 4. Bruns T, Zimmermann HW, Stallmach A. Risk factors and outcome of bacterial infections in cirrhosis. World J Gastroenterol 2014; 20: 2542–54. 5. Bruns T, Peter J, Hagel S, et al. The augmented neutrophil respiratory burst in response to Escherichia coli is reduced in liver cirrhosis during infection. Clin Exp Immunol 2011; 164: 346–56. 6. Tritto G, Bechlis Z, Stadlbauer V, et al. Evidence of neutrophil functional defect despite inflammation in stable cirrhosis. J Hepatol 2011; 55: 574–81. 7. 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: 705–15. 8. 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– 40. 9. Manakkat Vijay GK, Taylor NJ, Shawcross DL. The quest for the elusive factors that underpin neutrophil dysfunction in cirrhosis goes on. J Hepatol 2012; 56: 1212–3; author reply 1213–4. Aliment Pharmacol Ther 2014; 40: 982-989 ª 2014 John Wiley & Sons Ltd
