- Email: [email protected]
Infections worsen prognosis of patients with cirrhosis irrespective of the liver disease stage
EJINME-03671; No of Pages 3 European Journal of Internal Medicine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor Infections worsen prognosis of patients with cirrhosis irrespective of the liver disease stage
Dear Editor, Cirrhosis is the end stage of various diseases of the liver. The leading causes of liver diseases are hepatitis B and C viral infections (HBV and HCV), alcohol consumption and cryptogenetic disease [1]. Thanks to the advent of nucleot(s)ide HBV analogs and direct anti HCV agents, the long-term survival of patients affected by liver cirrhosis has improved significantly in recent years [2–4]. Nevertheless, even in case of viral suppression or viral clearance, patients with liver cirrhosis remain at risk for decompensation, hepatocellular carcinoma (HCC) and death. The more advanced the disease before antiviral-therapy, the higher the risk of complications or death [5]. This finding prompted studies of the factors associated with a reduced survival rate in patients with cirrhosis and end-stage liver disease. The onset of infections is the major cause of acute on chronic liver failure, a condition associated with a 30-day mortality rate as high as 25% [6]. Liver cirrhosis is considered an immunodeficiency status, and thus predisposes to infections [7]. Rates of bacterial infections in patients with liver cirrhosis are estimated to be between 32% and 34% in hospitalized patients and are considerably higher than the estimated rates of infections (5–7%) in the general hospitalized population [8]. Several factors are associated with the development of infections in patients with liver cirrhosis, namely, a low level of proteins in ascites [9], low serum vitamin D levels [10], use of a proton pump inhibitor (PPI) [11,12], and recent gastrointestinal bleeding [13]. Furthermore, general risk factors for infections, such as immunosuppressive therapies, malignancies and comorbidities (e.g. diabetes mellitus) are predictors of infections also in patients with liver cirrhosis [12]. In the attempt to assess the impact of infections in patients with liver cirrhosis we: (i) estimated the rate of infections in a cohort of inpatients with liver cirrhosis; (ii) identified, in this cohort of patients, factors associated with infections; and (iii) estimated the mortality rate of patients with infection and liver cirrhosis. We reviewed the charts of all patients with liver cirrhosis admitted to the Infectious Diseases Unit at the University of Naples “Federico II” from January 2008 to December 2015. Patients were followed-up until April 2016. We collected clinical and laboratory data at admission, one week after admission, and upon discharge. The last outpatient attendance and the eventual occurrence of death were recorded for survival analysis.
Abbreviations: HCC, hepatocellular carcinoma; SBP, spontaneous bacterial peritonitis; PPI, proton-pump inhibitor; CRP, C reactive protein; CKD, chronic kidney disease; AKI, acute kidney injury; MELD, Model for End-Stage Liver Disease.
This study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. The informed consent for data processing was obtained for all the involved patients. Statistical analysis was performed using the IBM© SPSS© Statistics v. 20 package. We used the Χ2 test or Fisher's exact test for group comparisons as appropriate, the logistic regression function for univariate and multivariate risk assessments, and the forward conditional stepwise method for binary logistic regression analysis. The dependent variable was the mortality assessed 30 days after hospital admission (30-day mortality). The cut-off values used for the stepwise method were: p = 0.05 for entry into the model and p = 0.10 for its removal. The Kaplan-Meier and the Cox regression tests were used to assess survival. For all tests, a p-value b 0.05 was considered statistically significant. Table 1 shows the main data of the 244 patients included in this analysis. A total of 470 hospital admissions were recorded, and the median length of hospitalization was 9 days (interquartile range, IQR: 5–17). In 88/470 (18.7%) cases, patients had been admitted to hospital during the previous month. Sixty-four (26.2%) patients had a diagnosis of diabetes mellitus, while 19 (7.9%) and 5 (2%) patients had chronic kidney disease (CKD) and acute kidney injury (AKI), respectively. We diagnosed an infection in 109 of the 470 hospital admissions (23.2%) and gram-negative bacteria were isolated in 74% of cases. Urinary tract infections (UTI) were the most frequently diagnosed infection, followed by spontaneous bacterial peritonitis, which encountered for 14% of cases. We found that 81/244 (33.2%) of patients had at least one infection during the observation period. Rates of infections were significantly higher in patients with a diagnosis of diabetes (28.4% vs 20.3%; χ2 = 3.87, p = 0.03), and in lymphopenic patients (28.4% vs 18.2%; χ2 = 6.74, p b 0.001) compared with rates of infections in patients without these risk factors. The rate of infections was higher, albeit not significantly higher, in neutropenic patients than in either patients with a normal neutrophil count (35% vs 22%; χ2 = 3.36, p = 0.067) or in patients with a diagnosis of HCC (24.8% vs 17%; χ2 = 3.31, p = 0.069). Similarly, other risk factors did not affect rates of infections (e.g. neutropenia, CKD, chronic therapy with PPI or immunosuppressant). At multivariate analysis, the occurrence of infection during hospitalization (OR: 2.33; 95CI 1.34–4.00, p b 0.01), HCC (4.34; 95CI 2.5–7.54, p b 0.01), and a hospital admission in the previous month (OR 2.32; 95CI 1.3–4.16, p b 0.01) were independent mortality risk factors. There was no significant association between 30-day mortality and comorbidities (diabetes mellitus, CKD, AKI, oesophageal varices, encephalopathy, SBP, gastrointestinal bleeding, refractory ascites). On the contrary, the type of microorganism isolated was associated with 30-day mortality. In fact, infections caused by Gram-positive bacteria (versus other pathogens) (OR: 2.82; 95CI 1.16–6.87, p b 0.05) or fungi (versus other pathogens) (OR: 3.65; 95CI 1.005–13.27, p b 0.05) were associated with a higher 30-day mortality, while no association was found when Gram-negative bacteria were the etiological agents.
http://dx.doi.org/10.1016/j.ejim.2017.09.014 0953-6205/© 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Gentile I, et al, , Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.09.014
2
Letter to the Editor Table 1 Baseline characteristics of patients at first admission (n = 244). Male (n, %) Age (years; median, IQR) Child-Pugh classification (n, %) – A – B – C – Missing MELD score (median, IQR) Etiology of cirrhosis (n, %)a – HCV – HBV – Alcohol abuse – HDV – Autoimmune – Dysmetabolic – Cryptogenic Hepatocellular carcinoma (n, %) Portal-systemic encephalopathy (n, %) Ascites (n, %) a
157 (64.3) 68 (60–73) 136 (55.7) 57 (23.4) 18 (7.4) 33 (13.5) 11 (9–15) 214 (87.7) 13 (5) 11 (4.5) 3 (1.3) 2 (1) 1 (0.5) 13 (5) 46 (18.9) 32 (13.1) 13 (5.3)
The sum of percentages is above 100% due to multiple etiologies for some patients.
A total of 79/244 (32.4%) patients died during the prospective, observational period (median duration: 12.6 months; IQR: 4.5–34.7). Mortality rates in infected patients were 27% 30 days after discharge and 47% at 12 months. Mortality in the whole cohort at 12 months was 30%. According to the Kaplan-Meier survival analysis, to have had at least one infection during hospitalization was significantly associated with death (p b 0.01) (Fig. 1). Other factors associated with death at the survival analysis were decompensated liver disease (defined as class B or C of the Child-Pugh classification versus A) (p b 0.01), Model for End-Stage Liver Disease (MELD) score ≥ 15 (vs b15) (p = 0.016) and age ≥ 68 years (vs b68 years) (p b 0.01). At Cox regression analysis, the only factors independently associated with death were the presence of at least one infection during the observation period (HR: 2.34; 95CI: 1.34–4.0, p b 0.01) and Child-Pugh classification B or C of the liver disease (HR: 2.76; 95CI: 1.49–5.1, p b 0.01), while an MELD ≥ 15 score and age ≥ 68 years were not significantly associated with reduced survival. Summing up, we found that the rate of infections in hospitalized patients with liver cirrhosis was as high as 23%, and that infections severely impact on survival during a median follow-up of about one year.
Gut bacterial translocation is probably the cause of the high rates of infections. In fact, as liver injury progresses, gut permeability increases, thereby leading to bacterial translocation and to the onset of infections, such as SBP, which can lead to such severe complications as hepatorenal syndrome [14]. Patients with liver cirrhosis have a high risk of immunodepression, and thus of infection, to such an extent that the term “cirrhosis acquired immune dysfunction” has been proposed [7]. A key finding of our study is that the occurrence of infection negatively affects the prognosis of patients with cirrhosis. In fact, in our series, the 12-month mortality of patients with infection was as high as 47%, while mortality 30 days after discharge in patients with infection was 27%. These results differ from a previous large study in which the mortality rate in infected patients was 38% (30.3% occurring at 1 month and 63% at 12 months), and in which infected patients had a four-fold higher mortality risk compared with patients without infection (OR: 3.76; 95CI 3.05–4.63) [6]. Given the negative impact that an incorrect empirical antibiotic therapy could have on the survival of patients with infections, specific training programs on the correct use of antibiotics are needed, especially in clinical settings where patients with immune dysfunctions are managed [15]. An intriguing finding of this study is that an infection is a risk factor for short- and long-term death in patients with liver cirrhosis, irrespective of disease stage. Notably, the occurrence of at least one infection is sufficient to impact on the long-term survival of these patients. However, given the retrospective nature of this study, it is not possible to determine whether the survival rate differed between patients who received early correct treatment and those who did not. However, the high mortality rates in patients with liver cirrhosis and infections highlight the importance of identifying infections in patients with cirrhosis who show acute decompensation of the liver disease. In conclusion, in patients affected by liver cirrhosis, the occurrence of an infection is a predictive factor for mortality irrespective of disease stage. As most infections are potentially treatable, ad hoc studies are needed to assess whether a prompt diagnosis and treatment of an infection improve the survival rate of patients affected by liver cirrhosis. Disclosure Conflict of interest I.G. acted as a consultant for AbbVie and MSD. He received a grant from Gilead Sciences (in the framework of Fellowship program). The other authors declare no conflict of interest. Financial support This study was performed without public or private financial support. References
Fig. 1. Cumulative survival according to the occurrence of at least one infection.
[1] Ge PS, Runyon BA. Treatment of patients with cirrhosis. N Engl J Med 2016;375: 767–77. [2] Lampertico P, Maini M, Papatheodoridis G. Optimal management of hepatitis B virus infection – EASL special conference. J Hepatol 2015;63:1238–53. [3] Gentile I, Buonomo AR, Zappulo E, Borgia G. Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert Rev Anti Infect Ther 2014;12:763–73. [4] Gentile I, Maraolo AE, Buonomo AR, Zappulo E, Borgia G. The discovery of sofosbuvir: a revolution for therapy of chronic hepatitis C. Expert Opin Drug Discovery 2015;10: 1363–77. [5] Sievert W, Razavi H, Estes C, Thompson AJ, Zekry A, Roberts SK, et al. Enhanced antiviral treatment efficacy and uptake in preventing the rising burden of hepatitis Crelated liver disease and costs in Australia. J Gastroenterol Hepatol 2014;29(Suppl. 1):1–9. [6] Arvaniti V, D'Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010;139:1246–56 [56.e1-5].
Please cite this article as: Gentile I, et al, , Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.09.014
Letter to the Editor [7] Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014;61:1385–96. [8] Borzio M, Salerno F, Piantoni L, Cazzaniga M, Angeli P, Bissoli F, et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001;33:41–8. [9] Runyon BA. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology 1986;91:1343–6. [10] Buonomo AR, Zappulo E, Scotto R, Pinchera B, Perruolo G, Formisano P, et al. Vitamin D deficiency is a risk factor for infections in patients affected by HCV-related liver cirrhosis. Int J Infect Dis 2017;63:23–9. [11] Dever JB, Sheikh MY. Review article: spontaneous bacterial peritonitis—bacteriology, diagnosis, treatment, risk factors and prevention. Aliment Pharmacol Ther 2015;41: 1116–31. [12] Fagiuoli S, Colli A, Bruno R, Burra P, Craxi A, Gaeta GB, et al. Management of infections in cirrhotic patients: report of a consensus conference. Dig Liver Dis 2014;46: 204–12. [13] Di Martino V, Weil D, Cervoni JP, Thevenot T. New prognostic markers in liver cirrhosis. World J Hepatol 2015;7:1244–50. [14] Garcia-Tsao G, Wiest R. Gut microflora in the pathogenesis of the complications of cirrhosis. Best Pract Res Clin Gastroenterol 2004;18:353–72.
3
[15] Gentile I, Landolfo D, Buonomo AR, Crispo M, Iula VD, Minei G, et al. A survey on antibiotic therapy knowledge among physicians of a tertiary care and university hospital. Infez Med 2015;23:12–7.
Ivan Gentile1 Antonio Riccardo Buonomo*,1 Riccardo Scotto Emanuela Zappulo Guglielmo Borgia Department of Clinical Medicine and Surgery – Section of Infectious Disease, University "Federico II" of Naples, Italy *Corresponding author at: Via Pansini 5, 80131 Naples, Italy. E-mail address: [email protected] (A.R. Buonomo). 4 September 2017 Available online xxxx
1
Equally contributed to this work.
Please cite this article as: Gentile I, et al, , Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.09.014
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Letter to the Editor Infections worsen prognosis of patients with cirrhosis irrespective of the liver disease stage
Dear Editor, Cirrhosis is the end stage of various diseases of the liver. The leading causes of liver diseases are hepatitis B and C viral infections (HBV and HCV), alcohol consumption and cryptogenetic disease [1]. Thanks to the advent of nucleot(s)ide HBV analogs and direct anti HCV agents, the long-term survival of patients affected by liver cirrhosis has improved significantly in recent years [2–4]. Nevertheless, even in case of viral suppression or viral clearance, patients with liver cirrhosis remain at risk for decompensation, hepatocellular carcinoma (HCC) and death. The more advanced the disease before antiviral-therapy, the higher the risk of complications or death [5]. This finding prompted studies of the factors associated with a reduced survival rate in patients with cirrhosis and end-stage liver disease. The onset of infections is the major cause of acute on chronic liver failure, a condition associated with a 30-day mortality rate as high as 25% [6]. Liver cirrhosis is considered an immunodeficiency status, and thus predisposes to infections [7]. Rates of bacterial infections in patients with liver cirrhosis are estimated to be between 32% and 34% in hospitalized patients and are considerably higher than the estimated rates of infections (5–7%) in the general hospitalized population [8]. Several factors are associated with the development of infections in patients with liver cirrhosis, namely, a low level of proteins in ascites [9], low serum vitamin D levels [10], use of a proton pump inhibitor (PPI) [11,12], and recent gastrointestinal bleeding [13]. Furthermore, general risk factors for infections, such as immunosuppressive therapies, malignancies and comorbidities (e.g. diabetes mellitus) are predictors of infections also in patients with liver cirrhosis [12]. In the attempt to assess the impact of infections in patients with liver cirrhosis we: (i) estimated the rate of infections in a cohort of inpatients with liver cirrhosis; (ii) identified, in this cohort of patients, factors associated with infections; and (iii) estimated the mortality rate of patients with infection and liver cirrhosis. We reviewed the charts of all patients with liver cirrhosis admitted to the Infectious Diseases Unit at the University of Naples “Federico II” from January 2008 to December 2015. Patients were followed-up until April 2016. We collected clinical and laboratory data at admission, one week after admission, and upon discharge. The last outpatient attendance and the eventual occurrence of death were recorded for survival analysis.
Abbreviations: HCC, hepatocellular carcinoma; SBP, spontaneous bacterial peritonitis; PPI, proton-pump inhibitor; CRP, C reactive protein; CKD, chronic kidney disease; AKI, acute kidney injury; MELD, Model for End-Stage Liver Disease.
This study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. The informed consent for data processing was obtained for all the involved patients. Statistical analysis was performed using the IBM© SPSS© Statistics v. 20 package. We used the Χ2 test or Fisher's exact test for group comparisons as appropriate, the logistic regression function for univariate and multivariate risk assessments, and the forward conditional stepwise method for binary logistic regression analysis. The dependent variable was the mortality assessed 30 days after hospital admission (30-day mortality). The cut-off values used for the stepwise method were: p = 0.05 for entry into the model and p = 0.10 for its removal. The Kaplan-Meier and the Cox regression tests were used to assess survival. For all tests, a p-value b 0.05 was considered statistically significant. Table 1 shows the main data of the 244 patients included in this analysis. A total of 470 hospital admissions were recorded, and the median length of hospitalization was 9 days (interquartile range, IQR: 5–17). In 88/470 (18.7%) cases, patients had been admitted to hospital during the previous month. Sixty-four (26.2%) patients had a diagnosis of diabetes mellitus, while 19 (7.9%) and 5 (2%) patients had chronic kidney disease (CKD) and acute kidney injury (AKI), respectively. We diagnosed an infection in 109 of the 470 hospital admissions (23.2%) and gram-negative bacteria were isolated in 74% of cases. Urinary tract infections (UTI) were the most frequently diagnosed infection, followed by spontaneous bacterial peritonitis, which encountered for 14% of cases. We found that 81/244 (33.2%) of patients had at least one infection during the observation period. Rates of infections were significantly higher in patients with a diagnosis of diabetes (28.4% vs 20.3%; χ2 = 3.87, p = 0.03), and in lymphopenic patients (28.4% vs 18.2%; χ2 = 6.74, p b 0.001) compared with rates of infections in patients without these risk factors. The rate of infections was higher, albeit not significantly higher, in neutropenic patients than in either patients with a normal neutrophil count (35% vs 22%; χ2 = 3.36, p = 0.067) or in patients with a diagnosis of HCC (24.8% vs 17%; χ2 = 3.31, p = 0.069). Similarly, other risk factors did not affect rates of infections (e.g. neutropenia, CKD, chronic therapy with PPI or immunosuppressant). At multivariate analysis, the occurrence of infection during hospitalization (OR: 2.33; 95CI 1.34–4.00, p b 0.01), HCC (4.34; 95CI 2.5–7.54, p b 0.01), and a hospital admission in the previous month (OR 2.32; 95CI 1.3–4.16, p b 0.01) were independent mortality risk factors. There was no significant association between 30-day mortality and comorbidities (diabetes mellitus, CKD, AKI, oesophageal varices, encephalopathy, SBP, gastrointestinal bleeding, refractory ascites). On the contrary, the type of microorganism isolated was associated with 30-day mortality. In fact, infections caused by Gram-positive bacteria (versus other pathogens) (OR: 2.82; 95CI 1.16–6.87, p b 0.05) or fungi (versus other pathogens) (OR: 3.65; 95CI 1.005–13.27, p b 0.05) were associated with a higher 30-day mortality, while no association was found when Gram-negative bacteria were the etiological agents.
http://dx.doi.org/10.1016/j.ejim.2017.09.014 0953-6205/© 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Gentile I, et al, , Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.09.014
2
Letter to the Editor Table 1 Baseline characteristics of patients at first admission (n = 244). Male (n, %) Age (years; median, IQR) Child-Pugh classification (n, %) – A – B – C – Missing MELD score (median, IQR) Etiology of cirrhosis (n, %)a – HCV – HBV – Alcohol abuse – HDV – Autoimmune – Dysmetabolic – Cryptogenic Hepatocellular carcinoma (n, %) Portal-systemic encephalopathy (n, %) Ascites (n, %) a
157 (64.3) 68 (60–73) 136 (55.7) 57 (23.4) 18 (7.4) 33 (13.5) 11 (9–15) 214 (87.7) 13 (5) 11 (4.5) 3 (1.3) 2 (1) 1 (0.5) 13 (5) 46 (18.9) 32 (13.1) 13 (5.3)
The sum of percentages is above 100% due to multiple etiologies for some patients.
A total of 79/244 (32.4%) patients died during the prospective, observational period (median duration: 12.6 months; IQR: 4.5–34.7). Mortality rates in infected patients were 27% 30 days after discharge and 47% at 12 months. Mortality in the whole cohort at 12 months was 30%. According to the Kaplan-Meier survival analysis, to have had at least one infection during hospitalization was significantly associated with death (p b 0.01) (Fig. 1). Other factors associated with death at the survival analysis were decompensated liver disease (defined as class B or C of the Child-Pugh classification versus A) (p b 0.01), Model for End-Stage Liver Disease (MELD) score ≥ 15 (vs b15) (p = 0.016) and age ≥ 68 years (vs b68 years) (p b 0.01). At Cox regression analysis, the only factors independently associated with death were the presence of at least one infection during the observation period (HR: 2.34; 95CI: 1.34–4.0, p b 0.01) and Child-Pugh classification B or C of the liver disease (HR: 2.76; 95CI: 1.49–5.1, p b 0.01), while an MELD ≥ 15 score and age ≥ 68 years were not significantly associated with reduced survival. Summing up, we found that the rate of infections in hospitalized patients with liver cirrhosis was as high as 23%, and that infections severely impact on survival during a median follow-up of about one year.
Gut bacterial translocation is probably the cause of the high rates of infections. In fact, as liver injury progresses, gut permeability increases, thereby leading to bacterial translocation and to the onset of infections, such as SBP, which can lead to such severe complications as hepatorenal syndrome [14]. Patients with liver cirrhosis have a high risk of immunodepression, and thus of infection, to such an extent that the term “cirrhosis acquired immune dysfunction” has been proposed [7]. A key finding of our study is that the occurrence of infection negatively affects the prognosis of patients with cirrhosis. In fact, in our series, the 12-month mortality of patients with infection was as high as 47%, while mortality 30 days after discharge in patients with infection was 27%. These results differ from a previous large study in which the mortality rate in infected patients was 38% (30.3% occurring at 1 month and 63% at 12 months), and in which infected patients had a four-fold higher mortality risk compared with patients without infection (OR: 3.76; 95CI 3.05–4.63) [6]. Given the negative impact that an incorrect empirical antibiotic therapy could have on the survival of patients with infections, specific training programs on the correct use of antibiotics are needed, especially in clinical settings where patients with immune dysfunctions are managed [15]. An intriguing finding of this study is that an infection is a risk factor for short- and long-term death in patients with liver cirrhosis, irrespective of disease stage. Notably, the occurrence of at least one infection is sufficient to impact on the long-term survival of these patients. However, given the retrospective nature of this study, it is not possible to determine whether the survival rate differed between patients who received early correct treatment and those who did not. However, the high mortality rates in patients with liver cirrhosis and infections highlight the importance of identifying infections in patients with cirrhosis who show acute decompensation of the liver disease. In conclusion, in patients affected by liver cirrhosis, the occurrence of an infection is a predictive factor for mortality irrespective of disease stage. As most infections are potentially treatable, ad hoc studies are needed to assess whether a prompt diagnosis and treatment of an infection improve the survival rate of patients affected by liver cirrhosis. Disclosure Conflict of interest I.G. acted as a consultant for AbbVie and MSD. He received a grant from Gilead Sciences (in the framework of Fellowship program). The other authors declare no conflict of interest. Financial support This study was performed without public or private financial support. References
Fig. 1. Cumulative survival according to the occurrence of at least one infection.
[1] Ge PS, Runyon BA. Treatment of patients with cirrhosis. N Engl J Med 2016;375: 767–77. [2] Lampertico P, Maini M, Papatheodoridis G. Optimal management of hepatitis B virus infection – EASL special conference. J Hepatol 2015;63:1238–53. [3] Gentile I, Buonomo AR, Zappulo E, Borgia G. Interferon-free therapies for chronic hepatitis C: toward a hepatitis C virus-free world? Expert Rev Anti Infect Ther 2014;12:763–73. [4] Gentile I, Maraolo AE, Buonomo AR, Zappulo E, Borgia G. The discovery of sofosbuvir: a revolution for therapy of chronic hepatitis C. Expert Opin Drug Discovery 2015;10: 1363–77. [5] Sievert W, Razavi H, Estes C, Thompson AJ, Zekry A, Roberts SK, et al. Enhanced antiviral treatment efficacy and uptake in preventing the rising burden of hepatitis Crelated liver disease and costs in Australia. J Gastroenterol Hepatol 2014;29(Suppl. 1):1–9. [6] Arvaniti V, D'Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010;139:1246–56 [56.e1-5].
Please cite this article as: Gentile I, et al, , Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.09.014
Letter to the Editor [7] Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014;61:1385–96. [8] Borzio M, Salerno F, Piantoni L, Cazzaniga M, Angeli P, Bissoli F, et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001;33:41–8. [9] Runyon BA. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology 1986;91:1343–6. [10] Buonomo AR, Zappulo E, Scotto R, Pinchera B, Perruolo G, Formisano P, et al. Vitamin D deficiency is a risk factor for infections in patients affected by HCV-related liver cirrhosis. Int J Infect Dis 2017;63:23–9. [11] Dever JB, Sheikh MY. Review article: spontaneous bacterial peritonitis—bacteriology, diagnosis, treatment, risk factors and prevention. Aliment Pharmacol Ther 2015;41: 1116–31. [12] Fagiuoli S, Colli A, Bruno R, Burra P, Craxi A, Gaeta GB, et al. Management of infections in cirrhotic patients: report of a consensus conference. Dig Liver Dis 2014;46: 204–12. [13] Di Martino V, Weil D, Cervoni JP, Thevenot T. New prognostic markers in liver cirrhosis. World J Hepatol 2015;7:1244–50. [14] Garcia-Tsao G, Wiest R. Gut microflora in the pathogenesis of the complications of cirrhosis. Best Pract Res Clin Gastroenterol 2004;18:353–72.
3
[15] Gentile I, Landolfo D, Buonomo AR, Crispo M, Iula VD, Minei G, et al. A survey on antibiotic therapy knowledge among physicians of a tertiary care and university hospital. Infez Med 2015;23:12–7.
Ivan Gentile1 Antonio Riccardo Buonomo*,1 Riccardo Scotto Emanuela Zappulo Guglielmo Borgia Department of Clinical Medicine and Surgery – Section of Infectious Disease, University "Federico II" of Naples, Italy *Corresponding author at: Via Pansini 5, 80131 Naples, Italy. E-mail address: [email protected] (A.R. Buonomo). 4 September 2017 Available online xxxx
1
Equally contributed to this work.
Please cite this article as: Gentile I, et al, , Eur J Intern Med (2017), http://dx.doi.org/10.1016/j.ejim.2017.09.014