Invited Editorials
Editorial: neutrophil dysfunction in patients with cirrhosis – authors’ reply N. J. Taylor, Y. Ma & D. L. Shawcross Institute of Liver Studies and Transplantation, King’s College London School of Medicine at King’s College Hospital, London, UK. E-mail: [email protected] doi:10.1111/apt.12935
We thank Asrani and Kamath for their insightful editorial on our study which adds to the growing evidence that neutrophil dysfunction in cirrhosis mirrors worsening severity of disease and predicts poor outcome.1, 2 Neutrophils show divergent responses in terms of phagocytosis of microorganisms and production of reactive oxygen species, thus neutrophils contribute both to susceptibility to infection and endothelial activation which is a prerequisite to the development of organ dysfunction.3 The difficulty, however, is determining whether this dysfunction is merely a surrogate marker of advancing disease or a consequence of chronic endotoxaemia and immune exhaustion. The supposition being that chronic low-grade endotoxaemia resulting from bacterial translocation across a leaky gut induces a pro-inflammatory plasma milieu leading to changes in neutrophil behaviour.4 Our study aimed to characterise the impact of cirrhosis on neutrophil function by prospectively monitoring function indices, but due to the heterogeneity of the cirrhotic population, low number of septic events and the number of subjects who underwent transplantation during follow-up, this led to confounders prohibitive to performing instructive sub-group analysis. Studying a highly selected group not listed for transplantation will thus give clues to the natural history of immune dysfunction in advancing cirrhosis. In addition, interventional studies interrogating the effect of therapies such as albumin,
Editorial: healing of refractory reflux oesophagitis – an ongoing unmet clinical need R. H. Hunt*, Y. Yuan* & C. Scarpignato† *Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada. Aliment Pharmacol Ther 2014; 40: 982-989 ª 2014 John Wiley & Sons Ltd
antibiotics modulating gut microbiota, immunosuppression and plasmapheresis are warranted. The exact causality of neutrophil dysfunction remains unclear, and while there is association with pro-inflammatory cytokine levels, there is no consistency. Neutrophil malfunction following exposure to ammonia in vivo and ex vivo does however, seem to be a consistent finding and may explain why neutrophil function deteriorates with advancing disease.5–7 Nevertheless, determining the cellular changes and role of inflammosome proteins and pathways appears likely to identify novel targets to modulate neutrophil function and may offer a potential strategy to improve outcomes in patients with cirrhosis.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2
REFERENCES 1. Asrani SK, Kamath PS. Editorial: neutrophil dysfunction in patients with cirrhosis. Aliment Pharmacol Ther 2014; 40: 986. 2. 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. 3. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006; 368: 157–69. 4. Bellot P, Garcia-Pagan JC, Frances R, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 2010; 52: 2044–52. 5. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010; 51: 1062–9. 6. Shawcross D, Wright G, Stadlbauer V, et al. Ammonia impairs neutrophil phagocytic function in liver disease. Hepatology 2008; 48: 1202–12. 7. Taylor NJ, Nishtala A, Manakkat Vijay GK, et al. Circulating neutrophil dysfunction in acute liver failure. Hepatology 2013; 57: 1142–52.
†
Clinical Pharmacology and Digestive Pathophysiology Unit, Department of Clinical and Experimental Medicine, University of Parma, Italy. E-mail: [email protected] doi:10.1111/apt.12933
987
Invited Editorials Refractory GERD remains a challenging problem. The article by Kahrilas1 is timely and welcome but unfortunate that the analysis has provided no new clinical directions. In results, Kahrilas found ‘significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63% P = 0.039)’ and in discussion ‘patients with refractory oesophagitis had a significantly higher prevalence of frequent regurgitation at baseline than slow healers, and a trend towards a higher prevalence of frequent regurgitation vs. rapid healers’. We believe that including only patients who had regurgitation at baseline (37/46 vs. 47/75) was incorrect. Calculating the ‘prevalence’ taking all patients who had refractory oesophagitis vs. slow healing oesophagitis (37/ 49 vs. 47/78), the difference between the two groups is no longer significant (P = 0.086). Although 93% of patients had concomitant regurgitation at baseline, when the sample size is small, a small change in numbers can alter the results significantly. Therefore, comparisons between refractory oesophagitis and slow healing oesophagitis should be interpreted with caution. It is unclear which patient characteristics were ‘independent predictors’ in the regression model. The patient characteristics assessed did not cover all the baseline variables in the tables. It is not clear whether Kahrilas took any patients with regurgitation (86%), or those with only frequent regurgitation (59%). Conversely, it is not clear if ‘logistic regression analysis’ was also used to study ‘possible predictors’ for group B, although the authors claimed at ‘Week 4 possible predictors of refractory vs. slow healing RE were also assessed, but none was statistically significant’. If so, only four or fewer predictors should be put into the model, considering the small sample size of refractory patients (n = 49) since logistic regression models require a minimum of 10 events per variable. Hiatal hernia (HH) was significantly increased only in patients not healed at 2 weeks vs. rapid healers, but unexpectedly, HH was not increased in slow healers (69%) vs. rapid healers (64%) vs. refractory patients (51%); and was
significantly lower in refractory patients vs. slow healers. The statement in discussion that ‘a higher proportion of patients with refractory reflux oesophagitis had HH at baseline than did rapid or slow healers’ is therefore incorrect. The authors suggested that this ‘may simply be due to the small sample sizes involved’; this is doubtful, because more than half the patients had HH and the sample size is not small, especially for rapid healers. The statement that ‘95% CIs for all mean QoLRAD scores overlapped, which may reflect the limited sample size after 8 weeks of therapy’ for refractory patients (n = 49) vs. slow healers (n = 78) and vs. rapid healers (n = 495) is incorrect. Overlapping 95% CIs do not indicate differences are nonsignificant, and are not necessarily related to sample size and here are not small for mean scores comparisons. Kahrilas1 confirmed the studies of the McMaster group (15–20 years ago), showing the complex relationship of acid suppression to oesophagitis healing2 and to speed of healing3; oesophagitis classification also impacts the evaluation of oesophagitis healing with PPIs4 and time pH
Editorial: neutrophil dysfunction in patients with cirrhosis – authors’ reply N. J. Taylor, Y. Ma & D. L. Shawcross Institute of Liver Studies and Transplantation, King’s College London School of Medicine at King’s College Hospital, London, UK. E-mail: [email protected] doi:10.1111/apt.12935
We thank Asrani and Kamath for their insightful editorial on our study which adds to the growing evidence that neutrophil dysfunction in cirrhosis mirrors worsening severity of disease and predicts poor outcome.1, 2 Neutrophils show divergent responses in terms of phagocytosis of microorganisms and production of reactive oxygen species, thus neutrophils contribute both to susceptibility to infection and endothelial activation which is a prerequisite to the development of organ dysfunction.3 The difficulty, however, is determining whether this dysfunction is merely a surrogate marker of advancing disease or a consequence of chronic endotoxaemia and immune exhaustion. The supposition being that chronic low-grade endotoxaemia resulting from bacterial translocation across a leaky gut induces a pro-inflammatory plasma milieu leading to changes in neutrophil behaviour.4 Our study aimed to characterise the impact of cirrhosis on neutrophil function by prospectively monitoring function indices, but due to the heterogeneity of the cirrhotic population, low number of septic events and the number of subjects who underwent transplantation during follow-up, this led to confounders prohibitive to performing instructive sub-group analysis. Studying a highly selected group not listed for transplantation will thus give clues to the natural history of immune dysfunction in advancing cirrhosis. In addition, interventional studies interrogating the effect of therapies such as albumin,
Editorial: healing of refractory reflux oesophagitis – an ongoing unmet clinical need R. H. Hunt*, Y. Yuan* & C. Scarpignato† *Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada. Aliment Pharmacol Ther 2014; 40: 982-989 ª 2014 John Wiley & Sons Ltd
antibiotics modulating gut microbiota, immunosuppression and plasmapheresis are warranted. The exact causality of neutrophil dysfunction remains unclear, and while there is association with pro-inflammatory cytokine levels, there is no consistency. Neutrophil malfunction following exposure to ammonia in vivo and ex vivo does however, seem to be a consistent finding and may explain why neutrophil function deteriorates with advancing disease.5–7 Nevertheless, determining the cellular changes and role of inflammosome proteins and pathways appears likely to identify novel targets to modulate neutrophil function and may offer a potential strategy to improve outcomes in patients with cirrhosis.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2
REFERENCES 1. Asrani SK, Kamath PS. Editorial: neutrophil dysfunction in patients with cirrhosis. Aliment Pharmacol Ther 2014; 40: 986. 2. 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. 3. Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006; 368: 157–69. 4. Bellot P, Garcia-Pagan JC, Frances R, et al. Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis. Hepatology 2010; 52: 2044–52. 5. Shawcross DL, Shabbir SS, Taylor NJ, Hughes RD. Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2010; 51: 1062–9. 6. Shawcross D, Wright G, Stadlbauer V, et al. Ammonia impairs neutrophil phagocytic function in liver disease. Hepatology 2008; 48: 1202–12. 7. Taylor NJ, Nishtala A, Manakkat Vijay GK, et al. Circulating neutrophil dysfunction in acute liver failure. Hepatology 2013; 57: 1142–52.
†
Clinical Pharmacology and Digestive Pathophysiology Unit, Department of Clinical and Experimental Medicine, University of Parma, Italy. E-mail: [email protected] doi:10.1111/apt.12933
987
Invited Editorials Refractory GERD remains a challenging problem. The article by Kahrilas1 is timely and welcome but unfortunate that the analysis has provided no new clinical directions. In results, Kahrilas found ‘significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63% P = 0.039)’ and in discussion ‘patients with refractory oesophagitis had a significantly higher prevalence of frequent regurgitation at baseline than slow healers, and a trend towards a higher prevalence of frequent regurgitation vs. rapid healers’. We believe that including only patients who had regurgitation at baseline (37/46 vs. 47/75) was incorrect. Calculating the ‘prevalence’ taking all patients who had refractory oesophagitis vs. slow healing oesophagitis (37/ 49 vs. 47/78), the difference between the two groups is no longer significant (P = 0.086). Although 93% of patients had concomitant regurgitation at baseline, when the sample size is small, a small change in numbers can alter the results significantly. Therefore, comparisons between refractory oesophagitis and slow healing oesophagitis should be interpreted with caution. It is unclear which patient characteristics were ‘independent predictors’ in the regression model. The patient characteristics assessed did not cover all the baseline variables in the tables. It is not clear whether Kahrilas took any patients with regurgitation (86%), or those with only frequent regurgitation (59%). Conversely, it is not clear if ‘logistic regression analysis’ was also used to study ‘possible predictors’ for group B, although the authors claimed at ‘Week 4 possible predictors of refractory vs. slow healing RE were also assessed, but none was statistically significant’. If so, only four or fewer predictors should be put into the model, considering the small sample size of refractory patients (n = 49) since logistic regression models require a minimum of 10 events per variable. Hiatal hernia (HH) was significantly increased only in patients not healed at 2 weeks vs. rapid healers, but unexpectedly, HH was not increased in slow healers (69%) vs. rapid healers (64%) vs. refractory patients (51%); and was
significantly lower in refractory patients vs. slow healers. The statement in discussion that ‘a higher proportion of patients with refractory reflux oesophagitis had HH at baseline than did rapid or slow healers’ is therefore incorrect. The authors suggested that this ‘may simply be due to the small sample sizes involved’; this is doubtful, because more than half the patients had HH and the sample size is not small, especially for rapid healers. The statement that ‘95% CIs for all mean QoLRAD scores overlapped, which may reflect the limited sample size after 8 weeks of therapy’ for refractory patients (n = 49) vs. slow healers (n = 78) and vs. rapid healers (n = 495) is incorrect. Overlapping 95% CIs do not indicate differences are nonsignificant, and are not necessarily related to sample size and here are not small for mean scores comparisons. Kahrilas1 confirmed the studies of the McMaster group (15–20 years ago), showing the complex relationship of acid suppression to oesophagitis healing2 and to speed of healing3; oesophagitis classification also impacts the evaluation of oesophagitis healing with PPIs4 and time pH
